tbuckley/cabot-search huggingface dataset:
Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8
Authors: Ahmed S Abdulamir, Rand R Hafidh, Fatimah Bakar
Journal: Molecular Cancer (2010)

Colorectal cancer (CRC) has long been associated with bacteremia and/or endocarditis by Streptococcus gallolyticus member bacteria (SGMB) but the direct colonization of SGMB along with its molecular carcinogenic role, if any, has not been investigated. We assessed the colonization of SGMB in CRC patients with history of bacteremia (CRC-w/bac) and without history of bacteremia (CRC-wo/bac) by isolating SGMB from feces, mucosal surfaces of colorectum, and colorectal tissues and detecting SGMB DNA, via PCR and in situ hybridization (ISH) assays targeting SodA gene in colorectal tissues. Moreover, mRNA of IL1, IL-8, COX-2, IFN-γ, c-Myc, and Bcl-2 in colorectal tissues of studied groups was assessed via ISH and RT-PCR. SGMB were found to be remarkably isolated in tumorous (TU) and non-tumorous (NTU) tissues of CRC-w/bac, 20.5% and 17.3%, and CRC-wo/bac, 12.8% and 11.5%, respectively while only 2% of control tissues revealed SGMB (P < 0.05); such contrast was not found in mucosal and fecal isolation of SGMB. The positive detection of SGMB DNA in TU and NTU of CRC-w/bac and CRC-wo/bac via PCR, 48.7%, 35.9%, 32.7%, and 23%, respectively, and ISH, 46.1%, 30.7%, 28.8%, and 17.3%, respectively, was higher than in control tissues, 4 and 2%, respectively (P < 0.05). SGMB count measured via quantitative PCR of SGMB DNA in terms of copy number (CN), in TU and NTU of CRC-w/bac and CRC-wo/bac, 2.96-4.72, 1.29-2.81, 2.16-2.92, and 0.67-2.07 log10 CN/g respectively, showed higher colonization in TU than in NTU and in CRC-w/bac than in CRC-wo/bac (P < 0.05). The PCR-based mRNA ratio and ISH-based percentage of positively stained cells of IL-1, 1.77 and 70.3%, COX-2, 1.63 and 44.8%, and IL-8, 1.73 and 70.3%, respectively, rather than IFN-γ, c-Myc, and Bcl-2, were higher in SGMB positive patients than in control or SGMB negative patients (P < 0.05). The current study indicated that colorectal cancer is remarkably associated with SGMB; moreover, molecular detection of SGMB in CRC was superior to link SGMB with CRC tumors highlighting a possible direct and active role of SGMB in CRC development through most probably inflammation-based sequel of tumor development or propagation via, but not limited to, IL-1, COX-2, and IL-8.
Subendocardial and subepicardial wall thickening during ischemia in exercising dogs.
Authors: D C Homans, E Sublett, P Lindstrom, T Nesbitt, R J Bache
Journal: Circulation (1988)

To determine whether ischemia in the exercising dog is associated with preservation of subepicardial thickening relative to subendocardial thickening, 10 dogs were chronically instrumented with circumflex artery flow probes, hydraulic occluders, and pairs of ultrasonic microcrystals for determination of wall thickness in the circumflex artery distribution. One pair of crystals spanned the entire ventricular wall (transmural), and the other spanned the outer half of the ventricular wall. Inner wall thickness was computed as the difference between transmural wall thickness and outer wall thickness. Dogs performed control treadmill exercise and exercise with a coronary stenosis that reduced circumflex artery flow to resting control levels. Percent systolic thickening at rest for the transmural, inner, and outer regions was 21.3 +/- 11.8%, 35.5 +/- 20.3%, and 10.3 +/- 5.0% (mean +/- SD), respectively. During exercise without stenosis, systolic thickening increased to 143 +/- 37% of control for outer wall crystals and 137 +/- 26% of control for the inner portion of the wall. During exercise, the addition of a coronary stenosis caused a reduction in thickening to 17.7 +/- 28.5% of control for the outer wall and 40.1 +/- 32.3% of control for the inner portion of the wall; these were not significantly different. In contrast, normalized inner wall blood flow during exercise with circumflex artery stenosis (25.0 +/- 16.0%) was significantly less than for the outer portion of the wall (48.5 +/- 20.9%). Further, there was a close relation between changes in inner wall thickening and inner wall blood flow (r = 0.84), whereas there was only a very weak relation between changes in outer wall blood flow and function (r = 0.62; p = 0.04). During ischemia in the exercising dog, outer wall thickening is depressed out of proportion to reductions in outer wall blood flow and is not preserved relative to inner wall thickening.
Phase II Study of Cisplatin Plus Epirubicin Salvage Chemotherapy in Refractory Germ Cell Tumors
Authors: Pablo M. Bedano, Mary J. Brames, Stephen D. Williams, Beth E. Juliar, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2006)

Initial cisplatin (CIS) combination chemotherapy will cure 70% of patients with disseminated testicular cancer. This phase II clinical trial evaluated the combination of CIS plus epirubicin (CIS-EPI) in patients with metastatic germ cell tumors (GCT) not amenable to cure with standard salvage therapy.Between March 2001 and August 2005, 30 patients with GCT, who had received at least one previous CIS-based regimen, were enrolled. All patients were males, with median age 36 (range, 24 to 45 years). Twenty-one patients (70%) had experienced late relapses (> 2 years). Patients received EPI 90 mg/m2 on day 1 and CIS 20 mg/m2 on days 1 to 5 every 3 weeks for maximum of four cycles.Nineteen (63%) of 30 patients received all four cycles. Toxicity was primarily hematologic: grade 3/4 neutropenia, four patients (one neutropenic fever); two patients had grade 3 thrombocytopenia, and five patients had grade 3/4 anemia. Nonhematologic toxicity was grade 3 acute renal failure in two patients; grade 3 electrolyte wasting in two patients; grade 3 nausea/vomiting in eight patients; grade 3 elevation of aminotransferases in one patient; and grade 3 diarrhea in one patient. There were no occurrences of severe mucositis, cardiotoxicity, or treatment-related deaths. Nine patients achieved a complete remission; seven of these patients remain without evidence of disease at 25+, 27+, 29+, 44+, 45+, 46+, and 48+ months. One patient remains alive with stable pulmonary nodules at 28+ months.CIS-EPI is an active regimen in metastatic GCT, with an acceptable toxicity profile. This regimen offers potential for long-term disease-free survival in this population.
Genetic Susceptibility to Type 2 Diabetes and Implications for Antidiabetic Therapy
Authors: Allan F. Moore, Jose C. Florez
Journal: Annual Review of Medicine (2007)

Despite major advances in our knowledge of glycemic pathophysiology and the availability of multiple therapeutic options to confront type 2 diabetes, unraveling the complex link between genetic risk and environmental factors in this burgeoning epidemic has proven difficult. Linkage approaches have clarified the etiology of monogenic diabetic syndromes and congenital lipodystrophies, and candidate gene association studies have identified a number of common variants implicated in type 2 diabetes. This year we have witnessed the advent of genome-wide association scanning: As many as nine genetic loci have now been reproducibly associated with type 2 diabetes in five genome-wide scans. Of particular interest are preliminary explorations of the connections between genetic risk and pharmacologic response. An improved understanding of genetic mechanisms should allow us to test whether behavioral or pharmacologic therapies can be tailored and thus the tremendous disease burden inflicted by type 2 diabetes alleviated.
Calcium Requirements for Cardiac Myofibrillar Activation
Authors: R. JOHN SOLARO, ROBERT M. WISE, JOHN S. SHINER, F. NORMAN BRIGGS
Journal: Circulation Research (1974)

The amounts of calcium required to achieve various levels of myofibrillar activation in the dog heart were determined by measuring the dependence of myofibrillar calcium binding, myofibrillar adenosinetriphosphatase (ATPase), and isometric tension on free calcium concentration. Myofibrillar ATPase was half-maximal at 2.4 x 10 -6 M free calcium, and tension development was half-maximal at 2.0 x 10 -6 M free calcium. No simple relation between calcium binding and activation was found. For example, between 10 -8 M and 10 -6 M free calcium, an appreciable amount of calcium was bound to the myofibrils, but there was little activation of isometric tension. On the other hand, myofibrillar calcium binding was not saturated at levels of free calcium at which both tension and ATPase were maximal; therefore, it appears that only a portion of the total myofibrillar calcium binding sites control ATPase and tension. Using the information derived from the binding and activation studies together with our determination of the myofibrillar content of the dog heart, 47.5 mg myofibrillar protein/g wet heart, we calculated the calcium required to achieve various levels of myofibrillar activation in the intact ventricle. By this calculation method, development of half-maximal tension required 22.4 µmoles calcium/kg wet heart, and development of maximal isometric tension required 92.8 µmoles/kg wet heart.
Heparin-Binding EGF-Like Growth Factor Is a Promising Target for Ovarian Cancer Therapy
Authors: Shingo Miyamoto, Michinari Hirata, Ayano Yamazaki, Takuya Kageyama, Hidetoshi Hasuwa, Hiroto Mizushima, Yoshihiro Tanaka, Hiroshi Yagi, Kenzo Sonoda, Masahiro Kai, Hideo Kanoh, Hitoo Nakano, Eisuke Mekada
Journal: Cancer Research (2004)

Abstract Ovarian cancer is the most frequent cause of cancer death among all gynecologic cancers. We demonstrate here that lysophosphatidic acid (LPA)-induced ectodomain shedding of heparin-binding EGF-like growth factor (HB-EGF) is a critical to tumor formation in ovarian cancer. We found that among the epidermal growth factor receptor (EGFR) family of growth factors, HB-EGF gene expression in cancerous tissues and HB-EGF protein levels in patients’ ascites fluid were significantly elevated. The human ovarian cancer cell lines SKOV3 and RMG-1 form tumors in nude mice. Tumor formation of these cells was enhanced by exogenous expression of pro-HB-EGF and completely blocked by pro-HB-EGF gene RNA interference or by CRM197, a specific HB-EGF inhibitor. Transfection with mutant forms of HB-EGF indicated that the release of soluble HB-EGF is essential for tumor formation. LPA, which is constitutively produced by ovarian cancer cells, induced HB-EGF ectodomain shedding in SKOV3 and RMG-1 cells, resulting in the transactivation of EGFR and the downstream kinase extracellular signal-regulated kinase/mitogen-activated protein kinase. LPA-induced transactivation was abrogated by HB-EGF gene RNA interference or by CRM197. Introduction of lipid phosphate phosphohydrolase, which hydrolyzes LPA, decreased the constitutive shedding of HB-EGF, EGFR transactivation, and the tumorigenic potential of SKOV3 and RMG-1 cells. These results indicate that HB-EGF is the primary member of the EGFR family of growth factors expressed in ovarian cancer and that LPA-induced ectodomain shedding of this growth factor is a critical step in tumor formation, making HB-EGF a novel therapeutic target for ovarian cancer.
Omega-3 polyunsaturated fatty acids inhibit transient outward and ultra-rapid delayed rectifier K+currents and Na+current in human atrial myocytes
Authors: Gui-Rong Li, Hai-Ying Sun, Xiao-Hua Zhang, Lik-Cheung Cheng, Shui-Wah Chiu, Hung-Fat Tse, Chu-Pak Lau
Journal: Cardiovascular Research (2008)

The omega-3 (n-3) polyunsaturated fatty acids (omega-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil were recently reported to have an anti-atrial fibrillation effect in humans; however, the ionic mechanisms of this effect are not fully understood. The present study was designed to determine the effects of EPA and DHA on transient outward and ultra-rapid delayed rectifier potassium currents (Ito and IKur) and the voltage-gated sodium current (INa) in human atrial myocytes. A whole-cell patch voltage clamp technique was employed to record Ito and IKur, and INa in human atrial myocytes. It was found that EPA and DHA inhibited Ito in a concentration-dependent manner (IC50: 6.2 µM for EPA; 4.1 µM for DHA) and positively shifted voltage-dependent activation of the current. In addition, IKur was suppressed by 1–50 µM EPA (IC50: 17.5 µM) and DHA (IC50: 4.3 µM). Moreover, EPA and DHA reduced INa in human atrial myocytes in a concentration-dependent manner (IC50: 10.8 µM for EPA; 41.2 µM for DHA) and negatively shifted the potential of INa availability. The INa block by EPA or DHA was use-independent. The present study demonstrates for the first time that EPA and DHA inhibit human atrial Ito, IKur, and INa in a concentration-dependent manner; these effects may contribute, at least in part, to the anti-atrial fibrillation of omega-3 PUFAs in humans.
Clinical impact of bone and calcium metabolism changes in sarcoidosis
Authors: G. Rizzato
Journal: Thorax (1998)

### BONE CHANGES

Even before the introduction of X-rays, Besnier1 had noted the association of swelling of the fingers with lupus pernio. In 1904 Karl Kreibich, later Professor of Dermatology in Prague but at that time working in Vienna, described four patients with cystic changes in the bones of the hand in connection with lupus pernio and gave an excellent radiographic reproduction of the hands in one and sarcoid histology of the skin in another.2 Other reports showing bone involvement by sarcoidosis were published soon thereafter.3-6 In 1919 Schaumann5 was the first to emphasise the location of the specific granuloma in the marrow. The first detailed accounts of the radiology were those of Fleiscner7 and Jungling8 who demonstrated that radiological involvement is more frequent in the bones of the hands and feet than in the long bones, vertebrae, or skull. James9 in 1959 was the first to recognise that bone involvement occurs very rarely in the absence of skin lesions but is common in patients with persistent disease, especially with lupus pernio and other skin lesions.10 The first study on trabecular osteoporosis in 49 untreated patients was possible only when computed tomography became available11; our group has shown that a mild trabecular bone loss may appear only in chronic sarcoidosis. This feature had never been noted before because simple radiographic studies are not sensitive enough to show a mild osteoporosis and because there is rarely an indication for biopsy of the bone affected by sarcoidosis. Our findings have been confirmed by two other groups.12 13 

Corticosteroids may, of course, cause osteoporosis14 which is spontaneously reversible, at least in young people, if the treatment can be discontinued for at least six months.15 

### CALCIUM METABOLISM CHANGES

Hypercalcaemia in sarcoidosis was first demonstrated in 1939.16 …
A Case-Match Study Comparing Unilateral With Synchronous Bilateral Breast Cancer Outcomes
Authors: Alan M. Nichol, Rinat Yerushalmi, Scott Tyldesley, Mary Lesperance, Chris D. Bajdik, Caroline Speers, Karen A. Gelmon, Ivo A. Olivotto
Journal: Journal of Clinical Oncology (2011)

Purpose There is controversy about whether patients with synchronous bilateral breast cancer (SBBC) have similar or worse outcomes compared with patients with unilateral breast cancer. The purpose of this study was to determine whether survival outcomes for patients with SBBC can be estimated from the characteristics of their individual cancers. Patients and Methods Patients had invasive breast cancer, without metastases or inflammatory disease, diagnosed in British Columbia between 1989 and 2000. There were 207 cases with SBBC (diagnosed ≤ 2 months apart) and 15,497 with unilateral breast cancer. By using 10-year breast cancer–specific survival (BCSS) estimates, the higher-risk cancer of each SBBC case was determined and matched with three breast cancers from the unilateral cohort to select 621 high-risk matches. The priority sequence of matching the prognostic and predictive variables was positive lymph node number, primary tumor size, age, grade, lymphovascular invasion, estrogen receptor status, local therapy used, margin status, treating clinic, diagnosis year, and type of systemic therapy used. Results With a median follow-up of 10.2 years, the overall 10-year BCSS was significantly higher for the unilateral cohort (81%; 95% CI, 81% to 82%) than for the SBBC cases (71%; 95% CI, 63% to 77%). The SBBC cases had significantly higher mean age and stage at presentation. The 10-year BCSS was 74% (95% CI, 69% to 77%) for the high-risk matches. Conclusion BCSS was not significantly different between the SBBC cases and their high-risk matches.
Prevention of Anastrozole-Induced Bone Loss with Monthly Oral Ibandronate during Adjuvant Aromatase Inhibitor Therapy for Breast Cancer
Authors: James E. Lester, David Dodwell, Omprakash P. Purohit, Sandra A. Gutcher, Susan P. Ellis, Ruth Thorpe, Janet M. Horsman, Janet E. Brown, Rosemary A. Hannon, Robert E. Coleman
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The aromatase inhibitor anastrozole is a highly effective well-tolerated treatment for postmenopausal endocrine-responsive breast cancer. However, its use is associated with accelerated bone loss and an increase in fracture risk. The ARIBON trial is a double-blind, randomized, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on bone mineral density (BMD) in women taking anastrozole. Experimental Design: BMD was assessed in 131 postmenopausal, surgically treated women with early breast cancer at two U.K. centers. Of these, 50 patients had osteopenia (T score −1.0 to −2.5) at either the hip or lumbar spine. All patients were treated with anastrozole 1 mg once a day and calcium and vitamin D supplementation. In addition, osteopenic patients were randomized to receive either treatment with ibandronate 150 mg orally every month or placebo. Results: After 2 years, osteopenic patients treated with ibandronate gained +2.98% (range −8.9, +19.9) and +0.60% (range −9.0, +6.9) at the lumbar spine and hip, respectively. Patients treated with placebo, however, lost −3.22% (range −16.0, +4.3) at the lumbar spine and −3.90% (range −12.3, +7.2) at the hip. The differences between the two treatment arms were statistically significant at both sites (P &amp;lt; 0.01). At 12 months, urinary n-telopeptide, serum c-telopeptide, and serum bone–specific alkaline phosphatase levels declined in patients receiving ibandronate (30.9%, 26.3%, and 22.8%, respectively) and increased in those taking placebo (40.3%, 34.9%, and 37.0%, respectively). Conclusions: Monthly oral ibandronate improves bone density and normalizes bone turnover in patients treated with anastrozole.
Diagnosis of common dermatophyte infections by a novel multiplex real-time polymerase chain reaction detection/identification scheme
Authors: M. Arabatzis, L.E.S. Bruijnesteijn van Coppenraet, E.J. Kuijper, G.S. de Hoog, A.P.M. Lavrijsen, K. Templeton, E.M.H. van der Raaij-Helmer, A. Velegraki, Y. Gräser, R.C. Summerbell
Journal: British Journal of Dermatology (2007)

In the absence of a functional dermatophyte-specific polymerase chain reaction (PCR), current diagnosis of dermatophytoses, which constitute the commonest communicable diseases worldwide, relies on microscopy and culture. This combination of techniques is time-consuming and notoriously low in sensitivity.Recent dermatophyte gene sequence records were used to design a real-time PCR assay for detection and identification of dermatophytes in clinical specimens in less than 24 h.Two assays based on amplification of ribosomal internal transcribed spacer regions and on the use of probes specific to relevant species and species-complexes were designed, optimised and clinically evaluated. One assay was for detecting the Trichophyton mentagrophytes species complex plus T. tonsurans and T. violaceum. The second assayed for the T. rubrum species complex, Microsporum canis and M. audouinii.The analytical sensitivity of both assays was 0.1 pg DNA per reaction, corresponding to 2.5-3.3 genomes per sample. The protocol was clinically evaluated over 6 months by testing 92 skin, nail and hair specimens from 67 patients with suspected dermatophytosis. Real-time PCR detected and correctly identified the causal agent in specimens from which T. rubrum, T. interdigitale, M. audouinii or T. violaceum grew in culture, and also identified a dermatophyte species in an additional seven specimens that were negative in microscopy and culture.This highly sensitive assay also proved to have high positive and negative predictive values (95.7% and 100%), facilitating the accurate, rapid diagnosis conducive to targeted rather than empirical therapy for dermatophytoses.
Gene Transfer of Neuronal Nitric Oxide Synthase to Carotid Body Reverses Enhanced Chemoreceptor Function in Heart Failure Rabbits
Authors: Yu-Long Li, Yi-Fan Li, Dongmei Liu, Kurtis G. Cornish, Kaushik P. Patel, Irving H. Zucker, Keith M. Channon, Harold D. Schultz
Journal: Circulation Research (2005)

Our previous studies showed that decreased nitric oxide (NO) production enhanced carotid body (CB) chemoreceptor activity in chronic heart failure (CHF) rabbits. In the present study, we investigated the effects of neuronal NO synthase (nNOS) gene transfer on CB chemoreceptor activity in CHF rabbits. The nNOS protein expression and NO production were suppressed in CBs (P<0.05) of CHF rabbits, but were increased 3 days after application of an adenovirus expressing nNOS (Ad.nNOS) to the CB. As a control, nNOS and NO levels in CHF CBs were not affected by Ad.EGFP. Baseline single-fiber discharge during normoxia and the response to hypoxia were enhanced (P<0.05) from CB chemoreceptors in CHF versus sham rabbits. Ad.nNOS decreased the baseline discharge (4.5+/-0.3 versus 7.3+/-0.4 imp/s at 105+/-1.9 mm Hg) and the response to hypoxia (18.3+/-1.2 imp/s versus 35.6+/-1.1 at 40+/-2.1 mm Hg) from CB chemoreceptors in CHF rabbits (Ad.nNOS CB versus contralateral noninfected CB respectively, P<0.05). A specific nNOS inhibitor, S-Methyl-L-thiocitrulline (SMTC), fully inhibited the effect of Ad.nNOS on the enhanced CB activity in CHF rabbits. In addition, nNOS gene transfer to the CBs also significantly blunted the baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in CHF rabbits (P<0.05). These results indicate that decreased endogenous nNOS activity in the CB plays an important role in the enhanced activity of the CB chemoreceptors and peripheral chemoreflex function in CHF rabbits.