tbuckley/cabot-search huggingface dataset:
Chemotherapy of Cancer
Authors: Thomas C. Hall
Journal: New England Journal of Medicine (1962)

THE introduction of potassium arsenite, or Fowler's solution, by Lissauer, at the suggestion of Rosencrantz1 in 1865 for the treatment of leukemia is usually considered the first successful attempt at cancer chemotherapy. The basic principles of chemotherapy were set down in the early twentieth century by Ehrlich. He also introduced the concepts of haptophore and toxophil to explain specific binding of drug by sites within the cell (Fig. 1) and in 1904 cured trypanosomiasis in rodents with a synthetic dye, trypan red, this being the first successful attempt at chemotherapy with a synthetic drug.2 Until increased knowledge of the intermediary . . .
Severe Acute Pancreatitis
Authors: Vege Santhi Swaroop
Journal: JAMA (2004)

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TAM Receptor Signaling in Immune Homeostasis
Authors: Carla V. Rothlin, Eugenio A. Carrera-Silva, Lidia Bosurgi, Sourav Ghosh
Journal: Annual Review of Immunology (2015)

The TAM receptor tyrosine kinases (RTKs)—TYRO3, AXL, and MERTK—together with their cognate agonists GAS6 and PROS1 play an essential role in the resolution of inflammation. Deficiencies in TAM signaling have been associated with chronic inflammatory and autoimmune diseases. Three processes regulated by TAM signaling may contribute, either independently or collectively, to immune homeostasis: the negative regulation of the innate immune response, the phagocytosis of apoptotic cells, and the restoration of vascular integrity. Recent studies have also revealed the function of TAMs in infectious diseases and cancer. Here, we review the important milestones in the discovery of these RTKs and their ligands and the studies that underscore the functional importance of this signaling pathway in physiological immune settings and disease.
The specific binding of peptide ligand to Ld class I major histocompatibility complex molecules determines their antigenic structure.
Authors: W R Lie, N B Myers, J M Connolly, J Gorka, D R Lee, T H Hansen
Journal: The Journal of Experimental Medicine (1991)

To better understand the biological implications of the association of ligand with major histocompatibility complex class I molecules, we have studied the Ld molecule of the mouse. The culturing of various nonselected cell lines with three different known Ld peptide ligands resulted in a two- to fourfold specific increase in surface Ld expression as detected by 10 of 11 different monoclonal antibodies (mAbs) recognizing Ld epitopes. These findings suggest that Ld molecules are not saturated with endogenous peptide ligands and thus have accessible binding sites. Exploiting this feature of Ld we demonstrate that the physical association of Ld with ligand is exquisitely specific, indicating that they function in determinant selection. In addition, a non-peptide-bound antigenic variant of Ld was specifically detected with an exceptional mAb designated 64-3-7. In comparison with other Ld molecules, 64-3-7+ Ld molecules are not peptide ligand inducible, are more susceptible to proteolysis, lack beta 2 microglobulin association, and display a slower rate of oligosaccharide maturation. In spite of their deficiencies, the non-ligand-associated 64-3-7 Ld molecules were detected on the surface of all cell types tested; however, they appear not to be recognized by alloreactive cytotoxic T lymphocytes.
Computed Axial Tomography Scans, Calories, and Computers
Authors: Surya P. Bhatt, Gaurav Kumar, Boulos S. Nassar
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Low-dose computed tomography (LDCT) has shown promise in the early detection of lung cancer in prior observational studies. The National Lung Screening Trial (NLST) is the largest multicenter, randomized, controlled trial comparing LDCT with chest radiography with an intention-to-screen analysis (1). High-risk (.30 pack-years) active or ex-smokers between 55 and 74 years of age (n 1⁄4 53,454) were screened three times at 1-year intervals and followed for a median of 6.5 years. Lesions suspicious for cancer (noncalcified nodules . 4 mm) were found in 39.1% of individuals with LDCT and 16.0% with radiography during the trial. A total of 96.4% of these lesions in the LDCT group and 94.5% in the radiography group were false-positive results. The LDCT group had 247 deaths from lung cancer per 100,000 person-years and the radiography group had 309 deaths per 100,000 person-years. This meant a 20% (95% CI, 6.8–26.7; P 1⁄4 0.004) relative reduction in mortality from lung cancer, and a 6.7% (95% CI, 1.2–13.6; P 1⁄4 0.02) reduction in all-cause mortality with LDCT screening. Of the 17,053 LDCT lesions suspicious for cancer in which cancer was not confirmed, 457 (2.7%) resulted in an invasive procedure, with 11 (0.06%) major complications. Multiple unanswered questions regarding lung cancer screening remain. First, this study was done at large centers of excellence, with potentially different results at smaller hospitals. Second, 1,060 individuals in the LDCT and 941 in the radiography group were found to have lung cancer, suggesting the possibility of overdiagnosis with LDCT (2). Are there individuals who die with, rather than from, lung cancer (3)? Third, the implications for smoking cessation are unclear. Smokers might use screening as a tool to continue smoking. Alternatively, a positive screening test might also induce smokers to quit. Last, there are unanswered questions about the optimal demographic group to screen (age, sex, and smoking history), frequency and duration of screening, risks of increasing radiation exposure, risks of false-positive tests, and cost. The number of LDCT screening tests needed to prevent one lung cancer death was 320. I believe this study should not inform health policy decision making until these questions are better answered.
Single-nutrient effects on immunologic functions. Report of a workshop sponsored by the Department of Food and Nutrition and its nutrition advisory group of the American Medical Association
Authors: W. R. Beisel
Journal: JAMA (1981)

Immune system dysfunction can result from single-nutrient deficiencies or excesses, alone or in combination with generalized protein-energy malnutrition. Acquired immune dysfunctions in man occur with deficiencies of iron, zinc, vitamins A and B<sub>12</sub>, pyridoxine, and folic acid and with excesses of essential fatty acids and vitamin E. Additional micronutrients are important for maintaining immunologic competence in animals. Deficits or excesses of many trace elements and single nutrients thus have potential for causing immune dysfunctions in man. Since nutritionally induced immune dysfunction is generally reversible, it is important to recognize and identify clinical illnesses in which immunologic dysfunctions are of nutritional origin. Correction of malnutrition should lead to prompt reversal of acquired immune dysfunctions. (<i>JAMA</i>1981;245:53-58)
Insulin Reduces Plasma Arginase Activity in Type 2 Diabetic Patients
Authors: Sangeeta R. Kashyap, Abigail Lara, Renliang Zhang, Young Mi Park, Ralph A. DeFronzo
Journal: Diabetes Care (2007)

OBJECTIVE—We sought to determine whether dysregulation of arginine metabolism is related to insulin resistance and underlies impaired nitric oxide (NO) generation in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—We measured plasma arginase activity, arginine metabolites, and skeletal muscle NO synthase (NOS) activity in 12 type 2 diabetic and 10 age-/BMI-matched nondiabetic subjects before and following a 4-h euglycemic-hyperinsulinemic clamp with muscle biopsies. Arginine metabolites were determined by tandem mass spectroscopy. Arginase activity was determined by conversion of [14C] guanidoinoarginine to [14C] urea. RESULTS—Glucose disposal (Rd) was reduced by 50% in diabetic versus control subjects. NOS activity was fourfold reduced in the diabetic group (107 ± 45 vs. 459 ± 100 pmol · min−1 · mg protein−1; P &amp;lt; 0.05) and failed to increase with insulin. Plasma arginase activity was increased by 50% in the diabetic versus control group (0.48 ± 0.11 vs. 0.32 ± 0.12 μmol · ml−1 · h−1; P &amp;lt; 0.05) and markedly declined in diabetic subjects with 4-h insulin infusion (to 0.13 ± 0.04 μmol · ml−1 · h−1 vs. basal; P &amp;lt; 0.05). In both groups collectively, plasma arginase activity correlated positively with fasting plasma glucose (R = 0.46, P &amp;lt; 0.05) and A1C levels (R = 0.51, P &amp;lt; 0.02) but not with Rd. CONCLUSIONS—Plasma arginase activity is increased in type 2 diabetic subjects with impaired NOS activity, correlates with the degree of hyperglycemia, and is reduced by physiologic hyperinsulinemia. Elevated arginase activity may contribute to impaired NO generation in type 2 diabetes, and insulin may ameliorate this defect via reducing arginase activity.
Can overweight/obesity and smoking have combined effects on bronchial hyperresponsiveness?
Authors: B. Sposato, M. Scalese
Journal: European Respiratory Journal (2014)

We wish to thank R.J. Kurukulaaratchy and co-workers for their positive response to our article [1].We were happy to see that our paper encouraged the Isle of Wight Birth Cohort (IOWBC) to assess the prognosis of early recurrent wheeze into the beginning adulthood.As the corresponding findings in the IOWBC, with its high 18-year follow-up rate of 90% [2], are in line with those from our Environment and Childhood Asthma Study, it strengthens the message that the longer term prognosis of early recurrent wheeze might not be as favourable as previously conceived [3, 4].Furthermore, the findings underline the importance of long-running birth cohorts enabling studies where recall bias is limited.As recent retrospective reports suggest that adult chronic obstructive pulmonary disease may have an early-life origin [5, 6], the need for long-term prospective cohorts to address this specific question is obvious.With the additional data now presented by R.J. Kurukulaaratchy and co-workers on the natural course of early life wheeze, we suggest a reconsideration of the possibility of diagnosing asthma in preschool children as well as caution when addressing the potential favourable long-term prognosis of early recurrent wheezy illness.
Modulation of Food Intake by Glucose in Patients With Type 2 Diabetes
Authors: Bernd Schultes, Achim Peters, Manfred Hallschmid, Christian Benedict, Volker Merl, Kerstin M. Oltmanns, Jan Born, Horst L. Fehm, Werner Kern
Journal: Diabetes Care (2005)

OBJECTIVE—A gain in body weight is a common adverse effect of glucose-lowering therapies in patients with type 2 diabetes, the mechanisms of which are not completely understood. Blood glucose is considered to play a crucial role in the regulation of food intake. On this background, we hypothesized that a short-term reduction of blood glucose concentration to normal values acutely increases food intake in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—To test this hypothesis, 12 patients with type 2 diabetes were examined twice, once during a euglycemic (5.0 mmol/l) clamp experiment and another time during a hyperglycemic (10.5 mmol/l) clamp. The experiments were performed in a single-blind fashion with the order of conditions balanced across patients. On both clamp conditions, insulin was infused at a constant rate of 2.5 mU/kg per min for 125 min. Simultaneously, a glucose solution was infused at a variable rate to achieve target glycemic levels. During the final 30 min of the clamps, the patients were allowed to eat as much as they liked from a standard breakfast buffet. RESULTS—Compared with the hyperglycemic condition, the patients ingested on average 25 ± 10% more energy during euglycemia (645 ± 75 vs. 483 ± 37 kcal; P = 0.029). The increased energy intake during euglycemia was equally distributed across macronutrient components, i.e., during euglycemia the patients ate more carbohydrates (+27.1 ± 11.4%; P = 0.037), fat (+22.5 ± 10.0%; P = 0.046), and proteins (+25.2 ± 11.2%; P = 0.046) than during hyperglycemia. Circulating levels of insulin, amylin, leptin, ghrelin, and glucagon-like peptide-1 did not differ between the euglycemic and hyperglycemia clamp, excluding a major contribution of these hormones to the difference in food intake. Summing up the glucose administered intravenously and the food ingested yielded a remarkably similar total energy influx in both conditions (794 ± 64 vs. 790 ± 53 kcal; P = 0.961). CONCLUSIONS—Together our data suggest that total energy supply to the organism is tightly regulated on a short-term basis independent of the route of influx. Alternatively, it can be hypothesized that euglycemia stimulated or that hyperglycemia suppressed food intake at the subsequent buffet meal in our type 2 diabetic patients. Regardless of these different interpretations, our data indicate an important regulatory role of glucose for food intake in type 2 diabetic patients that is of considerable clinical relevance.
Improved Glycemic Control Without Weight Gain Using Triple Therapy in Type 2 Diabetes
Authors: Suzanne M. Strowig, M. Larissa Avilés-Santa, Philip Raskin
Journal: Diabetes Care (2004)

OBJECTIVE—To evaluate the safety and effectiveness of triple therapy using insulin, metformin, and a thiazolidinedione following a course of dual therapy using insulin and metformin or insulin and a thiazolidinedione in type 2 diabetes. RESEARCH DESIGN AND METHODS—Twenty-eight type 2 diabetic subjects using insulin monotherapy (baseline HbAlc level 8.5%) who had been randomly assigned to insulin (INS) and metformin (MET) (INS + MET, n = 14) or INS and the thiazolidinedione troglitazone (TGZ) (INS + TGZ, n = 14) (dual therapy) for 4 months were given INS, MET, and TGZ (triple therapy: INS + MET, add TGZ; or INS + TGZ, add MET) for another 4 months. The INS dose was not increased. RESULTS—HbA1c levels decreased in both groups during dual therapy and improved further during triple therapy (INS + MET 7.0 ± 0.8, INS + TGZ 6.2 ± 0.8, P &amp;lt; 0.0001; INS + MET, add TGZ 6.1 ± 0.4%, P &amp;lt; 0.001; INS + TGZ, add MET 5.8 ± 0.6%, P &amp;lt; 0.05; and INS + TGZ vs. INS + MET, P = 0.02). Significant reductions in total daily insulin dose occurred in the INS + TGZ (−14.1 units, P &amp;lt; 0.0001), INS + TGZ add MET (−13.7 units, P &amp;lt; 0.01), and the INS + MET add TGZ groups (−17.3 units, P &amp;lt; 0.003), but not in the INS + MET group (−3.2 units) (INS + TGZ vs. INS + MET P &amp;lt; 0.05). Subjects in the INS + TGZ group experienced significant weight gain (4.4 ± 2.7 kg, P &amp;lt; 0.0005). No weight gain occurred in the INS + MET, INS + MET add TGZ, and INS + TGZ add MET groups. CONCLUSIONS—Triple therapy using INS, MET, and TGZ resulted in lower HbAlc levels and total daily insulin dose than during dual therapy. The use of triple therapy resulted in 100% of subjects achieving an HbAlc &amp;lt;7.0%, while decreasing the dose of INS. Weight gain was avoided when MET therapy preceded the addition of TGZ therapy. The addition of TGZ resulted in the greatest reductions in HbAlc levels and insulin dose. Triple therapy using INS, MET, and a thiazolidinedione (such as TGZ) can be a safe and effective treatment in type 2 diabetes.
Tumor necrosis factor-α induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes
Authors: W Song
Journal: Cardiovascular Research (2000)

Objective: It has been demonstrated that tumor necrosis factor-α (TNFα) induces apoptosis in cardiac myocytes. However, its mechanism of action is still not well understood. In the present study, we hypothesized that TNFα induces myocardial apoptosis by induction of inducible nitric oxide synthase (iNOS). Methods: Neonatal cardiac myocytes were isolated from iNOS (−/−) mutant and C57BL6 wild type mice. Cells were cultured for 3 days before treatment with an NO donor or TNFα. Following treatment with S-nitroso-N-acetyl-penicillamine (SNAP) or TNF-α, cells were tested for apoptosis by terminal deoxynucleotidyl transfer-mediated end labeling (TUNEL) staining and cell death detection ELISA. NO production was measured by nitrite concentration in the culture medium. Cardiomyocyte expression of iNOS and TNF type 1 receptor (TNFR1) mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Results: SNAP (0.01–100 μM) induced apoptosis of cardiac myocytes in a concentration-dependent manner in the wild type mice (n=5, P<0.01). TNFR1 mRNA was expressed in neonatal cardiomyocytes from both wild type and iNOS (−/−) mutant mice. TNFα induced a concentration-dependent increase in iNOS mRNA expression and nitrite production as well as significant apoptosis of cardiomyocytes in the wild type mice (n=4, P<0.01). However, without iNOS expression, the apoptotic effects of TNF-α were significantly attenuated in cardiomyocytes from iNOS (−/−) mutant mice (n=4, P<0.05). Conclusion: TNFα induces apoptosis via iNOS expression and NO production in neonatal mouse cardiomyocytes.
Novel Pheochromocytoma Susceptibility Loci Identified by Integrative Genomics
Authors: Patricia L.M. Dahia, Ke Hao, John Rogus, Christian Colin, Miguel A.G. Pujana, Ken Ross, Danielle Magoffin, Neil Aronin, Alberto Cascon, César Y. Hayashida, Cheng Li, Sérgio P.A. Toledo, Charles D. Stiles
Journal: Cancer Research (2005)

Abstract Pheochromocytomas are catecholamine-secreting tumors that result from mutations of at least six different genes as components of distinct autosomal dominant disorders. However, there remain familial occurrences of pheochromocytoma without a known genetic defect. We describe here a familial pheochromocytoma syndrome consistent with digenic inheritance identified through a combination of global genomics strategies. Multipoint parametric linkage analysis revealed identical LOD scores of 2.97 for chromosome 2cen and 16p13 loci. A two-locus parametric linkage analysis produced maximum LOD score of 5.16 under a double recessive multiplicative model, suggesting that both loci are required to develop the disease. Allele-specific loss of heterozygosity (LOH) was detected only at the chromosome 2 locus in all tumors from this family, consistent with a tumor suppressor gene. Four additional pheochromocytomas with a similar genetic pattern were identified through transcription profiling and helped refine the chromosome 2 locus. High-density LOH mapping with single nucleotide polymorphism–based array identified a total of 18 of 62 pheochromocytomas with LOH within the chromosome 2 region, which further narrowed down the locus to &amp;lt;2 cM. This finding provides evidence for two novel susceptibility loci for pheochromocytoma and adds a recessive digenic trait to the increasingly broad genetic heterogeneity of these tumors. Similarly, complex traits may also be involved in other familial cancer syndromes.
Profilin-1 suppresses tumorigenicity in pancreatic cancer through regulation of the SIRT3-HIF1α axis
Authors: Wantong Yao, Shunrong Ji, Yi Qin, Jingxuan Yang, Jin Xu, Bo Zhang, Wenyan Xu, Jiang Liu, Si Shi, Liang Liu, Chen Liu, Jiang Long, Quanxing Ni, Min Li, Xianjun Yu
Journal: Molecular Cancer (2014)

Tumor cells exhibit abnormal actin remodeling profiles, which involve the altered expressions of several important actin-binding proteins. Profilin1 (Pfn1), originally identified as an actin-associated protein, has been linked to several human malignancies. Our recent studies suggested that Pfn1 facilitates apoptosis in pancreatic cancer cells. Here, we investigated the exact role of Profilin1 (Pfn1) in pancreatic adenocarcinoma (PDAC) and the underlying mechanisms. Pfn1 protein expression in PDAC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing PDAC tumor tissue and corresponding normal tissue samples from 72 patients. The effect of Pfn1 expression on cancer proliferation was assessed in cells by up- and down-regulation of Pfn1 in vitro and in vivo. Immunoprecipitation and mass spectrometry were used to identify the Pfn1-associated proteins and potential pathways. Pfn1 was downregulated in clinical pancreatic adenocarcinoma specimens compared with the surrounding benign tissues. Univariate survival analysis of the PDAC cohorts showed that low expression of Pfn1 was significantly correlated with shortened patient survival (mean 14.2 months versus 20.9 months, P < 0.05). Restoration of Pfn1 in pancreatic cancer cells with low endogenous Pfn1 expression resulted in a nontumorigenic phenotype, suggesting that Pfn1 may be a negative regulator of pancreatic cancer progression. Overexpression of Pfn1 in vivo decreased the tumor volume in orthotopic xenograft nude mice models. Pfn1 upregulated the expression of SIRT3, leading to HIF1α destabilization. This data revealed that aberrant Pfn1 expression contributes to pancreatic cancer progression. Our data suggest that Pfn1 is a tumor suppressor in pancreatic cancer that acts via a novel mechanism of regulating the SIRT3-HIF1α axis, independently of its cytoskeleton-related activity.