tbuckley/cabot-search huggingface dataset:
The Cyclin-Dependent Kinase Inhibitor UCN-01 Plus Cisplatin in Advanced Solid Tumors: A California Cancer Consortium Phase I Pharmacokinetic and Molecular Correlative Trial
Authors: Primo N. Lara, Philip C. Mack, Timothy Synold, Paul Frankel, Jeff Longmate, Paul H. Gumerlock, James H. Doroshow, David R. Gandara
Journal: Clinical Cancer Research (2005)

Abstract Background: UCN-01 (7-hydroxy-staurosporine) is a novel antineoplastic agent targeting cyclin-dependent kinases, which shows potent in vitro and in vivo activity against a broad range of tumor types. Our group has previously shown that UCN-01 potentiates the apoptotic response of agents such as cisplatin in vitro by preventing sequence-specific abrogation of G2 arrest caused by DNA-damaging chemotherapies. Patients and Methods: This National Cancer Institute–sponsored phase I trial was designed to determine the safety, maximum tolerated dose, and pharmacokinetics of escalating doses of cisplatin in combination with UCN-01 in patients with advanced malignant solid tumors, as well as to do molecular correlative studies on tumor specimens. Cisplatin was infused over 1 hour before UCN-01 (45 mg/m2/d) given as a 72-hour continuous infusion. Escalation of cisplatin was planned through five dose levels at 20, 30, 45, 60, and 75 mg/m2. Results: Ten patients were accrued. Accrual was halted at dose level 2 (cisplatin, 30 mg/m2) due to dose-limiting toxicities consisting of grade 5 sepsis with respiratory failure associated with grade 3 creatinine (one patient) and grade 3 atrial fibrillation (one patient). Plasma and salivary pharmacokinetics of UCN-01 were unaffected by cisplatin. Pretreatment and posttreatment tumor biopsies showed that UCN-01 was active against a key molecular target, the checkpoint kinase Chk1. Conclusions: This phase I trial failed to achieve targeted therapeutic dose levels of cisplatin when combined with prolonged infusion UCN-01. However, because preclinical data indicate that UCN-01 potentiates response to platinum, further studies with alternative dose schedules of the combination, or with other platinum analogues, are warranted.
Therapy-Induced Senescence in Cancer
Authors: Jonathan A. Ewald, Joshua A. Desotelle, George Wilding, David F. Jarrard
Journal: JNCI Journal of the National Cancer Institute (2010)

Cellular senescence is a response to nonlethal stress that results in persistent cytostasis with a distinct morphological and biochemical phenotype. The senescence phenotype, detected in tumors through the expression of mRNA and protein markers, can be generated in cancer cells lacking functional p53 and retinoblastoma protein. Current research suggests that therapy-induced senescence (TIS) represents a novel functional target that may improve cancer therapy. TIS can be induced in immortal and transformed cancer cells by selected anticancer compounds or radiation, and accumulating data indicate that TIS may produce reduced toxicity-related side effects and increased tumor-specific immune activity. This review examines the current status of TIS-regulated mechanisms, agents, and senescence biomarkers with the goal of encouraging further development of this approach to cancer therapy. Remaining hurdles include the lack of efficient senescence-inducing agents and incomplete biological data on tumor response. The identification of additional compounds and other targeted approaches to senescence induction will further the development of TIS in the clinical treatment of cancer.
Pediatric and adult eosinophilic esophagitis: similarities and differences
Authors: A. Straumann, S. S. Aceves, C. Blanchard, M. H. Collins, G. T. Furuta, I. Hirano, A. M. Schoepfer, D. Simon, H.‐U. Simon
Journal: Allergy (2012)

Abstract Early in the 1990s, several case series described adults suffering from dysphagia and children with refractory reflux symptoms, both accompanied by an eosinophil‐predominant infiltration, thereby conclusively distinguishing it from gastroesophageal reflux disease. Eosinophilic esophagitis ( E o E ) was recognized as its own entity in the adult and in the pediatric literature. In the last decade, evidence has accumulated that E o E represents a T ‐helper ( T h)2‐type inflammatory disease. Remodeling of the esophagus is a hallmark of E o E , leading to esophageal dysfunction and bolus impaction. Familial occurrence and disease association with single‐nucleotide polymorphisms underscore the influence of genetics in this disease. Eosinophilic esophagitis may affect individuals at any age, although the clinical presentation is highly age dependent. There is a significant allergic bias in the E o E population, with the majority of patients having concurrent allergic rhinitis, asthma, eczema, and/or a history of atopy. One noteworthy difference is that in children, E o E seems to be primarily a food antigen–driven disease, whereas in adults, mainly aeroallergen sensitization has been observed. Treatment modalities for E o E include the 3 D s: drugs, diet, and dilation. The crucial question of whether adult and pediatric E o E are different phenotypes of one single entity or whether we are confronted with two different diseases is still open. Here, we review similarities and differences between E o E in adults and children.
A call for clinical reviews
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2013)

This month’s JRSM includes two clinical review articles.1,2 Whilst every medical journal’s ambition is that each article is read, journal editors know that most readers tend to read only a small fraction of what is published. Clinical review and other educational articles are usually popular with clinicians seeking a quick update. For a multispecialty journal like JRSM, review articles help readers stay abreast of best practice and recent developments in other specialties. Indeed, our era of super-specialization presents a greater challenge for clinicians to do so.

Research on learning habits of clinicians tells us that, unsurprisingly, people learn in different ways. Increasingly, clinicians use the Internet to remain up to date and rely on multimedia education, like online video and social media, to overcome the challenges of working in a fast paced, international specialty, with limited time. That doesn’t mean that more traditional forms of learning, like journal articles, are now redundant.

The educational role of any journal is an important one and JRSM will seek to publish more high-quality clinical reviews. Review articles that are published in JRSM may be commissioned but submissions are equally welcome and will be considered for publication. If a submitted review article is thought to be too specialized or too narrow in focus for JRSM, the authors may be redirected to our open access companion journal, JRSM Short Reports. Invariably, whether published in JRSM or JRSM Short Reports, review articles will only be published after peer review and satisfactory revision by the authors.

One of the challenges I have faced as editor of JRSM is how to develop the journal as an independent publication while offering an outlet for many of the excellent educational meetings that are organized at the Royal Society of Medicine each year. Admittedly, the objectives of JRSM don’t necessarily match the objectives of meeting organizers, and nor should they, but the review section of JRSM is an ideal platform to showcase the educational activity hosted by the RSM.

I urge you to take advantage of JRSM’s call for more clinical reviews. Your fellow readers will be grateful.
How Do Social Factors Explain Outcomes in Non–Small-Cell Lung Cancer Among Hispanics in California? Explaining the Hispanic Paradox
Authors: Manali I. Patel, Clayton W. Schupp, Scarlett L. Gomez, Ellen T. Chang, Heather A. Wakelee
Journal: Journal of Clinical Oncology (2013)

Purpose Hispanics in the United States have lower age-adjusted mortality resulting from non–small-cell lung cancer (NSCLC) compared with non-Hispanic whites (NHWs). The purpose of this study was to evaluate individual, clinical, and neighborhood factors in survival among Hispanics with NSCLC. Patients and Methods We performed a retrospective analysis of NHWs and Hispanics with NSCLC between 1998 and 2007 in the California Cancer Registry (follow-up to December 2009). Kaplan-Meier curves depict survival by nativity for Hispanics with NSCLC. Cox proportional hazards models estimated hazard of mortality by race with adjustment for individual (age, sex, marital status), clinical (histologic grade, surgery, irradiation, chemotherapy), and neighborhood factors (neighborhood socioeconomic status, ethnic enclave). Results We included 14,280 Hispanic patients with NSCLC. Foreign-born Hispanics had 15% decreased risk of disease-specific mortality resulting from NSCLC compared with NHWs (hazard ratio [HR], 0.85; 95% CI, 0.83 to 0.88) after adjustment for individual, clinical, and neighborhood factors. After adjustment for individual factors, compared with US-born Hispanics, foreign-born Hispanics had 10% decreased risk of disease-specific mortality (HR, 0.90; 95% CI, 0.87 to 0.96). Clinical and neighborhood factors slightly moderated the survival benefit for foreign-born patients. A modestly more pronounced survival advantage was seen for foreign-born Hispanics living in low socioeconomic and high Hispanic enclave neighborhoods as compared with US-born Hispanics (HR, 0.86; 95% CI, 0.81 to 0.90). Conclusion Foreign-born Hispanics with NSCLC have a decreased risk of disease-specific mortality compared with NHWs and US-born Hispanics with NSCLC. Neighborhood factors slightly moderate this survival advantage. This survival advantage is slightly more pronounced in lower socioeconomic and higher Hispanic enclave neighborhoods.
HDM2 Protein Overexpression and Prognosis in Primary Malignant Melanoma
Authors: D. Polsky
Journal: JNCI Journal of the National Cancer Institute (2002)

Overexpression of the oncogene HDM2 is observed in a substantial proportion of melanomas, including noninvasive and thin lesions, suggesting that HDM2 overexpression may be an early event in melanocyte transformation. To determine the role of HDM2 in the clinical progression of melanoma, we examined whether its expression was associated with patient survival. From November 1972 through November 1982, 134 patients with melanoma who participated in the New York University Melanoma Cooperative Group were studied, if representative tissues and follow-up were available. HDM2 protein expression was assessed immunohistochemically. Unexpectedly, we observed that HDM2 overexpression was statistically significantly associated with improved disease-free survival (relative risk [RR] = 0.47, 95% confidence interval [CI] = 0.24 to 0.89; two-sided chi(2) P =.021) and overall survival (RR = 0.55, 95% CI = 0.33 to 0.94; two-sided chi(2) P =.027) in multivariable analysis. HDM2 overexpression appears to be an independent predictor of survival for patients with primary melanoma; however, larger prospective studies are required for validation.
Language evolution: Two tracks are not enough
Authors: A. Charles Catania
Journal: Behavioral and Brain Sciences (2009)

Abstract This commentary argues that Evans &amp; Levinson (E&amp;L) should expand their two-track model to a three-track model in which biological and cultural evolution interact with the evolution of an individual's language repertories in ontogeny. It also comments on the relevance of the argument from the poverty of the stimulus and offers a caveat, based on analogous issues in biology, on the metaphor of language as a container, whether of meanings or of other content.
A Fully Synthetic Therapeutic Vaccine Candidate Targeting Carcinoma-Associated Tn Carbohydrate Antigen Induces Tumor-Specific Antibodies in Nonhuman Primates
Authors: Richard Lo-Man, Sophie Vichier-Guerre, Ronald Perraut, Edith Dériaud, Valérie Huteau, Lbachir BenMohamed, Ousmane M. Diop, Philip O. Livingston, Sylvie Bay, Claude Leclerc
Journal: Cancer Research (2004)

Abstract We recently developed an efficient strategy based on a fully synthetic dendrimeric carbohydrate display (multiple antigenic glycopeptide; MAG) to induce anticarbohydrate antibody responses for therapeutic vaccination against cancer. Here, we show the superior efficacy of the MAG strategy over the traditional keyhole limpet hemocyanin glycoconjugate to elicit an anticarbohydrate IgG response against the tumor-associated Tn antigen. We highlight the influence of the aglyconic carrier elements of such a tumor antigen for their recognition by the immune system. Finally, we additionally developed the MAG system by introducing promiscuous HLA-restricted T-helper epitopes and performed its immunological evaluation in nonhuman primates. MAG:Tn vaccines induced in all of the animals strong tumor-specific anti-Tn antibodies that can mediate antibody-dependent cell cytotoxicity against human tumor. Therefore, the preclinical evaluation of the MAG:Tn vaccine demonstrates that it represents a safe and highly promising immunotherapeutic molecularly defined tool for targeting breast, colon, and prostate cancers that express the carbohydrate Tn antigen.
Orientation and presence of epithelium are key to endotoxin-induced neutrophil migration
Authors: FM Peralta, TB Casale
Journal: European Respiratory Journal (1998)

The mechanisms by which endotoxins mediate neutrophil transepithelial migration and lung inflammation are unclear. It was hypothesized that both the presence and orientation of epithelial cells are critical to endotoxin-induced neutrophil migration. Neutrophil migration was compared through naked filters and filters with A549 lung epithelial monolayers grown on the upper and lower surface of permeable filters to simulate the apical and basal directional movement of neutrophils, respectively. The endotoxin, Pseudomonas aeruginosa lipopolysaccharide, was placed below the filter, acting as either a basal or an apical stimulus. Endotoxin without serum failed to stimulate neutrophil migration. In the presence of 1% human serum, endotoxin-induced neutrophil migration through naked filters was dose dependent. Endotoxin-induced neutrophil migration across A549 monolayers was minimal when the monolayers were cultured on the upper surface of the filters (basal stimulus). In contrast, neutrophil transepithelial migration was much greater and dependent on both dose and time when the monolayer was cultured on the lower surface of the filter (basal to apical neutrophil directional movement). Furthermore, enhanced neutrophil transepithelial migration was greater with an apical than with a basal stimulus. Endotoxin-induced neutrophil transepithelial migration was markedly inhibited (&gt;95%) by actinomycin D pretreatment of the monolayers, suggesting the necessity for intact protein synthesis capacity of the A549 cells. Thus, both the presence and orientation of airway epithelium are key in supporting endotoxin-mediated lung neutrophilic responses.
UG and acquisition in pidginization and creolization
Authors: Michel DeGraff
Journal: Behavioral and Brain Sciences (1996)

Abstract I examine the target articles hypothesis in light of pidginization and creolization (P/C) phenomena. L 1 -to-L 2 transfer has been argued to be the “central process” in P/C via relexification. This seems incompatible with the view that UC sans Li plays the central role in L2A. I sketch a proposal that reconciles the hypothesis in the target article with, inter alia, the effects of transfer in P/C.
Mechanisms of escape from desmopressin in the rat.
Authors: P A Gross, J K Kim, R J Anderson
Journal: Circulation Research (1983)

The mechanism(s) of renal escape from the hydro-osmotic effect of vasopressin is unknown. We therefore studied escape in conscious, unrestrained rats receiving continuous intravascular infusions of 1-deamino-8-arginine-vasopressin (desmopressin) and hypotonic fluid over 5 days. Escape from desmopressin started 8 hours after exposure and was characterized by a progressive increase in urine flow and decreases in urine osmolality and free water reabsorption. When positive water balance was prevented by matching the rate of infusion of hypotonic fluid to urine flow while maintaining the dose of desmopressin constant, escape did not occur. This suggested that water retention, rather than chronic exposure to desmopressin, mediated the escape. To elucidate the mechanism whereby water retention induces escape from desmopressin, urinary prostaglandin E2 excretion was measured and found to be increased concomitant with the onset of escape. Prevention of this increase in urinary prostaglandin E2 excretion with indomethacin resulted in additional water retention and a delay in the onset of escape. During the maintenance of escape, after significant water retention occurred, increases in mean arterial pressure, renal blood flow, and glomerular filtration rate were observed. Renal interstitial solute concentration remained constant through escape. Basal and vasopressin-stimulated collecting tubular and thick ascending limb adenylate cyclase did not differ when control and escape animals were compared. These results suggest that enhanced renal synthesis of prostaglandin E2 facilitates the early phase of escape; later, water retention results in plasma volume expansion with increases in cardiac index, arterial pressure, renal blood flow, and glomerular filtration rate. These systemic and renal hemodynamic alterations may be important in maintaining escape from desmopressin.
Atherogenic Dyslipidemia in HIV-Infected Individuals Treated With Protease Inhibitors
Authors: Daniel Périard, Amalio Telenti, Philippe Sudre, Jean-Jacques Cheseaux, Patricia Halfon, Marianne J. Reymond, Santica M. Marcovina, Michel P. Glauser, Pascal Nicod, Roger Darioli, Vincent Mooser
Journal: Circulation (1999)

Administration of protease inhibitors (PIs) to HIV-infected individuals has been associated with hyperlipidemia. In this study, we characterized the lipoprotein profile in subjects receiving ritonavir, indinavir, or nelfinavir, alone or in combination with saquinavir.Plasma lipoprotein levels were quantified in 93 HIV-infected adults receiving PIs. Comparison was done with pretreatment values and with 28 nonPI-treated HIV-infected subjects. An elevation in plasma cholesterol levels was observed in all PI-treated groups but was more pronounced for ritonavir (2.0+/-0.3 mmol/L [mean+/-SEM], n=46, versus 0.1+/-0.2 mmol/L in nonPI treated group, P<0.001) than for indinavir (0.8+/-0.2 mmol/L, n=26, P=0.03) or nelfinavir (1.2+/-0.2 mmol/L, n=21, P=0.01). Administration of ritonavir, but not indinavir or nelfinavir, was associated with a marked elevation in plasma triglyceride levels (1.83+/-0.46 mmol/L, P=0.002). Plasma HDL-cholesterol levels remained unchanged. Combination of ritonavir or nelfinavir with saquinavir did not further elevate plasma lipid levels. A 48% increase in plasma levels of lipoprotein(a) was detected in PI-treated subjects with pretreatment Lp(a) values >20 mg/dL. Similar changes in plasma lipid levels were observed in 6 children receiving ritonavir.Administration of PIs to HIV-infected individuals is associated with a marked, compound-specific dyslipidemia. The risk of pancreatitis and premature atherosclerosis due to PI-associated dyslipidemia remains to be established.
Kidney-Derived Stromal Cells Modulate Dendritic and T Cell Responses
Authors: Yanfei Huang, Peter Johnston, Borui Zhang, Asif Zakari, Tayseer Chowdhry, Rachel Ruckdeschel Smith, Eduardo Marbán, Hamid Rabb, Karl L. Womer
Journal: Journal of the American Society of Nephrology (2009)

Multipotent mesenchymal stromal cells from the bone marrow ameliorate acute kidney injury through a mechanism other than transdifferentiation into renal tissue. Stromal cells exert immunoregulatory effects on dendritic and T cells, both of which are important in the pathophysiology of immune-mediated kidney injury. We hypothesized that similar cells with immunoregulatory function exist within the adult kidney. We isolated murine kidney-derived cells with morphologic features, growth properties, and an immunophenotype characteristic of mesenchymal stromal cells. These cells lacked lineage markers and could be differentiated into mesodermal cell lineages, including osteocytes and adipocytes. Furthermore, these kidney-derived cells induced the generation of bone marrow-derived dendritic cells with significantly reduced MHC II expression, increased CD80 expression, increased IL-10 production and the inability to stimulate CD4+ T cell proliferation in allogeneic and nominal antigen-specific cultures. Experiments in mixed and transwell cultures demonstrated that the production of soluble immune modulators, such as IL-6, was responsible for these effects on dendritic cell differentiation and maturation. Contact-dependent mechanisms, however, inhibited mitogenic T cell proliferation. In summary, kidney-derived cells may suppress inflammation in the kidney in vivo; a better understanding of their biology could have therapeutic implications in a wide variety of immune-mediated kidney diseases.
Crohn's disease of the stomach and duodenum
Authors: J. F. Fielding, D. K. M. Toye, D. C. Beton, W. T. Cooke
Journal: Gut (1970)

Clinical and radiological abnormalities in 12 patients with gastroduodenal involvement were encountered amongst 300 patients followed by one of us between 1944 and 1969. Symptoms of dyspepsia were relatively mild and obstructive symptoms when present were readily relieved by bypass surgery. The patients have been followed for a mean of 9·7 years (range 1-20); two have died of other causes but the remaining 10 are well.
Metformin in Cancer Treatment and Prevention
Authors: Daniel R. Morales, Andrew D. Morris
Journal: Annual Review of Medicine (2014)

Patients with diabetes mellitus are at increased risk of cancer development. Metformin is a well-established, effective agent for the management of type 2 diabetes mellitus. Epidemiological studies have identified an association between metformin use and a beneficial effect on cancer prevention and treatment, which has led to increasing interest in the potential use of metformin as an anticancer agent. Basic science has provided a better understanding of the mechanism of action of metformin and the potential for metformin to modulate molecular pathways involved in cancer cell signaling and metabolism. This article outlines the link between metformin and cancer, the potential for metformin in oncology, and limitations of currently available evidence.