tbuckley/cabot-search huggingface dataset:
Phase I Pharmacokinetic Study of S-1 Plus Cisplatin in Patients With Advanced Gastric Carcinoma
Authors: Jaffer A. Ajani, Josephine Faust, Kazumasa Ikeda, James C. Yao, Hiroshi Anbe, Kelli L. Carr, Michele Houghton, Peter Urrea
Journal: Journal of Clinical Oncology (2005)

The conversion rate of tegafur (a component of S-1) to fluorouracil (FU) differs in Asians and whites because of polymorphic differences in the CYP2A6 gene. S-1 with cisplatin is considered highly active in Japanese gastric cancer patients. Therefore, we initiated a phase I pharmacokinetic study of this combination in our gastric cancer patients.Patients received cisplatin intravenously on day 1 and S-1 orally, twice daily, on days 1 to 21 every 28 days. At level 1, the S-1 dose was 25 mg/m2/dose (50 mg/m2/d), but it was increased by 5 mg/m2/dose for the next level. Cisplatin was administered at 75 mg/m2 (for levels 1 and 2) but was then reduced to 60 mg/m2 (level 1A). At every level, a cohort of three patients, which could be expanded to six patients, was studied. Maximum-tolerated dose (MTD) was determined based on the dose-limiting toxicity (DLT) in the first cycle. Patients with histologic proof of gastric adenocarcinoma and near-normal organ function were studied.Sixteen patients were enrolled. No DLTs occurred at level 1. However, DLTs occurred at levels 2 and 1A. The area under the curve for FU correlated significantly with DLT (P = .006) and grade 3 to 4 diarrhea (P = .004). Six partial responses were confirmed, including three at the MTD.At the established MTD of S-1 plus cisplatin, the S-1 dose (50 mg/m2/d for 21 days) is lower in our study than in the Japanese study (80 mg/m2/d for 21 days). A multi-institutional phase II study of this active combination is currently accruing patients.
PREVENTION OF CELL-TO-CELL SPREAD OF HERPES SIMPLEX VIRUS BY LEUKOCYTES
Authors: Donald Louis Lodmell, Akira Niwa, Kozaburo Hayashi, Abner Louis Notkins
Journal: The Journal of Experimental Medicine (1973)

Antibody to herpes simplex virus (HSV) plus complement destroyed HSV-infected cells but did not stop the spread of the infection. Studies on the relationship between the time of appearance of viral antigens on the cell surface, immunological destruction of the cells by antiviral antibody and complement, and transfer of the virus to adjacent cells showed that the virus spread from infected to uninfected cells before the infected cells were susceptible to immunological destruction. Incubation of infected monolayers with leukocytes, however, stopped the spread of the virus by nonspecifically damaging both infected and uninfected cells and by presumably breaking intercellular bridges. When leukocytes were removed from infected monolayers, viral plaques developed. If, however, antiviral antibody and complement were added to monolayers before the leukocytes were removed, the development of plaques was prevented. These findings suggest that both antibody and leukocytes are needed to cure HSV infections.
Using Gene Expression Ratios to Predict Outcome Among Patients With Mesothelioma
Authors: Gavin J Gordon, Roderick V Jensen, Li-Li Hsiao, Steven R Gullans, Joshua E Blumenstock, William G Richards, Michael T Jaklitsch, David J Sugarbaker, Raphael Bueno
Journal: JNCI Journal of the National Cancer Institute (2003)

We have recently demonstrated that simple ratios of the expression levels of selected genes in tumor samples can be used to distinguish among types of thoracic malignancies. We examined whether this technique could predict treatment-related outcome for patients with mesothelioma.We used gene expression profiling data previously collected from 17 mesothelioma patients with different overall survival times to define two outcome-related groups of patients and to train an expression ratio-based outcome predictor model. A Student's t test was used to identify genes among the two outcome groups that had statistically significant, inversely correlated expression levels; those genes were used to form prognostic expression ratios. We used a combination of several highly accurate expression ratios and cross-validation techniques to assess the internal consistency of this predictor model, quantitative reverse transcription-polymerase chain reaction of tumor RNA to confirm the microarray data, and Kaplan-Meier survival analysis to validate the model among an independent set of 29 mesothelioma tumors. All statistical tests were two-sided.We developed an expression ratio-based test capable of identifying 100% (17/17) of the samples used to train the model. This test remained highly accurate (88%, 15/17) after cross-validation. A four-gene expression ratio test statistically significantly (P =.0035) predicted treatment-related patient outcome in mesothelioma independent of the histologic subtype of the tumor.Gene expression ratio-based analysis accurately predicts treatment-related outcome in mesothelioma samples. This technique could impact the clinical treatment of mesothelioma by allowing the preoperative identification of patients with widely divergent prognoses.
Infections in Diabetic Burn Patients
Authors: Heidi Memmel, Areta Kowal-Vern, Barbara A. Latenser
Journal: Diabetes Care (2004)

OBJECTIVE— Diabetic burn patients comprise a significant population in burn centers. The purpose of the study was to determine the demographic characteristics of diabetic burn patients and their rate of community-acquired and nosocomial infections. RESEARCH DESIGN AND METHODS—This was a 46-month retrospective chart and patient registry review comparing diabetic with nondiabetic burn patients. Statistical analysis consisted of means ± SD, descriptive statistics, one-way ANOVA, and χ2 tests. RESULTS—Of 1,063 adult burn patients (aged 15–54 years), 68 (6%) diabetic burns were compared with burns of 995 adult nondiabetic patients. Of 193, 62 (32%) senior (≥55 years of age) diabetic burns were compared with 131 nondiabetic senior burns. The major mechanism of injury for the diabetic patients was scalding and contact, in contrast to that of nondiabetic patients who were injured mainly by scalding or flame burns. Adult diabetic patients had a significantly increased frequency of foot burns compared with adult nondiabetic patients (32 of 68 [68%] versus 144 of 995 [14%], P = 0.001). Adult diabetic burns had a significant increase in sepsis (P &amp;lt; 0.002) and community-acquired burn wound cellulitis (P &amp;lt; 0.001) compared with adult nondiabetic patients; and senior diabetic patients had a significantly increased frequency of urinary tract infections compared with senior nondiabetic burn patients (P &amp;lt; 0.04). The most common organisms in diabetic burn infections were Streptococcus, Proteus, Pseudomonas, Candida species, and MRSA (methicillin-resistant Staphylococcus aureus). Forty-two percent of the diabetic patients were admitted during the winter months and 25% in the spring. Only 49 of 130 (38%) diabetic burn patients presented for treatment within 48 h after injury compared with 669 of 1,126 (62%) nondiabetic patients (P = 0.001). CONCLUSIONS—Peripheral neuropathy may have precipitated and delayed medical treatment in lower-extremity burns of diabetic patients. Hospitalized diabetic burn patients were also at an increased risk for nosocomial infections, which prolonged hospitalization. Diabetic patient education must include not only caution about potential burn mishaps but also educate concerning the complications from burns that may ensue.
Exposure to Environmental Microorganisms and Childhood Asthma
Authors: Markus J. Ege, Melanie Mayer, Anne-Cécile Normand, Jon Genuneit, William O.C.M. Cookson, Charlotte Braun-Fahrländer, Dick Heederik, Renaud Piarroux, Erika von Mutius
Journal: New England Journal of Medicine (2011)

Children who grow up in environments that afford them a wide range of microbial exposures, such as traditional farms, are protected from childhood asthma and atopy. In previous studies, markers of microbial exposure have been inversely related to these conditions.
A Rapid Assay for Cytotoxicity of Unstimulated Human Monocytes23
Authors: H. W. Löms Ziegler-Heitbrock, Gert Riethmüller
Journal: JNCI Journal of the National Cancer Institute (1984)

Human peripheral blood mononuclear cells were used as effectors against the Wehi 164 mouse fibrosarcoma cell line grown in suspension culture. In a standard 7-hour 51 Cr release assay, specific release usually was below 10%. In contrast, pretreatment of Wehi 164 for 3 hours with dactinomycin (Act D), while leaving the tumor cells intact and viable, resulted in a drastic increase in its susceptibility to lysis, which reached 60% specific release. In terms of lytic units, this reflects up to a fiftyfold enhancement. Cell-separation experiments revealed that the effector cells were plastic-adherent and iron-phagocytic. Adherent cell fractions with 85–98% naphthol AS acetate-esterase (NAS)-positive cells were enriched in cytotoxicity, while nonadherent cells with less than 4% NAS-positive cells were almost devoid of activity. Depletion of phagocytic cells with iron and magnet resulted in a strong reduction of cytotoxicity by 82–95% compared to the cytotoxicity seen in control treated effector cells. In both kinds of analyses, natural killer cell activity showed a reciprocal behavior. The evidence indicates that the cytotoxic effector cells directed against Act D-treated Wehi 164 cells belong to the monocyte lineage. The system described should be useful in analyzing the cytotoxic function of unstimulated monocytes in a short-term assay without prior purification of the effector cells.
Lymphatic Zip Codes in Premalignant Lesions and Tumors
Authors: Lianglin Zhang, Enrico Giraudo, Jason A. Hoffman, Douglas Hanahan, Erkki Ruoslahti
Journal: Cancer Research (2006)

Blood vessels in tumors are morphologically and functionally distinct from normal resting blood vessels. We probed lymphatic vessels in premalignant lesions and tumors by in vivo screening of phage-displayed peptide libraries, asking whether they too have distinctive signatures. The resulting peptides begin to define such signatures. One peptide identified the lymphatics in a human melanoma xenograft. Another recognized the lymphatics in prostate cancers but not in premalignant prostate lesions; this peptide similarly identifies human prostate cancer lymphatics. A third was selective for the lymphatics in the premalignant prostate lesions. A fourth identified the lymphatics in dysplasias and squamous carcinomas of the cervix and skin. None recognize lymphatics in normal tissues. Thus, tumor development is associated with organ- and stage-specific changes in lymphatics. Systemic treatment of mice with fusions of a lymphatic homing peptide and a proapoptotic motif reduced the number of tumor lymphatics in prostate tumor and melanoma, forecasting future lymphatic targeting agents for detection and therapeutic intervention.
INFLUENCE OF ANESTHESIA ON EXPERIMENTAL NEUROTROPIC VIRUS INFECTIONS
Authors: S. Edward Sulkin, Christine Zarafonetis, Andres Goth
Journal: The Journal of Experimental Medicine (1946)

Anesthesia with diethyl ether significantly alters the course and outcome of experimental infections with the equine encephalomyelitis virus (Eastern or Western type) or with the St. Louis encephalitis virus. No comparable effect is observed in experimental infections produced with rabies or poliomyelitis (Lansing) viruses. The neurotropic virus infections altered by ether anesthesia are those caused by viruses which are destroyed in vitro by this anesthetic, and those infections not affected by ether anesthesia are caused by viruses which apparently are not destroyed by ether in vitro. Another striking difference between these two groups of viruses is their pathogenesis in the animal host; those which are inhibited in vivo by ether anesthesia tend to infect cells of the cortex, basal ganglia, and only occasionally the cervical region of the cord. On the other hand, those which are not inhibited in vivo by ether anesthesia tend to involve cells of the lower central nervous system and in the case of rabies, peripheral nerves. This difference is of considerable importance in view of the fact that anesthetics affect cells of the lower central nervous system only in very high concentrations. It is obvious from the complexity of the problem that no clear-cut statement can be made at this point as to the mechanism of the observed effect of ether anesthesia in reducing the mortality rate in certain of the experimental neurotropic virus infections. Important possibilities include a direct specific effect of diethyl ether upon the virus and a less direct effect of the anesthetic upon the virus through its alteration of the metabolism of the host cell.
Ratio of miR-196s to HOXC8 Messenger RNA Correlates with Breast Cancer Cell Migration and Metastasis
Authors: Yong Li, Maoxiang Zhang, Huijun Chen, Zheng Dong, Vadivel Ganapathy, Muthusamy Thangaraju, Shuang Huang
Journal: Cancer Research (2010)

Expression profiling has identified metastasis-associated microRNAs (miRNA) but technical limitations hinder the discovery of metastasis-suppressing miRNAs. In this study, we sought metastasis-suppressing miRNAs by functional screening. Individual miRNAs were lentivirally introduced into metastatic MDA-MB-231 breast cancer cells and analyzed for effects on cell migration, a critical step in cancer metastasis. Among 486 miRNAs screened, 14 were identified that included all of the members of the miRNA-196 family (miR-196a1, miR-196a2, and miR-196b). Enforced expression of miR-196a1/2 or miR-196b abrogated in vitro invasion and in vivo spontaneous metastasis of breast cancer cells, indicating that members of the miR-196 family are potent metastasis suppressors. We found that miR-196 inhibited the expression of transcription factor HOXC8. Functional linkage was implied by small interfering RNA-mediated knockdown of HOXC8, which suppressed cell migration and metastasis, and by ectopic expression of HOXC8, which prevented the effects of miR-196 on cell migration and metastasis. Unlike other metastasis-associated miRNAs that have been described, the expressions of miR-196 were not correlated with breast cancer cell migration or the metastatic status of clinical breast tumor specimens. Instead, we detected an excellent correlation between the ratio of miR-196 to HOXC8 messages and the migratory behavior of breast cancer cell lines as well as the metastatic status of clinical samples. Our findings identify miRNA-196s as potent metastasis suppressors and reveal that the ratio of miR-196s to HOXC8 mRNA might be an indicator of the metastatic capability of breast tumors.
The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Methodological Report Phase I
Authors: J. Funovits, D. Aletaha, V. Bykerk, B. Combe, M. Dougados, P. Emery, D. Felson, G. Hawker, J. M. Hazes, T. Huizinga, J. Kay, T. K. Kvien, J. S. Smolen, D. Symmons, P. P. Tak, A. Silman
Journal: Annals of the Rheumatic Diseases (2010)

To apply a data-driven approach to investigate, in patients newly presenting with undifferentiated inflammatory synovitis, key variables that discriminate the subset of patients at sufficiently high risk of persistent or erosive disease for the purpose of developing new criteria for rheumatoid arthritis (RA).In this first phase of the collaborative effort of the American College of Rheumatology and European League Against Rheumatism to develop new criteria for RA, a pooled analysis of early arthritis cohorts made available by the respective investigators is presented. All the variables associated with the gold standard of treatment with methotrexate during the first year after enrolment were first identified. Principal component analysis was then used to identify among the significant variables those sets that represent similar domains. In a final step, from each domain one representative variable was extracted, all of which were then tested for their independent effects in a multivariate regression model. From the OR in that final model, the relative weight of each variable was estimated.The final domains and variables identified by this process (and their relative weights) were: swelling of a metacarpophalangeal joint (MCP; 1.5), swelling of a proximal interphalangeal joint (PIP; 1.5), swelling of the wrist (1.5), tenderness of the hand (ie, MCP, PIP or wrist (2)), acute phase reaction (ie, C reactive protein or erythrocyte sedimentation rate and weights for moderate or high elevations of either one (1 for moderate, 2 for high elevation)) and serological abnormalities (ie, rheumatoid factors or anti-citrullinated protein antibodies, again with separate weights for moderate or high elevations (2 and 4, respectively)).The results of this first phase were subsequently used in the second phase of the project, which is reported in a separate methodological paper, and for derivation of the final set of criteria.
Assessment of passive respiratory mechanics in infants: double<i>versus</i>single occlusion?
Authors: I. Goetz, A.F. Hoo, S. Lum, J. Stocks
Journal: European Respiratory Journal (2001)

The single breath or occlusion technique (SOT) is widely used to assess passive respiratory mechanics in infants, but depends on various underlying assumptions. Recently, it has been proposed that such measurements could be internally validated by performing two brief airway occlusions during the same expiration. The aim of this study was to evaluate the use of the double occlusion technique (DOT) using a new commercially available program (Jaeger MasterScreen BabyBody Erich Jaeger GmbH, Würzburg, Germany). Paired measurements of respiratory system compliance ( C rs ) and resistance ( R rs ) using both SOT and DOT were obtained in 18 healthy sedated infants (age range 4–41 weeks, weight 2.7–9.9 kg). There was close agreement between both methods of assessing C rs in all infants, the mean within-subject difference (95% confidence interval (CI)) for DOT−SOT being −0.06 (−0.55–+0.42) mL·kPa −1 ·kg −1 . By contrast, estimates of R rs , DO were on average 20% lower than those for R rs , SO , (mean within-subject difference (95% CI) being −0.67 (−1.04–−0.31) kPa·L −1 ·s; p&lt;0.01). The relatively lower values obtained for R rs , DO may reflect the higher mean lung volume at which it was calculated. Further work is required to investigate the clinical and epidemiological relevance of this new approach, and whether there are any advantages of using both techniques when assessing passive mechanics in infants.
Normal nasal mucociliary clearance in CF children: evidence against a CFTR‐related defect
Authors: D. McShane, J.C. Davies, T. Wodehouse, A. Bush, D. Geddes, E.W.F.W. Alton
Journal: European Respiratory Journal (2004)

Studies on mucociliary clearance (MCC) in cystic fibrosis (CF) have produced conflicting results. This study aimed to differentiate primary (ion transport-related) from secondary (inflammatory) causes of delayed MCC in CF. Nasal MCC was measured in 50 children (CF, primary ciliary dyskinesia (PCD) and no respiratory disease). Nasal lavage fluid was analysed for interleukin (IL)‐8 and tumour necrosis factor‐α. Similar measurements were obtained in adult CF patients with and without chronic sinusitis (CS). Children with CF had neither delayed MCC nor increased levels of cytokines. Conversely, children with PCD had prolonged MCC times (all &gt;30 min) and significantly raised levels of IL‐8. CS‐positive CF adults had significantly slower MCC than CS‐negative subjects, but IL‐8 levels were low and similar in both groups. Decreased airway surface liquid and delayed mucociliary clearance are the postulated primary mechanisms in cystic fibrosis. However, the current study reports that cystic fibrosis children have normal nasal mucociliary clearance. Abnormalities appeared in cystic fibrosis adults with symptoms of chronic sinus disease, suggesting a secondary rather than primary phenomenon. Studies to explore this mechanism in the distal, more sparsely-ciliated airways could aid an understanding of pathogenesis and the development of new treatments.
Gastrin, growth, and colon neoplasia
Authors: G J DOCKRAY
Journal: Gut (2000)

See article on page 820 

The ability of the gastric hormone gastrin to stimulate gut epithelial cell proliferation has been appreciated since the late 1960s.1 However, aside from the special case of gastric carcinoid tumours arising from enterochromaffin-like cells, the contribution of gastrin to gastrointestinal neoplasia has been uncertain. Several developments now suggest a role for gastrin in both gastric and colorectal cancer. In the case of gastric cancer, recent evidence indicates a synergy between gastrin and Helicobacter infection in accelerating progression to atrophy and cancer.2 Different issues are involved in colorectal cancer. The important emerging concepts here are that (a) the gastrin gene is expressed in colorectal cancer cells, but (b) the main products of gene expression in these cells are not ligands for the gastrin-cholesystokinin receptor B (CCKB), although (c) they do act as colon growth factors. The paper by Smith and Watson3 now shows that gastrin mRNA, detected by reverse transcription-polymerase chain reaction, is expressed in early stage polyps, that the main forms of gastrin detected by immunohistochemistry are biosynthetic precursor peptides, and that there is also parallel expression of the …
A mass assembly of associative mechanisms: A dynamical systems account of natural social interaction
Authors: Nicholas D Duran, Rick Dale, Daniel C Richardson
Journal: Behavioral and Brain Sciences (2014)

Abstract The target article offers a negative, eliminativist thesis, dissolving the specialness of mirroring processes into a solution of associative mechanisms. We support the authors' project enthusiastically. What they are currently missing, we argue, is a positive, generative thesis about associative learning mechanisms and how they might give way to the complex, multimodal coordination that naturally arises in social interaction.
Spatial and Temporal Inhomogeneities During Ca <sup>2+</sup> Release From the Sarcoplasmic Reticulum in Pig Ventricular Myocytes
Authors: Frank R. Heinzel, Virginie Bito, Paul G.A. Volders, Gudrun Antoons, Kanigula Mubagwa, Karin R. Sipido
Journal: Circulation Research (2002)

The [Ca 2+ ] i transient of ventricular myocytes during normal excitation-contraction coupling is the summation of primary Ca 2+ release events, which originate at the junction of the sarcoplasmic reticulum (SR) and the T-tubular system. Studies in small mammals have shown a high density of release sites, but little is known of larger mammals. We have studied the spatial distribution of SR Ca 2+ release in pig ventricular myocytes using a confocal microscopy. In 69 of 107 cells, large inhomogeneities of Ca 2+ release were observed along the longitudinal scan line. Areas where the increase of [Ca 2+ ] i was delayed (time to 50% of peak F/F 0 [where F indicates fluorescence intensity, and F 0 indicates F at rest] was 26±1 ms in delayed areas versus 11±2 ms in early areas) and smaller (peak F/F 0 was 2.27±0.10 for delayed areas versus 2.69±0.13 for early areas; n=13 cells, P &lt;0.05) could be up to 26 μm wide. The sum of all delayed areas could make up to 55% of the line scan. The spatial pattern was constant during steady-state stimulation and was not altered by enhancing Ca 2+ channel opening or SR Ca 2+ content (Bay K8644, isoproterenol). Imaging of sarcolemmal membranes revealed several areas devoid of T tubules, but SR Ca 2+ release channels were homogeneously distributed. In contrast, compared with pig myocytes, mouse myocytes had a very dense T-tubular network, no large inhomogeneities of release, and a faster rate of rise of [Ca 2+ ] i . In conclusion, in pig ventricular myocytes, areas of delayed release are related to regional absence of T tubules but not ryanodine receptors. This lower number of functional couplons contributes to a slower overall rate of rise of [Ca 2+ ] i .