Addressing high cervical cancer rates in the Rio Grande Valley along the Texas-Mexico border: a community-based initiative focused on education, patient navigation, and medical provider training/telementoring.

AIMS: Cervical cancer incidence and mortality rates are approximately 55% higher in the Rio Grande Valley (RGV) along the Texas-Mexico border compared with the average rates in the US. Our aim was to improve cervical cancer prevention efforts in the RGV through a comprehensive multilevel intervention initiative focused on community education, patient navigation, and training of local providers. METHODS: We initiated a program in the RGV which consisted of (1) community education, (2) patient navigation, and (3) a training/mentoring program for local medical providers including hands-on training courses coupled with telementoring using Project ECHO® (Extension for Community Health Outcomes). We assessed the number of women undergoing cervical cancer screening, diagnosis, and treatment at three participating clinics caring for underserved women in the region. RESULTS: From November 2014 to October 2018, 14,846 women underwent cervical cancer screening. A total of 2030 (13.7%) women underwent colposcopy for abnormal results (179% increase over baseline) and 453 women underwent loop electrosurgical excision procedures (LEEPs) for treatment of cervical dysplasia. Invasive cancer was diagnosed in 39 women who were navigated to a gynecologic oncologist for treatment. Seven local medical providers were trained to perform colposcopy and/or LEEP. Project ECHO telementoring videoconferences were held every 2 weeks for a total 101 sessions with an average of 22 participants per session and a total of 180 patient cases presented and discussed. CONCLUSIONS: Our program led to a large number of women undergoing diagnosis and treatment of cervical dysplasia in the RGV. If sustained, we anticipate these efforts will decrease cervical cancer rates in the region. The program is currently being expanded to additional underserved areas of Texas and globally to low- and middle-income countries.

The feasibility of home monitoring of young people with cystic fibrosis: Results from CLIMB-CF.

BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.

Robotic multivisceral pelvic resection: experience from an exenteration unit.

BACKGROUND: Pelvic exenteration remains a viable and effective treatment option for the management of locally advanced or recurrent pelvic malignancy. The aim of this study was to present an early experience of robotic multivisceral resection of pelvic malignancy, and to compare this experience with similar series through a systematic review of the literature. METHODS: A retrospective study was performed on patients who had robotic-assisted multi-visceral resection for pelvic malignancy at a single Colorectal Surgical unit based between two tertiary academic hospitals. Primary outcomes observed included operation type, operation time, perioperative complications, and hospital length of stay. Secondary outcomes included R0 resection status, lymph node harvest, and rate of recurrence at clinical follow-up. RESULTS: Eight cases of robotic multivisceral resection were performed for primary locally advanced pelvic malignancy involving a rectal resection as part of their operative management. The median age of patients undergoing resection was 56 years (range 29-83 years). The male:female ratio was 6:2. The mean total operating time was 8.3 h (range 6-10 h). Perioperative blood transfusion requirements were minimal. Mean hospital length of stay was 15 days (range 7-26 days). No patients experienced any serious postoperative morbidity or mortality. All patients had clear margins on histological assessment and no patients have recurrence at 12-month follow-up. CONCLUSIONS: Robotic multivisceral resection for malignant disease of the pelvis is a safe and feasible minimally invasive approach in highly selected cases.

Abdominoperineal excision in Australasia: clinical outcomes, predictive factors and recent trends of nonrestorative rectal cancer surgery.

AIM: The decision to perform an abdominoperineal excision (APR) rather than restorative bowel resection relies on a number of clinical factors. There remains great variability in APR rates internationally. The aim of this study was to demonstrate trends of APR surgery in low rectal cancer (< 6 cm from the anal verge) in Australasia and identify predictors of nonrestoration. METHOD: This study reviewed a prospectively maintained colorectal registry - the Binational Colorectal Cancer Audit (BCCA) - from general/colorectal surgical units across Australia and New Zealand. Data were analysed to determine factors predictive of nonrestorative resection. Patients were analysed based on the presence (control) or absence (comparison) of a primary anastomosis. RESULTS: Of 3628 patients with rectal cancer, 2096 were diagnosed with low rectal cancer between 2007 and 2017. The incidence of APR remained constant over the study period, with 58% of all resections of low rectal cancer being APR. The majority of resections were performed by consultants in urban hospitals (86% vs 14%). Tumours ≤ 3 cm from the anal verge, T4, M1 disease and neoadjuvant therapy were the greatest predictors of APR (P < 0.001). A significantly increased rate of restorative surgery was observed in public hospital settings (59% vs 41%, P < 0.05). The rate of positive circumferential resection margin (CRM) was 7.95%, with significantly increased rates in patients undergoing APR (12.2% vs 6.2%, P < 0.001). CRM positivity was increased in open approaches, T4, N2 and M1 staged disease and in an emergency/urgent setting (P < 0.001 and P < 0.045, respectively). Significantly increased wound and pulmonary complications were observed in the APR cohort (P < 0.01). CONCLUSION: The rates of APR in Australia and New Zealand remain high but are comparable to international figures, with one-third of rectal cancers being treated by APR. The main determinants of APR are tumour height, T stage and neoadjuvant therapy requirement. CRM positivity was higher in APR patients.

Robotic transanal minimally invasive surgery - technical, oncological and patient outcomes from a single institution.

AIM: Robotic transanal minimally invasive surgery (R-TAMIS) is gaining traction around the globe as an alternative to laparoscopic conventional TAMIS for local excision of benign and early malignant rectal lesions. The aim was to analyse patient and oncological outcomes of R-TAMIS for consecutive cases in a single centre. METHODS: A prospective analysis of consecutive R-TAMIS procedures over a 12-month period was performed. Data were collated from hospital databases and theatre registers. RESULTS: Eleven patients (six men, five women), mean age 69.81 years (51-92 years), underwent R-TAMIS over 12 months utilizing a da Vinci Xi platform. The mean lesion size was 36 mm (20-60 mm) with a mean distance from the anal verge of 7.5 cm (3-14 cm). Five lesions were posterior in anatomical location, four anterior, one right lateral and one left lateral. All procedures were performed in the lithotomy position using a GelPOINT Path Platform. Mean operative time was 64 min (40-100 min). Complete resection was achieved in 10/11 patients with two patients being upgraded to a diagnosis of adenocarcinoma. Nine patients were diagnosed with dysplastic lesions. Four patients had a false positive diagnosis of an invasive tumour on MRI. Six patients required suturing for full-thickness resections. One patient had a postoperative bleed requiring repeat endoscopy and clipping. One patient (full-thickness resection of T3 tumour) proceeded to a formal resection without difficulty with no residual disease (T0N0, 0/22). One patient with a fully resected T2 tumour is undergoing a surveillance protocol. The mean length of stay was 1 day with two patients having a length of stay of 2 days and one patient of 4 days. CONCLUSION: R-TAMIS could potentially represent a safe novel approach for local resection of rectal lesions.

Outcomes of extended radical resections for locally advanced and recurrent pelvic malignancy involving the aortoiliac axis.

AIM: Currently, there is no clear consensus on the role of extended pelvic resections for locally advanced or recurrent disease involving major vascular structures. The aims of this study were to report the outcomes of consecutive patients undergoing extended resections for pelvic malignancy involving the aortoiliac axis. METHODS: Prospective data were collected on patients having extended radical resections for locally advanced or recurrent pelvic malignancies, with aortoiliac axis involvement, requiring en bloc vascular resection and reconstruction, at a single institution between 2014 and 2018. RESULTS: Eleven patients were included (median age 60 years; range 31-69 years; seven women). The majority required resection of both arterial and venous systems (n = 8), and the technique for vascular reconstruction was either interposition grafts or femoral-femoral crossover grafts. The median operative time was 510 min (range 330-960 min). Clear resection margins (R0) were achieved in nine patients. The median length of stay was 25 days (range 7-83 days). Seven patients did not suffer an early complication. There was one serious complication (Clavien-Dindo ≥ 3), an arterial graft occlusion secondary to thrombus in the immediate postoperative period, requiring a return to theatre and thrombectomy. The median length of follow-up in this study was 22 months (range 4-58 months). CONCLUSION: This series demonstrates that en bloc major vascular resection and reconstruction can be performed safely and can achieve clear resection margins in selected patients with locally advanced or recurrent pelvic malignancy at specialist surgery centres.

Genomic and metabolomic analysis of step-wise malignant transformation in human skin fibroblasts.

Metabolic changes accompanying a step-wise malignant transformation was investigated using a syngeneic lineage of human fibroblasts. Cell immortalization was associated with minor alterations in metabolism. Consecutive loss of cell cycle inhibition in immortalized cells resulted in increased levels of oxidative phosphorylation (OXPHOS). Overexpression of the H-Ras oncoprotein produced cells forming sarcomas in athymic mice. These transformed cells exhibited increased glucose consumption, glycolysis and a further increase in OXPHOS. Because of the markedly increased OXPHOS in transformed cells, the impact of a transaminase inhibitor, aminooxyacetic acid (AOA), which decreases glutamine influx to the tricarboxylic acid (TCA) cycle, was tested. Indeed, AOA significantly decreased proliferation of malignantly transformed fibroblasts and fibrosarcoma-derived cells in vitro and in vivo. AOA also decreased proliferation of cells susceptible to malignant transformation. Metabolomic studies in normal and transformed cells indicated that, in addition to the anticipated effect on the TCA cycle, AOA decreased production of nucleotides adenosine triphosphate (ATP) and uridine monophosphate. Exogenous nucleotides partially rescued decreased proliferation of the malignant cells treated with AOA. Our data indicate that AOA blocks several metabolic pathways essential for growth of malignant cells. Therefore, OXPHOS may provide important therapeutic targets for treatment of sarcoma.

Alberta CancerBridges development of a care plan evaluation measure.

BACKGROUND: No standardized measures specifically assess cancer survivors' and healthcare providers' experience of Survivor Care Plans (scps). We sought to develop two care plan evaluation (cpe) measures, one for survivors (cpe-s) and one for healthcare providers (cpe-p), examine initial psychometric qualities in Alberta, and assess generalizability in Manitoba, Canada. METHODS: We developed the initial measures using convenience samples of breast (n = 35) and head and neck (n = 18) survivors who received scps at the end of active cancer-centre treatment. After assessing Alberta's scp concordance with Institute of Medicine (iom) recommendations using a published coding scheme, we examined psychometric qualities for the cpe-s and cpe-p. We examined generalizability in Manitoba, Canada, with colorectal survivors discharged to primary care providers for follow-up (n = 75). RESULTS: We demonstrated acceptable internal consistency for the cpe-s and cpe-p subscales and total score after eliminating one item per subscale for cpe-s, two for cpe-p, resulting in revised scales with four 7-item and 6-item subscales, respectively. Subscale scores correlated highly indicating that for each measure the total score may be the most reliable and valid. We provide initial cpe-s discriminant, convergent, and predictive validity using the total score. Using the Manitoba sample, initial psychometrics similarly indicated good generalizability across differences in tumour groups, scp, and location. CONCLUSIONS: We recommend the revised cpe-s and cpe-p for further use and development. Studies documenting the creation and standardization of scp evaluations are few, and we recommend further development of patient experience measures to improve both clinical practice and the specificity of research questions.

Calcineurin inhibitor cyclosporine A activates renal Na-K-Cl cotransporters via local and systemic mechanisms.

Calcineurin dephosphorylates nuclear factor of activated T cells transcription factors, thereby facilitating T cell-mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation but may cause side effects, including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA). An involvement of major hormones like angiotensin II or arginine vasopressin (AVP) has been proposed. To resolve this issue, the effects of CsA treatment in normal Wistar rats, AVP-deficient Brattleboro rats, and cultured renal epithelial cells endogenously expressing either NKCC2 or NCC were studied. Acute administration of CsA to Wistar rats rapidly augmented phosphorylation levels of NKCC2, NCC, and their activating kinases suggesting intraepithelial activating effects. Chronic CsA administration caused salt retention and hypertension, along with stimulation of renin and suppression of renal cyclooxygenase 2, pointing to a contribution of endocrine and paracrine mechanisms at long term. In Brattleboro rats, CsA induced activation of NCC, but not NKCC2, and parallel effects were obtained in cultured cells in the absence of AVP. Stimulation of cultured thick ascending limb cells with AVP agonist restored their responsiveness to CsA. Our results suggest that the direct epithelial action of calcineurin inhibition is sufficient for the activation of NCC, whereas its effect on NKCC2 is more complex and requires concomitant stimulation by AVP.

Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus.

INTRODUCTION: Anal squamous cell cancers are uncommon, and primary treatment is radical chemoradiotherapy. The role of radical surgery is in salvage of patients with residual and recurrent disease. The primary aim of the study is to determine how often such salvage surgery is required, while the secondary aim is to determine which features indicate salvage surgery may be required and to determine the outcome of salvage surgery. METHODS: A prospective database was analysed of all patients with anal cancer over an 18 year period (Dec 1996-Jan 2015). The records of patients requiring salvage surgery were reviewed. RESULTS: 203 Patients were identified with anal cancers, of which 180 had squamous cell anal carcinoma. 112 Female (median age 59.4, range 33-92) 68 male (median age 63.8 range 36-87). Of these 27 patients (15%) required salvage surgery. 23 Patients had a R0 resection. 18 Patients had an extended resection (16 R0) while 9 had a routine APR (7 R0). The 30-day post-operative mortality rate was 0%. The overall 5 year survival was 78%, not significantly different from those not requiring salvage surgery (p = 0.23). Age, gender, AJCC stage, T stage, radiation therapy alone, were not predicators of the need for salvage surgery. CONCLUSIONS: Salvage surgery is uncommonly required. Extended surgery beyond routine APR is often required to obtain an R0 resection. Excellent patient survival can be achieved in highly selected cases. There were no identifiable clinical predictors of those needing salvage surgery, and consideration should be given to explore molecular and genetic factors.

Dysregulated bioenergetics: a key regulator of joint inflammation.

OBJECTIVES: This study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation. METHODS: Primary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates. Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays. RASF metabolism was assessed by the XF24-Flux Analyzer. Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM). In vivo synovial tissue oxygen (tpO2 mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology. A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging. RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). RESULTS: DMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01). This was coupled with altered mitochondrial morphology. Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05). In vivo glycolytic markers were inversely associated with synovial tpO2 levels <20 mm Hg, in contrast ATP was significantly reduced (all p<0.05). Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO2 in tumour necrosis factor alpha inhibitor (TNFi) responders. Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation. 3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions. CONCLUSIONS: Hypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.

Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterised by synovitis and destruction of articular cartilage/bone. Janus-kinase and signal transducer and activator of transcription (JAK-STAT) signalling pathway is implicated in the pathogenesis of PsA. OBJECTIVES: To examine the effect of tofacitinib (JAK inhibitor) on proinflammatory mechanisms in PsA. METHODS: Primary PsA synovial fibroblasts (PsAFLS) and ex vivo PsA synovial explants were cultured with tofacitinib (1 µM). PhosphoSTAT3 (pSTAT3), phosphoSTAT1 (pSTAT1), suppressor of cytokine signaling-3 (SOCS3), protein inhibitor of activated Stat3 (PIAS3) and nuclear factor kappa B cells (NFκBp65) were quantified by western blot. The effect of tofacitinib on PsAFLS migration, invasion, Matrigel network formation and matrix metallopeptidase (MMP)2/9 was quantified by invasion/migration assays and zymography. Interleukin (IL)-6, IL-8, IFN-gamma-inducible protein 10 (IP-10) monocyte chemoattractant protein (MCP)-1, IL-17, IL-10, MMP3 and tissue inhibitor of metalloproteinases 3 (TIMP3) were assessed by ELISA. RESULTS: Tofacitinib significantly decreased pSTAT3, pSTAT1, NFκBp65 and induced SOCS3 and PIAS3 expression in PsAFLS and synovial explant cultures (p<0.05). Functionally, PsAFLS invasion, network formation and migration were inhibited by tofacitinib (all p<0.05). In PsA explant, tofacitinib significantly decreased spontaneous secretion of IL-6, IL-8, MCP-1, MMP9/MMP2, MMP3 (all p<0.05) and decreased the MMP3/TIMP3 ratio (p<0.05), with no effect observed for IP-10 or IL-10. CONCLUSIONS: This study further supports JAK-STAT inhibition as a therapeutic target for the treatment of PsA.

Surface ligand-directed pair-wise hydrogenation for heterogeneous phase hyperpolarization.

para-Hydrogen induced polarization is a technique of magnetic resonance hyperpolarization utilizing hydrogen's para-spin state for generating signal intensities at magnitudes far greater than state-of-the-art magnets. Platinum nanoparticle-catalysts with cysteine-capping are presented. The measured polarization is the highest reported to date in water, paving pathways for generating medical imaging contrast agents.

Malignancy and mesenteric panniculitis.

AIM: Mesenteric panniculitis (MP) is a chronic inflammatory process of the small bowel mesentery that has been reported in conjunction with malignancy. The objectives of the present study were to identify the frequency and type of cancers that may coexist with MP and whether these can be seen on the initial diagnostic computerised tomography (CT). METHOD: A prospective database was kept of patients diagnosed with MP in the Canterbury region of New Zealand between 1 January 2003 and 31 December 2014. CT scans were independently reviewed. Clinical records were reviewed and family doctors were contacted for additional information. RESULTS: There were 302 patients with possible MP identified and 259 in whom it was confirmed on review. Seventy-eight patients had a diagnosis of malignancy, with 54 having a current cancer (59 total cancers), 33 a past cancer and nine both. Of the 59 current cancers the most common primary sites were colorectum (19), lymph nodes (17), kidney (six) and prostate (four). Fifty-four were at sites included on an abdominal CT scan. At all sites [except prostate (0/4)] there were high rates of detection on CT with 44/54 cancers visible including 20/23 gastrointestinal tract, 14/17 lymphomas and 9/9 non-prostate urogenital tract malignancies. Six people were subsequently diagnosed with cancer after the index CT. CONCLUSION: When MP occurs in association with malignancy, the commonest primary sites are large bowel, the lymph nodes and the urogenital tract. In those with MP on imaging, any cancer except prostate can usually be seen on the index CT. Further extensive investigation in asymptomatic patients is therefore likely to be of low yield.

Qualitative evaluation of care plans for Canadian breast and head-and-neck cancer survivors.

BACKGROUND: Survivorship care plans (scps) have been recommended as a way to ease the transition from active cancer treatment to follow-up care, to reduce uncertainty for survivors in the management of their ongoing health, and to improve continuity of care. The objective of the demonstration project reported here was to assess the value of scps for cancer survivors in western Canada. METHODS: The Alberta CancerBridges team developed, implemented, and evaluated scps for 36 breast and 21 head-and-neck cancer survivors. For the evaluation, we interviewed 12 of the survivors, 9 nurses who delivered the scps, and 3 family physicians who received the scps (n = 24 in total). We asked about satisfaction, usefulness, emotional impact, and communication value. We collected written feedback from the three groups about positive aspects of the scps and possible improvements (n = 85). We analyzed the combined data using qualitative thematic analysis. RESULTS: Survivors, nurses, and family physicians agreed that scps could ease the transition to survivorship partly by enhancing communication between survivors and care providers. Survivors appreciated the individualized attention and the comprehensiveness of the plans. They described positive emotional impacts, but wanted a way to ensure that their physicians received the scps. Nurses and physicians responded positively, but expressed concern about the time required to implement the plans. Suggestions for streamlining the process included providing survivors with scp templates in advance, auto-populating the templates for the nurses, and creating summary pages for physicians. CONCLUSIONS: The results suggest ways in which scps could help to improve the transition to cancer survivorship and provide starting points for larger feasibility studies.

Assessing the in vivo efficacy of doxorubicin loaded hyaluronan nanoparticles.

Magnetic nanoparticles are attractive platforms for biomedical applications including diagnosis and treatment of diseases. We have shown previously that hyaluronan-coated superparamagnetic iron oxide nanoparticles (HA-SPIONs) enhanced the efficacy of the conjugated anticancer drug doxorubicin (DOX) in vitro against drug-sensitive and drug-resistant human ovarian cancer cells. In this manuscript, we report our findings on the efficacy of DOX loaded HA-SPIONs in vivo using subcutaneous and intraperitoneal SKOV-3 ovarian tumor models in nude mice. The accumulation of the nanoparticles in subcutaneous tumors following an intravenous nanoparticle administration was confirmed by magnetic resonance imaging, and its distribution in the tumors was evaluated by confocal microscopy and Prussian blue staining. DOX delivered by nanoparticles accumulated at much higher levels and distributed wider in the tumor tissue than intravenously injected free DOX, leading to significant reduction of tumor growth. The IVIS Spectrum for in vivo bioluminescence imaging was used to aid in therapy assessment of the DOX-loaded nanoparticles on intraperitoneal ovarian tumors formed by firefly luciferase expressing human ovarian SKOV-3 cells. DOX-loaded HA-SPIONs significantly reduced tumor growth, delayed tumor development, and extended the survival of mice. Thus, utilizing HA-SPIONs as drug delivery vehicles constitutes a promising approach to tackle CD44 expressing ovarian cancer.

Population-scale analysis of human microsatellites reveals novel sources of exonic variation.

Using our microsatellite specific genotyping method, we analyzed tandem repeats, which are known to be highly variable with some recognized as biomarkers causative of disease, in over 500 individuals who were exon sequenced in a 1000 Genomes Project pilot study. We were able to genotype over 97% of the microsatellite loci in the targeted regions. A total of 25,115 variations were observed, including repeat length and single nucleotide polymorphisms, corresponding to an average of 45.6 variations per individual and a density of 1.1 variations per kilobase. Standard variant detection did not report 94.2% of the exonic repeat length variations in part because the alignment techniques are not ideal for repetitive regions. Additionally some standard variation detection tools rely on a database of known variations, making them less likely to call repeat length variations as only a small percent of these loci (~6000) have been accurately characterized. A subset of the hundreds of non-synonymous variations we identified was experimentally validated, indicating an accuracy of 96.5% for our microsatellite-based genotyping method, with some novel variants identified in genes associated with cancer. We propose that microsatellite-based genotyping be used as a part of large scale sequencing studies to identify novel variants.

Exploiting identifiability and intergene correlation for improved detection of differential expression.

Accurate differential analysis of microarray data strongly depends on effective treatment of intergene correlation. Such dependence is ordinarily accounted for in terms of its effect on significance cutoffs. In this paper, it is shown that correlation can, in fact, be exploited to share information across tests and reorder expression differentials for increased statistical power, regardless of the threshold. Significantly improved differential analysis is the result of two simple measures: (i) adjusting test statistics to exploit information from identifiable genes (the large subset of genes represented on a microarray that can be classified a priori as nondifferential with very high confidence], but (ii) doing so in a way that accounts for linear dependencies among identifiable and nonidentifiable genes. A method is developed that builds upon the widely used two-sample t-statistic approach and uses analysis in Hilbert space to decompose the nonidentified gene vector into two components that are correlated and uncorrelated with the identified set. In the application to data derived from a widely studied prostate cancer database, the proposed method outperforms some of the most highly regarded approaches published to date. Algorithms in MATLAB and in R are available for public download.

Reprint of BMCL_19101.

The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.

Attenuation of collagen-induced arthritis by orally available imidazoline-based NF-κB inhibitors.

The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.