Angiosarcoma in the breast: a population-based cohort from Sweden.

BACKGROUND: Breast angiosarcoma is a rare disease mostly observed in breast cancer (BC) patients who have previously received radiotherapy (RT). Little is known about angiosarcoma aetiology, management, and outcome. The study aim was to estimate risk and to characterize breast angiosarcoma in a Swedish population-based cohort. METHODS: The Swedish Cancer Registry was searched for breast angiosarcoma between 1992 and 2018 in three Swedish healthcare regions (population 5.5 million). Information on previous BC, RT, management, and outcome were retrieved from medical records. RESULTS: Overall, 49 angiosarcomas located in the breast, chest wall, or axilla were identified, 8 primary and 41 secondary to BC treatment. Median age was 51 and 73 years, respectively. The minimum latency period of secondary angiosarcoma after a BC diagnosis was 4 years (range 4-21 years). The cumulative incidence of angiosarcoma after breast RT increased continuously, reaching 1.4‰ after 20 years. Among 44 women with angiosarcoma treated by surgery, 29 developed subsequent local recurrence. Median recurrence-free survival was 3.4 and 1.8 years for primary and secondary angiosarcoma, respectively. The 5-year overall survival probability for the whole cohort was 50 per cent (95 per cent c.i., 21 per cent-100 per cent) for primary breast angiosarcoma and 35 per cent (95 per cent c.i., 23 per cent-54 per cent) for secondary angiosarcoma. CONCLUSION: Breast angiosarcoma is a rare disease strongly associated with a history of previous BC RT. Overall survival is poor with high rates of local recurrences and distant metastasis.

Long-term outcome after surgical resection of non-high-risk gastrointestinal stromal tumours without adjuvant therapy.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common intra-abdominal sarcoma. Risk classification systems, commonly the modified National Institutes of Health consensus criteria, identify tumour properties relating to patient outcomes. However, owing to limited long-term evidence, most guidelines recommend up to 10-year follow-up for all risk groups except very low-risk GIST. METHODS: This retrospective multicentre study included patients who had complete resection of primary, non-metastatic GIST from three Scandinavian sarcoma centres: Gothenburg (2004-2020), Stockholm (2000-2019), and Oslo (2000-2017). Medical records were reviewed for clinical details regarding diagnosis, treatment, and follow-up, and recurrence-free and disease-specific survival evaluated. RESULTS: The total cohort consisted of 1213 patients with GIST. High-risk patients and those treated with tyrosine kinase inhibitors were excluded. The remaining 649 patients were included in the present analysis: 118 with very low-, 381 with low-, and 150 with intermediate-risk GISTs. Five-year recurrence-free survival rates were 100, 98.5, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.246). Disease-specific survival rates 10 years after surgery were 100, 98.4, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.262). CONCLUSION: Patients with completely resected non-high-risk GISTs have an excellent long-term outcome, irrespective of risk group. Follow-up programmes to detect disease recurrences in these patients are probably not indicated.

Gastrointestinal stromal tumours (GISTs) originate from the muscle layer of the gastrointestinal tract. They are divided into risk groups according to size, location, and how quickly they grow. Patients with GIST, regardless of risk group, have been followed with imaging for several years after their tumour has been successfully removed with an operation. The aim of this study was to evaluate whether follow-up is necessary for patients in the lower-risk groups. Six hundred and forty-nine patients with GISTs from the lower-risk groups were followed for 5 years (median). Only 1.2 per cent of the patients experienced a recurrence of their cancer. It was concluded that patients with GIST in the lower-risk groups do not need follow-up with imaging after a successful operation.

Testicular teratoma with nephroblastoma in an adult - case report and literature review.

Testicular germ cell tumours are the most common malignancies in young men. Germ cell tumours can be classified as seminomas or non-seminomas, each with different clinical features and treatment approaches. Germ cell tumours are occasionally associated with somatic-type malignancy, particularly in metastatic lymph nodes after adjuvant chemotherapy. Adenocarcinomas and rhabdomyosarcoma are the most common malignancies in this setting. In this report, we present a unique case of a 37-year-old patient who presented with a testicular teratoma containing a nephroblastoma component. The tumour exhibited characteristic morphology that resembled foetal kidney and expressed nuclear WT-1 and PAX-8 on immunohistochemistry. Following surgery, the patient opted for active surveillance and remains disease-free. To date, only 7 cases of nephroblastoma in primary testicular teratoma have been reported. This case highlights the importance of considering this rare entity in the differential diagnosis of testicular teratomas and the need for careful pathological examination.

Current clinical practice in the management of phyllodes tumors of the breast: an international cross-sectional study among surgeons and oncologists.

PURPOSE: Phyllodes tumors of the breast are rare fibroepithelial lesions that are classified as benign, borderline or malignant. There is little consensus on best practice for the work-up, management, and follow-up of patients with phyllodes tumors of the breast, and evidence-based guidelines are lacking. METHODS: We conducted a cross-sectional survey of surgeons and oncologists with the aim to describe current clinical practice in the management of phyllodes tumors. The survey was constructed in REDCap and distributed between July 2021 and February 2022 through international collaborators in sixteen countries across four continents. RESULTS: A total of 419 responses were collected and analyzed. The majority of respondents were experienced and worked in a university hospital. Most agreed to recommend a tumor-free excision margin for benign tumors, increasing margins for borderline and malignant tumors. The multidisciplinary team meeting plays a major role in the treatment plan and follow-up. The vast majority did not consider axillary surgery. There were mixed opinions on adjuvant treatment, with a trend towards more liberal regiments in patients with locally advanced tumors. Most respondents preferred a five-year follow-up period for all phyllodes tumor types. CONCLUSIONS: This study shows considerable variation in clinical practice managing phyllodes tumors. This suggests the potential for overtreatment of many patients and the need for education and further research targeting appropriate surgical margins, follow-up time and a multidisciplinary approach. There is a need to develop guidelines that recognize the heterogeneity of phyllodes tumors.

The role of neoadjuvant imatinib in gastrointestinal stromal tumor patients: 20 years of experience from a tertial referral center.

Surgery is the cornerstone of gastrointestinal stromal tumor (GIST) treatment, and adjuvant therapy with imatinib has improved survival for high-risk tumors. The use of imatinib preoperatively has been increasing, but efficacy and impact on patient outcomes have not been formally investigated. This is a retrospective study from a single-center cohort of patients diagnosed with GIST and treated with neoadjuvant imatinib at Karolinska University Hospital in Stockholm, Sweden over a 20-year period. Eighty-four patients diagnosed with GIST and treated with neoadjuvant imatinib were identified and included. Tumors were located throughout the whole gastrointestinal tract but most frequently in the stomach (n = 29; 35%) and the small intestine (n = 30; 36%), followed by the rectum (n = 12; 14%) and the gastroesophageal junction (n = 10; 12%). The tumors were large (mean 10.5 cm) and decreased after treatment (mean 7.6 cm). Main indications for neoadjuvant imatinib were tumor size or anatomical location. None of the patients with stomach tumors and four patients with tumors near the gastroesophageal junction underwent gastrectomy. Three patients with tumors in the small intestine underwent pancreaticoduodenectomy, whereas seven patients with rectal tumors underwent rectal amputation. After surgery, 94% (n = 79) of the tumors had R0-resection. About one-fourth experienced local relapse or distant metastasis. In conclusion, neoadjuvant imatinib can reduce tumor size and prevent high morbidity due to more extensive surgery, or at least reduce the extent of the surgery, especially for tumors in the stomach or small intestine.

Dysregulation of COVID-19 related gene expression in the COPD lung.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection. METHODS: We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects. RESULTS: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of -0.26 (p = 0.033) and - 0.40, (p = 0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E-06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively). CONCLUSION: This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required.

Sarcoma of the breast: breast cancer history as etiologic and prognostic factor-A population-based case-control study.

PURPOSE: Sarcomas of the breast account for about 1% of all breast malignancies. The aim of this national survey was to explore etiologic and prognostic factors. METHODS: Utilizing national Swedish registers, all patients registered with mesenchymal tumors in the breast during the period 1993-2013 (n = 344) were identified and compared to up to ten age and gender matched controls. Cancer history was retrieved for cases and controls. Conditional Poisson regression models were used for calculation of odds ratios. RESULTS: Previous breast cancer was overrepresented among patients with angiosarcoma. The highest risk occurred ≥ 5 years after treatment for breast cancer (OR 73.9, 95% confidence interval, CI, 25.4-215; P < 0.001). An increase in incidence of angiosarcoma was observed during the study period (1.10, 95% CI 1.05-1.16; P < 0.001). The overall incidence of breast sarcoma increased from 1.52 to 2.04 cases per million per year. Angiosarcoma of the breast was associated with a significant excess mortality compared to age-matched controls (HR 4.65, 95% CI 3.01-7.19; P < 0.001). CONCLUSIONS: Angiosarcoma increased in incidence and displayed a more severe clinical course, with significantly shorter survival. The strong association between a history of breast cancer 5 years or more prior to the diagnosis of angiosarcoma points to radiotherapy as a contributing factor.

Voice Tremor Response to Deep Brain Stimulation in Relation to Electrode Location in the Posterior Subthalamic Area.

BACKGROUND: Deep brain stimulation of the motor thalamus or the posterior subthalamic area (PSA) shows promising results for patients with voice tremor, although only for about 50% of patients. There are indications that voice tremor requires more focused stimulation within the target area compared with hand tremor. The objective of the present study was to determine the most efficient location for reducing voice tremor within the PSA. METHODS: Thirty-seven patients with essential tremor were evaluated off stimulation and in a set of experimental conditions with unilateral stimulation at increasing amplitude levels. Two listeners performed blinded assessments of voice tremor from recordings of sustained vowel productions. RESULTS: Twenty-five patients (68%) had voice tremor. Unilateral stimulation reduced voice tremor for the majority of patients, and only 6 patients had poor outcomes. Contacts yielding efficient voice tremor reduction were deeper relative to the midcommissural point (MCP) and more posterior relative to the posterior tip of the subthalamic nucleus (pSTN) (zMCP = -3.1, ypSTN = -0.2) compared with poor contacts (zMCP = -0.7, ypSTN = 1.0). High-amplitude stimulation worsened voice tremor for 7 patients and induced voice tremor in 2 patients. Hand tremor improved to a greater extent than voice tremor, and improvements could be seen throughout the target area. CONCLUSIONS: Our results indicate that efficient voice tremor reduction can be achieved by stimulating contacts located in the inferior part of the PSA, close or slightly posterior to the pSTN. We observed cases in which voice tremor was induced by high-amplitude stimulation.

Extracellular vesicles induce minimal hepatotoxicity and immunogenicity.

Extracellular vesicles (EVs) mediate cellular communication through the transfer of active biomolecules, raising interest in using them as biological delivery vehicles for therapeutic drugs. For drug delivery applications, it is important to understand the intrinsic safety and toxicity liabilities of EVs. Nanoparticles, including EVs, typically demonstrate significant accumulation in the liver after systemic administration in vivo. We confirmed uptake of EVs derived from Expi293F cells into HepG2 cells and did not detect any signs of hepatotoxicity measured by cell viability, functional secretion of albumin, plasma membrane integrity, and mitochondrial and lysosomal activity even at high exposures of up to 5 × 1010 EVs per mL. Whole genome transcriptome analysis was used to measure potential effects on the gene expression in the recipient HepG2 cells at 24 h following exposure to EVs. Only 0.6% of all genes were found to be differentially expressed displaying less than 2-fold expression change, with genes related to inflammation or toxicity being unaffected. EVs did not trigger any proinflammatory cytokine response in HepG2 cells. However, minor changes were noted in human blood for interleukin (IL)-8, IL-6, and monocyte chemotactic protein 1 (MCP-1). Administration of 5 × 1010 Expi293F-derived EVs to BALB/c mice did not result in any histopathological changes or increases of liver transaminases or cytokine levels, apart from a modest increase in keratinocyte chemoattractant (KC). The absence of any significant toxicity associated with EVs in vitro and in vivo supports the prospective use of EVs for therapeutic applications and for drug delivery.

Long-term effects of unilateral deep brain stimulation on voice tremor in patients with essential tremor.

INTRODUCTION: Voice tremor (VT) is a common symptom of Essential tremor (ET). Deep brain stimulation (DBS) is an established treatment for ET overall, however, its effect on VT is less clear. The aim of this study was to evaluate long-term effects of DBS on VT and to investigate how VT symptoms develop over time in patients with ET. METHODS: VT scores for the cohort of 81 ET patients that had undergone DBS surgery in the caudal zona incerta (cZi) were analyzed retrospectively. Thirty-four patients had preoperative VT and long-term evaluations were available for 19 patients. Longitudinal effects of cZi-DBS were investigated 1, 3 and 5 years postoperatively. VT progression was evaluated based on preoperative-, and off stimulation postoperative assessments. RESULTS: Unilateral cZi-DBS reduced average voice tremor by 58% at the 3-year follow-up and by 67% 5 years after surgery. Four patterns of VT development were identified among patients, and the effectiveness of cZi-DBS in alleviating voice tremor symptoms showed differing patterns for these subgroups. CONCLUSIONS: This retrospective analysis of a small cohort of patients suggests that cZi-DBS may reduce VT in the long-term for patients with ET overall, but the pattern of VT progression likely influences the effectiveness of the treatment. These results also suggest that unilateral cZi-DBS may be more efficacious when treating patients with mild to moderate VT. A prospective, blinded, controlled clinical trial in patients with ET is needed to determine developmental patterns of VT, and the safety and efficacy of cZi-DBS for the treatment of VT.

Wide Surgical Margin Improves the Outcome for Patients with Gastrointestinal Stromal Tumors (GISTs).

BACKGROUND: Surgical resection is still the main treatment for gastrointestinal stromal tumor (GIST), and R0 excision, regardless of surgical margins, is considered sufficient. METHODS: A cohort of 79 consecutive GIST cases treated at the Karolinska University Hospital, who were without metastasis at diagnosis and who had not received any pre-or postoperative treatment with tyrosine kinase inhibitors, was included. Surgical margins were evaluated at the time of surgery and classified as wide, marginal or intralesional. Time to local/peritoneal recurrence, distant metastasis, and survival were recorded. Cox regression analysis was used to investigate the association between surgical margin, and recurrence and survival. RESULTS: Local/peritoneal recurrence was diagnosed in 2/39 cases with wide margins, in 7/22 cases with marginal margins, and in 13/18 cases with intralesional surgery. Compared to wide margins this gives a hazard ratio of 6.8 (confidence interval 1.4-32.7) for marginal margins and 13.5 (3-61) for intralesional margins. In multivariate analysis, adjusting for size, site, and mitotic index, surgical margin remained an independent significant predictor of risk for recurrence. When classifying patients according to R0/R1 surgery, patients with R0 surgery showed longer time to peritoneal recurrence and better recurrence-free and disease-specific survival as compared to those with R1 resection. However, when excluding patients operated with wide surgical margin, no significant difference was observed. CONCLUSION: Wide surgical margins are of significant prognostic importance, supporting the strategy of en bloc resection with good margin and careful handling of the tumor to avoid damaging the peritoneal surface in surgical resection of GIST.

Strategies to improve usability and preserve accuracy in biological sequence databases.

Biology is increasingly dependent on large-scale analysis, such as proteomics, creating a requirement for efficient bioinformatics. Bioinformatic predictions of biological functions rely upon correctly annotated database sequences, and the presence of inaccurately annotated or otherwise poorly described sequences introduces noise and bias to biological analyses. Accurate annotations are, for example, pivotal for correct identification of polypeptide fragments. However, standards for how sequence databases are organized and presented are currently insufficient. Here, we propose five strategies to address fundamental issues in the annotation of sequence databases: (i) to clearly separate experimentally verified and unverified sequence entries; (ii) to enable a system for tracing the origins of annotations; (iii) to separate entries with high-quality, informative annotation from less useful ones; (iv) to integrate automated quality-control software whenever such tools exist; and (v) to facilitate postsubmission editing of annotations and metadata associated with sequences. We believe that implementation of these strategies, for example as requirements for publication of database papers, would enable biology to better take advantage of large-scale data.

Voice Tremor in Patients with Essential Tremor: Effects of Deep Brain Stimulation of Caudal Zona Incerta.

OBJECTIVES: The present study aimed at evaluating the effect of deep brain stimulation (DBS) of the caudal zona incerta (cZi) on voice tremor in patients with essential tremor (ET). STUDY DESIGN: This is a prospective nonrandomized design with consecutive patients. METHODS: Twenty-six patients operated with cZi DBS were evaluated under two conditions: without stimulation (Stim OFF) and with stimulation (Stim ON). Voice tremor was assessed on the basis of recordings of sustained vowel productions using a four-point rating scale in a blinded and randomized procedure. Averaged values of multiple assessments for each stimulus were used in statistical testing. The group of patients with voice tremor in Stim OFF was analyzed separately from the group of patients without voice tremor. RESULTS: Voice tremor was significantly reduced on stimulation compared with off for the subgroup with initial voice tremor. Voice tremor prevalence was found to be 50% (13 patients). Individual differences in voice tremor outcome were noticeable. Six of the patients with voice tremor at baseline improved substantially by cZi DBS treatment. CONCLUSIONS: On the group level, voice tremor in patients with ET was found to reduce when stimulating the cZi. Bilateral stimulation was indicated to be more effective in reducing voice tremor than unilateral stimulation. However, individual voice tremor outcomes suggest that not all patients benefit from cZi DBS. Severity of voice tremor at baseline may not be a good predictor of voice tremor outcome after cZi DBS. Patients should be informed before surgery regarding individual differences in response to DBS treatment.

Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation.

Bariatric surgery is currently the most effective procedure for the treatment of obesity. Given the role of the gut microbiota in regulating host metabolism and adiposity, we investigated the long-term effects of bariatric surgery on the microbiome of patients randomized to Roux-en-Y gastric bypass or vertical banded gastroplasty and matched for weight and fat mass loss. The two surgical procedures induced similar and durable changes on the gut microbiome that were not dependent on body mass index and resulted in altered levels of fecal and circulating metabolites compared with obese controls. By colonizing germ-free mice with stools from the patients, we demonstrated that the surgically altered microbiota promoted reduced fat deposition in recipient mice. These mice also had a lower respiratory quotient, indicating decreased utilization of carbohydrates as fuel. Our results suggest that the gut microbiota may play a direct role in the reduction of adiposity observed after bariatric surgery.

Functional role of the Ca²âº-activated Cl⁻ channel DOG1/TMEM16A in gastrointestinal stromal tumor cells.

DOG1, a Ca(2+)-activated Cl(-) channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl(-) currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target.

Articulatory closure proficiency in patients with Parkinson's disease following deep brain stimulation of the subthalamic nucleus and caudal zona incerta.

PURPOSE: The present study aimed at comparing the effects of deep brain stimulation (DBS) treatment of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) on the proficiency in achieving oral closure and release during plosive production of people with Parkinson's disease. METHOD: Nineteen patients participated preoperatively and 12 months after DBS surgery. Nine patients had implantations in the STN, 7 bilaterally and 2 unilaterally (left). Ten had bilateral implantations in the cZi. Postoperative examinations were made off and on stimulation. All patients received simultaneous L-dopa treatment in all conditions. For a series of plosives extracted from a reading passage, absolute and relative measures of duration of frication and amplitude of plosive release were compared between conditions within each treatment group. RESULTS: Relative duration of frication increased in voiceless plosives in the on-stimulation condition in cZi patients. Similar trends were observed across the data set. Duration of prerelease frication and the release peak prominence increased in voiceless plosives on stimulation for both groups. CONCLUSION: The increased release prominence suggests that patients achieved a stronger closure gesture because of DBS but that the increased energy available resulted in increased frication.

Genome-scale metabolic reconstructions of Bifidobacterium adolescentis L2-32 and Faecalibacterium prausnitzii A2-165 and their interaction.

BACKGROUND: The gut microbiota plays an important role in human health and disease by acting as a metabolic organ. Metagenomic sequencing has shown how dysbiosis in the gut microbiota is associated with human metabolic diseases such as obesity and diabetes. Modeling may assist to gain insight into the metabolic implication of an altered microbiota. Fast and accurate reconstruction of metabolic models for members of the gut microbiota, as well as methods to simulate a community of microorganisms, are therefore needed. The Integrated Microbial Genomes (IMG) database contains functional annotation for nearly 4,650 bacterial genomes. This tremendous new genomic information adds new opportunities for systems biology to reconstruct accurate genome scale metabolic models (GEMs). RESULTS: Here we assembled a reaction data set containing 2,340 reactions obtained from existing genome-scale metabolic models, where each reaction is assigned with KEGG Orthology. The reaction data set was then used to reconstruct two genome scale metabolic models for gut microorganisms available in the IMG database Bifidobacterium adolescentis L2-32, which produces acetate during fermentation, and Faecalibacterium prausnitzii A2-165, which consumes acetate and produces butyrate. F. prausnitzii is less abundant in patients with Crohn's disease and has been suggested to play an anti-inflammatory role in the gut ecosystem. The B. adolescentis model, iBif452, comprises 699 reactions and 611 unique metabolites. The F. prausnitzii model, iFap484, comprises 713 reactions and 621 unique metabolites. Each model was validated with in vivo data. We used OptCom and Flux Balance Analysis to simulate how both organisms interact. CONCLUSIONS: The consortium of iBif452 and iFap484 was applied to predict F. prausnitzii's demand for acetate and production of butyrate which plays an essential role in colonic homeostasis and cancer prevention. The assembled reaction set is a useful tool to generate bacterial draft models from KEGG Orthology.

Intracellular concentration of the tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumor cells.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract. In most GISTs, the underlying mechanism is a gain-of-function mutation in the KIT or the PDGFRA gene. Imatinib is a tyrosine kinase inhibitor that specifically blocks the intracellular ATP-binding sites of these receptors. A correlation exists between plasma levels of imatinib and progression-free survival, but it is not known whether the plasma concentration correlates with the intracellular drug concentration. We determined intracellular imatinib levels in two GIST cell lines: the imatinib-sensitive GIST882 and the imatinib-resistant GIST48. After exposing the GIST cells to imatinib, the intracellular concentrations were evaluated using LC-MS (TOF). The concentration of imatinib in clinical samples from three patients was also determined to assess the validity and reliability of the method in the clinical setting. Determination of imatinib uptake fits within detection levels and values are highly reproducible. The GIST48 cells showed significantly lower imatinib uptake compared with GIST882 in therapeutic doses, indicating a possible difference in uptake mechanisms. Furthermore, imatinib accumulated in the tumor tissues and showed intratumoral regional differences. These data show, for the first time, a feasible and reproducible technique to measure intracellular imatinib levels in experimental and clinical settings. The difference in the intracellular imatinib concentration between the cell lines and clinical samples indicates that drug transporters may contribute toward resistance mechanisms in GIST cells. This highlights the importance of further clinical studies to quantify drug transporter expression and measure intracellular imatinib levels in GIST patients.

Pitch variability in patients with Parkinson's disease: effects of deep brain stimulation of caudal zona incerta and subthalamic nucleus.

PURPOSE: The purpose of the present study was to examine the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) pitch characteristics of connected speech in patients with Parkinson's disease (PD). METHOD: The authors evaluated 16 patients preoperatively and 12 months after DBS surgery. Eight patients were implanted in the STN (ages 51-72 years; M = 63 years). Six received bilateral implantation and 2 unilateral (left) implantation. Eight patients were bilaterally implanted in the cZi (ages 49-71 years; M = 60.8 years). Preoperative assessments were made after a levodopa challenge (approximately 1.5 times the ordinary dose). All postoperative examinations were made off and on stimulation with a clinically optimized dose of levodopa. Measurements of pitch range and variability were obtained from each utterance in a recorded read speech passage. RESULTS: Pitch range and coefficient of variation showed an increase in patients under STN-DBS. Patients under cZi-DBS showed no significant effects of treatment on investigated pitch properties. CONCLUSION: STN-DBS was shown to increase pitch variation and range. The results provided no evidence of cZi-DBS having a beneficial effect on PD patients' pitch variability.

Deep brain stimulation of caudal zona incerta and subthalamic nucleus in patients with Parkinson's disease: effects on voice intensity.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson's disease (PD) affects speech inconsistently. Recently, stimulation of the caudal zona incerta (cZi-DBS) has shown superior motor outcomes for PD patients, but effects on speech have not been systematically investigated. The aim of this study was to compare the effects of cZi-DBS and STN-DBS on voice intensity in PD patients. Mean intensity during reading and intensity decay during rapid syllable repetition were measured for STN-DBS and cZi-DBS patients (eight patients per group), before- and 12 months after-surgery on- and off-stimulation. For mean intensity, there were small significant differences on- versus off-stimulation in each group: 74.2 (2.0) dB contra 72.1 (2.2) dB (P = .002) for STN-DBS, and 71.6 (4.1) dB contra 72.8 (3.4) dB (P = .03) for cZi-DBS, with significant interaction (P < .001). Intensity decay showed no significant changes. The subtle differences found for mean intensity suggest that STN-DBS and cZi-DBS may influence voice intensity differently.