tbuckley/cabot-search huggingface dataset:
Phase I and Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin in Adult Patients with Refractory Advanced Cancers
Authors: Ramesh K. Ramanathan, Merrill J. Egorin, Julie L. Eiseman, Suresh Ramalingam, David Friedland, Sanjiv S. Agarwala, S. Percy Ivy, Douglas M. Potter, Gurkamal Chatta, Eleanor G. Zuhowski, Ronald G. Stoller, Cynthia Naret, Jianxia Guo, Chandra P. Belani
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week. Experimental Design: Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly × 3 weeks, every 4 weeks) were 100, 125, 150, 175, and 200 mg/m2 and for schedule B (twice weekly × 2 weeks, every 3 weeks) were 150, 200, and 250 mg/m2. Peripheral blood mononuclear cells (PBMC) were collected for assessment of heat shock protein (HSP) 90 and HSP90 client proteins. Results: Forty-four patients were enrolled, 32 on schedule A and 12 on schedule B. On schedule A at 200 mg/m2, DLTs were seen in two of six patients (one grade 3 thrombocytopenia and one grade 3 abdominal pain). On schedule B, both patients treated at 250 mg/m2 developed DLT (grade 3 headache with nausea/vomiting). Grade 3/4 toxicities seen in &amp;gt;5% of patients were reversible elevations of liver enzymes (47%), nausea (9%), vomiting (9%), and headache (5%). No objective tumor responses were observed. The only consistent change in PBMC proteins monitored was a 0.8- to 30-fold increase in HSP70 concentrations, but these were not dose dependent. The increase in PBMC HSP70 persisted throughout the entire cycle of treatment but returned to baseline between last 17AAG dose of cycle 1 and first 17AAG dose of cycle 2. Conclusions: The recommended phase II doses of 17AAG are 175 to 200 mg/m2 when given twice a week and consistently cause elevations in PBMC HSP70.
Radiofrequency catheter ablation of left lateral accessory pathways via the coronary sinus.
Authors: M Haissaguerre, F Gaita, B Fischer, P Egloff, P Lemetayer, J F Warin
Journal: Circulation (1992)

The purpose of this study was to describe a new technique for catheter ablation of left lateral accessory pathways (APs) by radiofrequency energy applied at the epicardium through the coronary sinus wall using a unipolar configuration.In an overall group of 212 patients with left lateral APs, multiple endocardial ablation attempts of the AP were unsuccessful in eight patients. The mean +/- SD cumulative duration of previous attempts was 12 +/- 9 hours, using DC shocks and/or radiofrequency energy applied both at the atrial and/or ventricular AP insertions. Epicardial AP insertion was determined by bipolar and unipolar unfiltered distal electrograms by scanning the coronary sinus with a steerable 6F or 7F catheter with a 4-mm distal electrode. The local atrial to ventricular electrogram amplitude ratio was 0.3-1.6. At the ablation site, the catheter tip was slightly deflected toward the annulus to increase both the ventricular component of electrograms and contact with the epicardium. In four patients, epicardial electrogram timings were earlier than endocardial ones. The AP was ablated in seven of the eight patients with 20-30 W applied for 10-60 seconds. No complications occurred except a marked nonspecific pain during radiofrequency energy application; however, the catheter remained adherent to the coronary sinus wall, and its withdrawal was performed during a new radiofrequency application to decrease the risk of coronary sinus rupture. After ablation, echocardiograms, coronary artery angiograms, and levophase coronary sinus angiograms showed no abnormality in all patients except two who had a probable mural thrombus in the coronary sinus. AP conduction remained abolished for 1-10 months of follow-up in seven patients.Radiofrequency catheter ablation of left lateral APs can be achieved effectively and relatively safely via the mid or distal coronary sinus when endocardial approaches are unsuccessful.
Noninvasive Detection of Prostate Cancer by Quantitative Analysis of Telomerase Activity
Authors: Galina I. Botchkina, Roger H. Kim, Inna L. Botchkina, Alex Kirshenbaum, Zelik Frischer, Howard L. Adler
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Prostate cancer is the most common male malignancy and the second leading cause of male cancer death; therefore, there is urgent necessity for noninvasive assays for early detection of prostate cancer. Obtaining prostate tumor samples surgically is problematic because the malignancy is heterogeneous and multifocal and early-stage tumors are nonpalpable. In contrast, exfoliated cells represent the cancer status of the entire gland better due to the general tendency of cancer cells to exfoliate into biological fluids. The purpose of this study was to clarify whether quantitative analysis of telomerase activity in exfoliated cells in urine could serve as a reliable molecular marker of prostate malignancy. Experimental Design: We analyzed prospectively post-prostatic examination–exfoliated cells from the urine of 56 patients undergoing routine prostate screening. Epithelial cells were isolated and enriched by immunomagnetic separation. Telomerase activity was analyzed by quantitative real-time PCR telomeric-repeat amplification protocol assay using Opticon MJ research instrument. Results: We report now that all prostate cancer patients revealed high levels of telomerase activity thereby showing 100% of the assay sensitivity. In contrast, the majority of patients with clinically confirmed benign prostatic hyperplasia (BPH) did not express any telomerase activity (70% of all BPH patients), most likely presenting cancer-free cases, or expressed low levels of activity (18%). However, about 12% of BPH patients revealed high levels of telomerase activity that potentially can reflect hidden prostate cancer. Conclusions: We suggest that the quantitative analysis of telomerase activity can be useful for the selection of prostate cancer and cancer-free cases.
Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning
Authors: Wolfgang A. Bethge, Ute Hegenbart, Monic J. Stuart, Barry E. Storer, Michael B. Maris, Mary E. D. Flowers, David G. Maloney, Thomas Chauncey, Benedetto Bruno, Ed Agura, Stephen J. Forman, Karl G. Blume, Dietger Niederwieser, Rainer Storb, Brenda M. Sandmaier
Journal: Blood (2003)
Distinct Luminal-Type Mammary Carcinomas Arise from Orthotopic <i>Trp53</i>-Null Mammary Transplantation of Juvenile versus Adult Mice
Authors: David H. Nguyen, Haoxu Ouyang, Jian-Hua Mao, Lynn Hlatky, Mary Helen Barcellos-Hoff
Journal: Cancer Research (2014)

Age and physiologic status, such as menopause, are risk factors for breast cancer. Less clear is what factors influence the diversity of breast cancer. In this study, we investigated the effect of host age on the distribution of tumor subtypes in mouse mammary chimera consisting of wild-type hosts and Trp53 nullizygous epithelium, which undergoes a high rate of neoplastic transformation. Wild-type mammary glands cleared of endogenous epithelium at 3 weeks of age were subsequently transplanted during puberty (5 weeks) or at maturation (10 weeks) with syngeneic Trp53-null mammary tissue fragments and monitored for one year. Tumors arose sooner from adult hosts (AH) compared with juvenile hosts (JH). However, compared with AH tumors, JH tumors grew several times faster, were more perfused, exhibited a two-fold higher mitotic index, and were more highly positive for insulin-like growth factor receptor phosphorylation. Most tumors in each setting were estrogen receptor (ER)-positive (80% JH vs. 70% AH), but JH tumors were significantly more ER-immunoreactive (P = 0.0001) than AH tumors. A differential expression signature (JvA) of juvenile versus adult tumors revealed a luminal transcriptional program. Centroids of the human homologs of JvA genes showed that JH tumors were more like luminal A tumors and AH tumors were more like luminal B tumors. Hierarchical clustering with the JvA human ortholog gene list segregated luminal A and luminal B breast cancers across datasets. These data support the notion that age-associated host physiology greatly influences the intrinsic subtype of breast cancer.
Human Dendritic Cells Activate Resting Natural Killer (NK) Cells and Are Recognized via the NKp30 Receptor by Activated NK Cells
Authors: Guido Ferlazzo, Ming L. Tsang, Lorenzo Moretta, Giovanni Melioli, Ralph M. Steinman, Christian Münz
Journal: The Journal of Experimental Medicine (2002)

During the innate response to many inflammatory and infectious stimuli, dendritic cells (DCs) undergo a differentiation process termed maturation. Mature DCs activate antigen-specific naive T cells. Here we show that both immature and mature DCs activate resting human natural killer (NK) cells. Within 1 wk the NK cells increase two– to fourfold in numbers, start secreting interferon (IFN)-γ, and acquire cytolytic activity against the classical NK target LCL721.221. The DC-activated NK cells then kill immature DCs efficiently, even though the latter express substantial levels of major histocompatibility complex (MHC) class I. Similar results are seen with interleukin (IL)-2–activated NK cell lines and clones, i.e., these NK cells kill and secrete IFN-γ in response to immature DCs. Mature DCs are protected from activated NK lysis, but lysis takes place if the NK inhibitory signal is blocked by a human histocompatibility leukocyte antigen (HLA)-A,B,C–specific antibody. The NK activating signal mainly involves the NKp30 natural cytotoxicity receptor, and not the NKp46 or NKp44 receptor. However, both immature and mature DCs seem to use a NKp30 independent mechanism to act as potent stimulators for resting NK cells. We suggest that DCs are able to control directly the expansion of NK cells and that the lysis of immature DCs can regulate the afferent limb of innate and adaptive immunity.
The Bb fragment of complement factor B acts as a B cell growth factor.
Authors: M G Peters, J L Ambrus, A S Fauci, E J Brown
Journal: The Journal of Experimental Medicine (1988)

The process of B cell growth and differentiation into plasma cells is highly regulated and may be influenced by a large number of inflammatory mediators, including complement components. We have studied the regulatory influence of Bb, a 60-kD peptide created during the cleavage of complement Factor B by Factor D and C3b. Purified Bb alone had no effect on proliferation and differentiation of human splenic or tonsillar B cells. However, when B cells were activated by Staphylococcus aureus Cowan I (SAC), Bb enhanced proliferation in a dose-dependent manner. Bb also enhanced proliferation when cocultured with SAC and suboptimal concentrations of purified 60-kD B cell growth factor (HMW-BCGF), a previously described lymphokine that is known to possess growth-promoting activity. However, Bb had no effect on cells treated with optimal concentrations of HMW-BCGF. Like HMW-BCGF, Bb's major effect was on the larger in vivo activated B cells. Half-maximal enhancement of proliferation was reached at a Bb concentration of 1-10 nM. Of note is the fact that antibody to Factor B recognized HMW-BCGF, and an mAb to HMW-BCGF also recognized Factor B and Bb, but not Ba. Moreover, radiolabeled Bb bound saturably to activated B cells and to an EBV-transformed human B cell line. The binding of Bb was inhibited by HMW-BCGF but not by Ba or IgG. Thus, Bb is antigenically and functionally related to HMW-BCGF, and can act as a B cell growth and differentiation factor at potentially physiologic concentrations. These data suggest that Bb may be important in amplifying the immune response in areas of inflammation. Since complement activation occurs at inflammatory sites long before induction of HMW-BCGF synthesis, Bb may be an early signal for the clonal expansion of antigen-activated B cells.
Circulating concentrations of soluble L-selectin (CD62L) in patients with primary Sjogren's syndrome
Authors: M. Garcia-Carrasco
Journal: Annals of the Rheumatic Diseases (2000)

Serum concentrations of soluble (s) L-selectin (CD62L) were measured in patients with primary Sjögren's syndrome (SS) to relate these concentrations to clinical and immunological features of SS.The study included 40 consecutive patients (38 women and two men) with a mean age of 61 years (range 24-78) who fulfilled four or more of the preliminary diagnostic criteria for SS proposed by the European Community Study Group in 1993, and 33 healthy blood donors from the hospital blood bank. A sandwich enzyme linked immunosorbent assay (ELISA) was used to detect the soluble form of human sL-selectin (CD62L).The mean (SEM) values of sL-selectin (CD62L) were 861 (66) microg/ml for patients with SS and 986 (180) microg/ml for healthy blood donors, but there was no significant difference. In patients with primary SS, serum sL-selectin (CD62L) concentrations were significantly higher in patients with Raynaud's phenomenon (1275 (112) microg/ml versus 789 (69) microg/ml, p=0.007), autoimmune thyroiditis (1162 (113) microg/ml versus 787 (69) microg/ml, p=0.02) and rheumatoid factor (993 (95) microg/ml versus 684 (70) microg/ml, p=0.01) when compared with patients without these features.The presence of Raynaud's phenomenon, autoimmune thyroiditis and rheumatoid factor is associated with higher concentrations of circulating sL-selectin (CD62L) in the sera of patients with primary SS.
Loa loa. An unusual case of chronic urticaria and angioedema in the United States
Authors: R. G. Van Dellen
Journal: JAMA (1985)

THE CAUSE of chronic urticaria and angioedema remains unknown in many instances. We report a case in which the cause was found to be a filarial infection with<i>Loa loa</i>. <h3>Report of a Case</h3> A 49-year-old woman from Maine came to Mayo Clinic, Rochester, Minn, in July 1979 with a chief complaint of intermittent swellings for 14 months. In June 1977, she wakened with swelling of the left eyelid, which lasted two days. She assumed that she had been stung or bitten. One month later, swelling of the other eyelid occurred. Following this she had recurrent, painless swelling, at times pruritic, in various parts of the body. The swellings became more frequent and involved the eyes, cheeks, face, forearms, wrists, and trunk. The swellings lasted two to three days and occurred several times weekly. With the swellings she described typical urticaria. On at least one occasion, the patient noted "strangling"
Variables related to increased mortality following out-patient pulmonary rehabilitation
Authors: DA Gerardi, L Lovett, ML Benoit-Connors, JZ Reardon, RL ZuWallack
Journal: European Respiratory Journal (1996)

Although patients with advanced pulmonary diseases have significant improvement in exercise ability and functional status following comprehensive out-patient pulmonary rehabilitation (OPR), their long-term prognosis once they have reached this stage of their diseases remains poor. To further evaluate predictors of increased mortality in these patients, we related patient characteristics and short-term outcome obtained during OPR assessment of 158 patients to subsequent survival. The time period from OPR to death or collection of survival data was 40.0 +/- 17.1 months. The following variables were tested individually and in stepwise fashion using a proportional hazards model: 1) age; 2) gender; 3) pulmonary diagnosis; 4) prebronchodilator forced expiratory volume in one second (FEV1); 5) arterial oxygen tension (Pa,O2) and arterial carbon dioxide tension (Pa,CO2); 6) body mass index (BMI); 7) pre- and post-OPR 12 min walking distance (12-MW); 8) pre- and post-OPR quality of life, using the Chronic Respiratory Disease Questionnaire (CRDQ); 9) number and type of nonpulmonary diagnoses; and 10) number of medications. Separate survival analyses were performed for all deaths (the total group), respiratory deaths only (nonrespiratory deaths excluded), and nonrespiratory deaths only (respiratory deaths excluded). Forty three patients (27%) died during the study period; and the 3 year survival was 80%. For all three survival analyses, the post-OPR 12-MW was the most significant variable related to prognosis: patients with low timed walking distance had increased mortality both from respiratory and nonrespiratory causes. Other variables related to increased mortality included: elevated Pa,CO2; low pre-OPR 12-MW; reduced Pa,O2; low FEV1; low BMI, increased number of medications, and increased CRDQ dyspnoea. These results indicate that the timed walking distance following out-patient pulmonary rehabilitation is an important predictor of survival in patients with advanced pulmonary disease.
Total oxidative stress, total antioxidant status and paraoxanase activity in pediatric patients with bronchiolitis obliterans
Authors: Ahmet Hakan Gedik, Erkan Cakir, Yasemin Gokdemir, Zeynep Seda Uyan, Abdurrahim Kocyigit, Emel Torun, Bulent Karadag, Refika Ersu, Fazilet Karakoc
Journal: European Respiratory Journal (2014)

Introduction and Aim:  Oxidants are normal part of cell metabolism and important in cell hemostasis. Airway mucosa developed antioxidant system to protect itself from harmful oxidants. Imbalance between these systems may caused cell damage. Paraoxonase (PON), is an antioxidizing enzyme, increased with diseases characterized by high oxidative stress. Oxidative stress is supposedly down-regulates serum PON1 expression. We aim to determine total oxidative stress (TOS), total antioxidant status (TAS) and PON levels and compare with control group in pediatric Bronchiolitis Obliterans (BO) patients.  Method:  The patients between 0-16 years-old was admitted between 2012-2013 september and age and gender matched healthy controls were enrolled in the multi-center study. Serum TOS, TAS, and PON levels were determined with ELISA method and compared with control group.  Findings:  Sixty-three BO patients, sixty-seven percent of them were male, enrolled in the study. Median age was 74±58 months. Sixty-five children included to the study as control group and age and gender distribution were not statistically different between the two groups (p>0,05). TAS, TOS, and PON levels were significantly higher in BO group compared with healthy controls (p=0.01, p=0.011, p Conclusion  :  This is the first study about TAS, TOS, and PON levels in pediatric post-infectious BO patients. According to preliminary report, TAS levels were significantly lower in BO patients. Oxidant and antioxidant system may have important role in immune pathogenesis of BO patients.
5HT2a receptor T102C polymorphism and schizophrenia
Authors: C Piers Clifford, DerekJ.R Nunez, AnilK Malhotra, David Goldman, Robert Buchanan, Alan Breier, David Pickar, Erik Jönsson, MarkusM Nöthen, Roland Bunzel, Peter Propping, Göran Sedvall, MariaJ Arranz, Ming-Wei Lin, John Powell, Robert Kerwin, David Collier, Tsukasa Sasaki, Mineko Hattori, Rimmei Fukuda, Hiroshi Kunugi, Shinichiro Nanko, T.J Crow
Journal: The Lancet (1996)
Irritable bowel syndrome
Authors: A. C. Ford, N. J. Talley
Journal: BMJ (2012)

#### Summary points

Irritable bowel syndrome (IBS) is one of the commonest gastrointestinal conditions encountered in primary or secondary care. The disorder is more common in younger people, and women. The diagnosis should be reached using symptom based clinical criteria, rather than excluding underlying organic disease by exhaustive investigation. There is no single known unifying cause, but biological markers have been identified. Treatment should be directed towards relief of the predominant symptom (or symptoms) reported, although these may change over time. Since there is no medical therapy established to alter the natural history of IBS in the longer term, the disorder represents a considerable financial burden to the health service, owing to medical consultations and the consumption of other valuable resources. Since the publication of management guidelines from the National Institute for Health and Clinical Excellence in 2008,w1 there have been some significant developments in terms of synthesis of existing evidence, as well as emerging therapies. We therefore summarise recent systematic reviews, meta-analyses, and randomised controlled trials in order to provide a general update as to how to effectively identify and manage this disorder.

#### Sources and selection criteria

We searched Medline, Embase, the Cochrane Database of Systematic Reviews, …
Multiple Epithelioid Spitz Nevi or Tumors With Loss of BAP1 Expression
Authors: Klaus J. Busam, Michelle Wanna, Thomas Wiesner
Journal: JAMA Dermatology (2013)

Importance: Recently, a group of melanocytic tumors with loss of BAP1 expression has been described.The lesions may occur sporadically or as part of a familial cancer syndrome.They have distinct histopathologic features characterized by a nevuslike silhouette and cytologic composition of large epithelioid melanocytes with oval vesicular nuclei, distinct nucleoli, and abundant cytoplasm.The large melanocytes are immunohistochemically characterized by loss of nuclear labeling for BAP1.Observations: We describe a 21-year-old patient with multiple combined melanocytic proliferations composed of both a nevus component with strong BAP1 expression and a large epithelioid melanocyte population with loss of BAP1 expression.The occurrence of multiple BAP1 loss melanocytic lesions raised concerns about a possible germline mutation.Sequence analysis of DNA from lesional and nonlesional skin confirmed a BAP1 germline mutation. Conclusions and Relevance:The presence of multiple clinically banal-appearing melanocytic lesions with childhood onset suggests that the combined lesions with BAP1 loss large epithelioid melanocytes described herein are probably combined nevi.Our findings also illustrate how the detection of a histopathologically distinct melanocytic lesion, coupled with knowledge of its possible association with a hereditary tumor syndrome, can lead to the suspicion and confirmation of a germline mutation.
Prospect of Targeting the CD40 Pathway for Cancer Therapy
Authors: Robert H. Vonderheide
Journal: Clinical Cancer Research (2007)

Abstract The cell surface molecule CD40 is a member of the tumor necrosis factor receptor superfamily and is broadly expressed by immune, hematopoietic, vascular, epithelial, and other cells, including a wide range of tumor cells. CD40 itself lacks intrinsic kinase or other signal transduction activity but rather mediates its diverse effects via an intricate series of downstream adapter molecules that differentially alter gene expression depending on cell type and microenvironment. As a potential target for novel cancer therapy, CD40 may mediate tumor regression through both an indirect effect of immune activation and a direct cytotoxic effect on the tumor, resulting in a “two-for-one” mechanism of action of CD40 agonists. Several drug formulations that target the CD40 pathway have undergone phase 1 clinical evaluation in advanced-stage cancer patients, and initial findings show objective clinical responses and immune modulation in the absence of major toxicity.