Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

Cochrane Airways Group reviews were prioritized for updating using a pragmatic approach.

OBJECTIVES: Cochrane Reviews should address the most important questions for guideline writers, clinicians, and the public. It is not possible to keep all reviews up-to-date, so the Cochrane Airways Group (CAG) decided to prioritize updates and new reviews without requesting additional resources. The aim of the objective was to develop pragmatic and transparent prioritization techniques to identify 25 to 35 high-priority updates from a total of 270 CAG Reviews and become more selective over which new reviews we publish. STUDY DESIGN AND SETTING: We used elements from existing prioritization processes, including existing health care uncertainties, expert opinion, and a decision tool. We did not conduct a full face-to-face workshop or an iterative group decision-making process. RESULTS: We prioritized 30 reviews in need of updating and aimed to update these within 2 years. Within the first 18 months, nine of these have been published. CONCLUSION: A pragmatic approach to prioritization can indicate priority reviews without an excessive drain on time and resources. The steps provide us with better control over the reviews in our scope and can be built on in the future.

Expression of integrin alpha 10 is transcriptionally activated by pRb in mouse osteoblasts and is downregulated in multiple solid tumors.

pRb is known as a classic cell cycle regulator whose inactivation is an important initiator of tumorigenesis. However, more recently, it has also been linked to tumor progression. This study defines a role for pRb as a suppressor of the progression to metastasis by upregulating integrin α10. Transcription of this integrin subunit is herein found to be pRb dependent in mouse osteoblasts. Classic pRb partners in cell cycle control, E2F1 and E2F3, do not repress transcription of integrin α10 and phosphorylation of pRb is not necessary for activation of the integrin α10 promoter. Promoter deletion revealed a pRb-responsive region between -108 bp to -55 bp upstream of the start of the site of transcription. pRb activation of transcription also leads to increased levels of integrin α10 protein and a greater concentration of the integrin α10 protein at the cell membrane of mouse osteoblasts. These higher levels of integrin α10 correspond to increased binding to collagen substrate. Consistent with our findings in mouse osteoblasts, we found that integrin α10 is significantly underexpressed in multiple solid tumors that have frequent inactivation of the pRb pathway. Bioinformatically, we identified data consistent with an 'integrin switch' that occurs in multiple solid tumors consisting of underexpression of integrins α7, α8, and α10 with concurrent overexpression of integrin ß4. pRb promotes cell adhesion by inducing expression of integrins necessary for cell adhesion to a substrate. We propose that pRb loss in solid tumors exacerbates aggressiveness by debilitating cellular adhesion, which in turn facilitates tumor cell detachment and metastasis.

Differences in binding affinities of MDA, MDMA, MDEA, Amphetamine, Methamphetamine, and their deuterated analogues to solid-phase extraction cartridges.

This study evaluated the potential for partial separation of drugs from their deuterated internal standards using Cerex(®) Polycrom™ CLIN II solid-phase extraction (SPE) cartridges. After elution from the column and derivatization, gas chromatography-mass spectrometry results showed that the target compound eluted from the SPE cartridge prior to its deuterated form. This elution separation effect was greater for 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (MAMP) than for the other drugs studied. When the drugs were eluted in 0.5 mL increments from a 50 mg sorbent bed, no drug appeared in the first fraction. The drug to internal standard ratios (expected value 1.00) for subsequent fractions collected were 1.30, 1.07, and 0.83 for MDA/MDA-d(5); 1.65, 1.18, 0.67, and 0.56 for MDMA/MDMAd(5); and 1.37, 1.18, and 0.95 for MDEA/MDEA-d(6). For d-AMP and d-MAMP, the expected ratio was 0.40. The subsequent ratios were 0.63, 0.46, 0.35, and 0.34 for d-AMP/d-AMP-d(11); and 1.00, 0.59, 0.25, and 0.18 for d-MAMP/d-MAMP-d(14). The affinity of d-MAMPd(14) was shown to be greater than that of d-MAMP-d(5), and deuteration at the propyl end of the molecule was shown to increase binding more than deuteration on the phenyl group.

Changes in C-reactive protein during weight loss and the association with changes in anthropometric variables in men and women: LIFE Study.

OBJECTIVE: To investigate whether sex differences exist in the pattern of change in C-reactive protein (CRP) levels during weight loss, and whether the associations between weight change and CRP change differ by the types of anthropometric variables. DESIGN: Longitudinal, prospective analysis of subjects participating in an intentional weight loss trial (the Lose It For Ever: LIFE Study) followed-up for 30 months. SUBJECTS: A total of 212 healthy, obese men and women (age: 23-77 years, body mass index (BMI): 30-39 kg m(-2)) took part in this study. MEASUREMENTS: BMI, waist and hip circumferences, and waist-to-hip ratio, CRP and lifestyle variables repeatedly measured at baseline, 6, 12, 18 and 30-month follow-up. RESULTS: Weight change was J shaped with a nadir at 12 months in both men and women (P for month(2) <0.0001). CRP level was consistently higher in women than in men, but the differences were less prominent and were not statistically significant at 12- and 18-month follow-up. CRP changes between any two consecutive visits were significantly associated with changes in BMI during the same period in women. However, the associations between CRP changes and changes in waist or hip circumference were not as consistent, especially between 18- and 30-month follow-up when CRP significantly increased. The associations in men were generally similar among the different anthropometric measures. The association between changes in BMI and CRP was stronger in men than in women. CONCLUSION: BMI change generally correlated well with CRP changes in both men and women in the course of follow-up. Significant sex difference in CRP level at baseline diminished at 12- and 18-month follow-up, when both sexes had maintained the lost weight.

Retrospective analysis of the relationship between time of thoracostomy drain removal and discharge time.

OBJECTIVES: The objective of this study was to evaluate the relationship between the volume of fluid being produced at the time of thoracostomy drain removal and the time to hospital discharge in dogs and cats. METHODS: Records of 101 dogs and 26 cats with thoracostomy drains were reviewed. Three subgroups were created according to the reason for thoracostomy drain placement: P (postsurgical), A (air) and F (fluid). A generalised linear model with Poisson Errors was performed to test the relationship between the volume of fluid produced at the time of thoracostomy drain removal and the time to discharge. The volume of fluid produced and the time to discharge were compared between species and subgroups. RESULTS: No significant relationship was found between the volume of fluid produced at the time of thoracostomy drain removal and the time to discharge in either species or between the time to discharge and the reason for thoracostomy drain placement. Animals with a volume of fluid higher than 2 ml/kg/day at the time of thoracostomy drain removal did not have increased hospitalisation times. CLINICAL SIGNIFICANCE: Thoracostomy drain can be removed, without clinical compromise, when the volume of fluid produced exceeds 2 ml/kg/day. However, other clinical parameters must be taken into consideration.

Sublingual salivary gland sialolithiasis in a dog.

A case of sialolithiasis of the sublingual/mandibular salivary gland and duct complex in a dog was reported. Sialoadenectomy of the ipsilateral glands successfully treated the associated sialocele.

Emulsification preparation of chitosan-urethane microbeads in the presence of a water-soluble blocked diisocyanate, containing furanone homosyrine lactone bacterial inhibitors.

Chitosan is an abundant naturally occurring biopolymer that is biocompatible, of low toxicity and is well suited as a carrier for a range of active agents. Restrictions imposed by this biopolymers unique solubility requirements make if difficult to process. One approach to an internal setting system is to employ the water-soluble blocked isocyanate hexamethylene-1,6-di(aminocarboxysulphonate) (HDACS) in order to cross-link the chitosan and form microspheres in situ utilizing simple emulsion systems. Chitothane microspheres are capable of delivering active agents at controlled release rates and offers a viable alternative to external set methodologies utilizing aldehydes or similar cross-linking agents.

Allogeneic BMT and patient eligibility based on psychosocial criteria: a survey of BMT professionals.

BMT professionals were compared regarding their willingness to proceed with allogeneic BMT given select psychosocial issues. A questionnaire was sent to 660 physician members of ASBMT, 92 social work members of BMT Special Interest Group, Association of Oncology Social Work, and 626 nurse members of BMT Special Interest Group, Oncology Nursing Society; 597 responded with a response rate of 43.5%. Items included background information, followed by 17 case vignettes; each represented a different psychosocial issue to which respondents indicated whether or not they would recommend proceeding with allogeneic BMT. In every vignette, at least 10% of respondents indicated they would not proceed. In six vignettes, at least 64% indicated do not proceed: suicidal ideation (86.8%), uses addictive illicit drugs (81.7%), history of noncompliance (80.5%), no lay caregiver (69.3%), alcoholic (64.8%), and mild dementia/Alzheimer's (64.4%). In 10 vignettes, at least 73% indicated proceed. On four vignettes, professional subgroups differed in their recommendation on whether or not to proceed with allogeneic BMT. Qualitative data suggest that this decision is contingent on the perceived acuity, severity, and currency of the psychosocial issue, patient ability to comply with treatment given the issue, and its manageability as a risk factor for treatment related vulnerability and outcomes.

Factors influencing the short-term outcome following thoracic surgery in 98 dogs.

OBJECTIVES: To evaluate the factors influencing the short-term (<14 days) outcome of thoracic surgery in dogs. METHODS: A retrospective review of 98 dogs undergoing thoracotomy over a five-year period was undertaken. RESULTS: A pre-operative diagnosis was achieved in 69 per cent of cases. Intrathoraic neoplasia had the lowest pre-operative diagnosis rate (5.5 per cent). Mortality rates of 21 per cent were recorded and were significantly higher for intrathoracic neoplasia (50 per cent) and significantly lower for persistent ductus arteriosus (7.4 per cent) and vascular ring anomaly (0 per cent). Median sternotomy was the preferred approach for pyothorax (85 per cent) and penetrating thoracic injuries (66 per cent). Intercostal thoracotomy was the preferred approach for all other diseases. Postoperative complications occurred in 39 per cent of cases. Wound complications were more common for pyothorax (45 per cent) and following median sternotomy (71 per cent). Thoracic drains were placed in 77 per cent of cases and complications were recorded in 23 per cent. Pyothorax and chylothorax had thoracic drains maintained for significantly longer periods of time. Longer thoracic drain duration was correlated significantly with increased complication rates. CLINICAL SIGNIFICANCE: The short-term outcome following thoracic surgery is influenced by diagnosis. The thoracic approach is determined by intrathoracic disease, but may influence outcome by affecting the incidence of postoperative wound complications. The risk of thoracic drain complications increases with drain duration, which is influenced by the underlying disease. Drains should be maintained for the minimal amount of time possible.

Current practice relating to equine castration in the UK.

This study aimed to characterise current practice relating to equine castration in the UK. A questionnaire was posted to all 655 veterinary practices specified to provide veterinary care for horses, or classified as specialist equine practices. Respondents were asked to cite the number of equine castrations performed annually by the practice, describe techniques used for castration, outline anaesthetic/sedative/analgesic drug protocols used and provide details of post-operative medication. There was a 43% response rate to the questionnaire. Considerable variation in techniques and analgesia provision was identified, with the majority of respondents using a number of sedation/anaesthetic protocols rather than a single technique. This characterisation of current practice provides a useful platform from which subsequent investigations into welfare implications of current equine castration techniques can be directed.

Complications of exploratory coeliotomy in 70 cats.

Records of all cats that had undergone exploratory coeliotomy at the University of Edinburgh during the period November 1995 to July 2002 were reviewed. Seventy records were retrieved. There were 30 cats in which infection or inflammatory disorders predominated, 17 cats with neoplasia, three cats with trauma and 20 cats with other disorders. Exploratory coeliotomy was performed for diagnostic purposes in 28 cats (40 per cent), treatment in 34 cats (49 per cent) and for diagnosis and treatment in eight cats (11 per cent). Methods of intraoperative diagnosis included incisional biopsy of abdominal organs (52 cats), cytology (two cats), microbiology (17 cats) and gross appearance (17 cats). Fifty-eight cats (83 per cent) survived the hospitalisation period. Complications occurred in 18 cats (26 per cent) and were related to anaesthesia (four cats), the underlying disease process (15 cats), surgery (five cats) and were undetermined in one cat.

Infliximab for hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic disease characterized by significant morbidity. Current medical therapies are only minimally effective at treating the disease. Infliximab is a chimeric monoclonal antibody with high affinity for tumour necrosis factor (TNF)-alpha. TNF-alpha is known to induce proinflammatory cytokines and may play an important role in the therapy of a number of disparate inflammatory disorders. Infliximab has shown promise for the therapy of rheumatoid arthritis and psoriasis. OBJECTIVES: Retrospectively to evaluate the effectiveness of infliximab for the treatment of HS. METHODS: A retrospective chart review was performed for patients who received infliximab at the University of Miami Department of Dermatology. Patients were contacted and asked retrospectively to rate their disease activity immediately prior to and after therapy. RESULTS: Patients' self-reported disease activity scores were significantly decreased (P = 0.0001, paired t-test) following infliximab infusion. This correlated with physician-observed clinical improvement. CONCLUSIONS: Infliximab is a promising agent for the treatment of HS. These initial results suggest that infliximab is associated with objective and subjective improvement in HS. Further controlled studies of the efficacy of infliximab and its effect on the course of the disease are warranted.

Pilot epidemiological study of attitudes towards pain in horses.

This preliminary study investigated the attitudes, and evaluated the current practice of a sample of the veterinary profession in the UK in relation to the management of pain in horses. In June 2001, a questionnaire was posted to 260 veterinarians in specialised equine practice, and 140 veterinarians in general practice with a significant equine caseload. There was a 25 per cent response rate to the questionnaire, which recorded information about the availability and prescription of analgesic drugs, the factors influencing the selection of analgesics and their administration, and estimates of the severity of pain associated with selected clinical conditions. There were considerable variations in the practices applied to manage pain in horses, implying that there are similar attitudinal barriers to the optimal management of pain in horses as have been identified in other domestic spedes.

Decrease in beta-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig.

Most insulin is secreted in discrete pulses at an interval of approximately 6 min. Increased insulin secretion after meal ingestion is achieved through the mechanism of amplification of the burst mass. Conversely, in type 2 diabetes, insulin secretion is impaired as a consequence of decreased insulin pulse mass. beta-cell mass is reported to be deficient in type 2 diabetes. We tested the hypothesis that decreased beta-cell mass leads to decreased insulin pulse mass. Insulin secretion was examined before and after an approximately 60% decrease in beta-cell mass achieved by a single injection of alloxan in a porcine model. Alloxan injection resulted in stable diabetes (fasting plasma glucose 7.4 +/- 1.1 vs. 4.4 +/- 0.1 mmol/l; P < 0.01) with impaired insulin secretion in the fasting and fed states and during a hyperglycemic clamp (decreased by 54, 80, and 90%, respectively). Deconvolution analysis revealed a selective decrease in insulin pulse mass (by 54, 60, and 90%) with no change in pulse frequency. Rhythm analysis revealed no change in the periodicity of regular oscillations after alloxan administration in the fasting state but was unable to detect stable rhythms reliably after enteric or intravenous glucose stimulation. After alloxan administration, insulin secretion and insulin pulse mass (but not insulin pulse interval) decreased in relation to beta-cell mass. However, the decreased pulse mass (and pulse amplitude delivered to the liver) was associated with a decrease in hepatic insulin clearance, which partially offset the decreased insulin secretion. Despite hyperglycemia, postprandial glucagon concentrations were increased after alloxan administration (103.4 +/- 6.3 vs. 92.2 +/- 2.5 pg/ml; P < 0.01). We conclude that an alloxan-induced selective decrease in beta-cell mass leads to deficient insulin secretion by attenuating insulin pulse mass, and that the latter is associated with decreased hepatic insulin clearance and relative hyperglucagonemia, thereby emulating the pattern of islet dysfunction observed in type 2 diabetes.

Preliminary clinical observations on the use of piroxicam in the management of rectal tubulopapillary polyps.

Rectal tubulopapillary polyps were diagnosed in eight dogs following proctoscopy and mucosal pinch biopsy. Histological examination of the pinch biopsies revealed evidence of malignant transformation in three of the cases. The remaining cases were diagnosed as benign polyps. Inflammatory changes were observed in four cases. Seven dogs were treated with piroxicam suppositories and one with oral piroxicam. All dogs were re-examined after four to six weeks of piroxicam therapy and the extent of haematochezia, tenesmus and faecal mucus production was reduced in all cases. The owners of seven of the dogs considered the improvement in clinical signs to be good or excellent. Cases with and without evidence of inflammation responded equally well. This finding supports the hypothesis that piroxicam has an antineoplastic effect due to apoptosis and alteration in the cell cycle. Medical management with piroxicam may provide a non-invasive treatment option for dogs with rectal polyp formation in which surgical treatment is likely to be associated with complications such as incontinence, infection and wound breakdown, or where the owner declines such treatment.