tbuckley/cabot-search huggingface dataset:
A phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study of the histone deacetylase (HDAC) inhibitor PXD101 in patients (pts) with advanced solid tumours
Authors: N. Steele, L. Vidal, J. Plumb, G. Attard, A. Rasmussen, P. Buhl-Jensen, R. Brown, S. Blagden, J. Evans, J. de Bono
Journal: Journal of Clinical Oncology (2005)

3035 BackgroundPXD101 is a novel HDAC inhibitor with potent antiproliferative activity in vitro. PXD101 inhibits tumour growth in vivo in pre-clinical models. We present a phase 1 trial of PXD101 in pts with advanced solid tumours re fractory to standard therapy. Methods Sequential cohorts of 3–6 pts were recruited to this study to determine the maximum tolerated dose of PXD101 administered as a 30 minute IV infusion on days 1 - 5 of a 21 day cycle. The PK profile of PXD101 was calculated by non-compartmental analysis of plasma and urine from 2–4 pts at each dose level. Acetylation of histones extracted from PMN cells was measured by Western blotting. The PK profile of a single oral dose of PXD101 was evaluated in 3 pts. Results 21 pts (median age 58 years, range 39–72); 10M 11F; all ECOG PS ≤ 2) have been treated with a total of 57 cycles of PXD101 (median 2; range 1 to 7) at 5 escalating dose levels: 150mg/m2(4pts), 300 mg/m2(4pts), 600 mg/m2 (6pts), 900 mg/m2 (3pts) and 1200mg/m2 (3pts). No haematological toxicity was observed. Dose limiting toxicity was seen in 3 pts: G3 fatigue (1 pt) at 600 mg/m2, reversible atrial fibrillation (1 pt) at 1200 mg/m2and G3 diarrhoea and lethargy (1pt) at 1200mg/m2. All other adverse effects were ≤ G2. PXD101 displays linear kinetics. Dose-proportional Cmax (range 2.1 - 68.1μg/ml) was reached at the end of the infusion. The elimination half-life of 0.5–1 hr was independent of dose. PXD101 was detected in plasma at low levels after 10 hrs at 1200 mg/m2but undetectable after 8–10 hrs at lower doses. There was no drug accumulation on repeated dosing. Mean oral bioavailability of PXD101 was 33% (range 32–35%). Histone H4 hyperacetylation was observed at the end of each infusion and was sustained for 4–24 hrs in a dose-dependent manner. PXD101 induced p21, p19 and Apaf-1 expression in PMN cells. To date, stable disease has been achieved in 3pts for 2 cycles; 2pts for 4 cycles and 2 pts for 6 cycles. ConclusionsThe novel HDAC inhibitor PXD101 is well tolerated and exhibits dose-dependent PD effects. 1200mg/m2 was the maximally administered dose and dose escalation has ceased. Recruitment to a 1000mg/m2 dose level continues. Further studies of oral PXD101 are planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Topotarget Topotarget Topotarget
Late Results of Optical Urethrotomy
Authors: P J B Smith, A V Kaisary, A J Ball
Journal: Journal of the Royal Society of Medicine (1984)

Of 46 patients who underwent optical urethrotomy for differing strictures of the urethra, 41 (89.1%) remained free of stricture symptoms at follow up 6 years later. The initial effectiveness of this procedure in improving stricture symptoms is sustained in the long term.
Expression of small proline rich proteins in neoplastic and inflammatory skin diseases
Authors: M. De Heller-Milev, M. Huber, R. Panizzon, D. Hohl
Journal: British Journal of Dermatology (2000)

Background The formation of the cornified cell envelope (CE) during the late stages of epidermal differentiation is essential for epidermal barrier function and protects the body against environmental attack and water loss. Formation of the CE involves the replacement of the plasma membrane by cross‐linkage of precursor proteins such as involucrin, small proline rich proteins (SPRR) and loricrin. In normal epidermis, SPRR1 is restricted to appendages, SPRR2 is also expressed in interfollicular areas, while SPRR3 is completely absent; the latter is most abundant in oral epithelium. This differential expression indicates an important part for SPRRs in specific barrier requirements, and reflects their importance in the biomechanical properties of the CE. Objectives We report here on the expression of SPRR1, SPRR2 and SPRR3 in a wide range of cutaneous neoplastic and inflammatory diseases. Methods We used immunohistochemistry; in addition, Northern blot analysis of malignant tumours was performed. Results Increased suprabasal expression of SPRR1 and SPRR2, but no SPRR3 expression, was noted in inflammatory dermatoses with orthokeratotic and parakeratotic squamous differentiation. By contrast, differentiating epidermal tumours such as Bowen's disease, keratoacanthoma and squamous cell carcinoma expressed SPRR3. Conclusions As SPRRs were originally cloned on the basis of their expression in ultraviolet light‐irradiated keratinocytes, the expression of SPRR3 in actinic lesions is of interest, and might serve as a diagnostic tool.
Major activity of cladribine in patients with de novo B-cell prolymphocytic leukemia.
Authors: A Saven, T Lee, M Schlutz, A Jacobs, D Ellison, R Longmire, L Piro
Journal: Journal of Clinical Oncology (1997)

De novo B-cell prolymphocytic leukemia (B-PLL) is a distinct clinicopathologic entity usually characterized by marked lymphocytosis, massive splenomegaly, an aggressive course, and refractoriness to therapy. Cladribine (2-chlorodeoxyadenosine [2-CdA]; Ortho Biotech, Raritan, NJ) is a newer purine analog with potent activity against indolent lymphoproliferative disorders.We treated eight patients with cladribine 0.1 mg/kg/d for 7 days by continuous infusion or 0.14 mg/kg/d over 2 hours for 5 days, every 28 to 35 days, for a median of three courses (range, two to five). There were five men and three women, with a median age of 62 years and a median pretreatment duration of 6 months; four patients were previously untreated.All eight patients were assessable: five achieved a complete response with a median response duration of 14 months (range, 1+ to 55+), and three achieved a partial response with a median duration of 3 months (range, 1 to 3). Of four patients who achieved a complete response and in whom a peripheral-blood immunophenotypic analysis was performed, two had no circulating B-PLL cells and one had no residual disease on Southern blot analysis. Myelosuppression and infection were the major toxicities: three patients developed grade 3 or 4 myelosuppression, four had bacterial infections, and two had herpes zoster infections.In this small study of patients with de novo B-PLL, cladribine was an active agent that induced a high overall and complete response rate. These results require confirmation in larger numbers of B-PLL patients.
Clinical relevance of circulating heat shock protein 70 in acute leukemias
Authors: Chen-Hsiung Yeh, Richard Tseng, Susan O'Brien, Alison Hannah, Zeev Estrov, Elihu Estey, Hagop Kantarjian, Maher Albitar
Journal: Clinical Cancer Research (2008)

B13   Heat shock protein 70 (HSP70) is one of a family of proteins involved in the protection of cells upon exposure to various types of stress. Plasma circulating HSP70 (cHSP70) is believed to play a role in the anti-tumor immune response, and its levels in plasma may reflect levels of danger or disease state. Using the Meso Scale Discovery system, we measured cHSP70 levels in the plasma of patients with acute myeloid leukemia (AML) (#96), myelodysplastic syndrome (MDS) (#28), and acute lymphoblastic leukemia (ALL) (#40) and compared levels with those in normal individuals (#99). cHSP70 levels were significantly higher in AML (median, 10.71 ng/mL; range, 1.93-79.0 ng/mL) and ALL (median, 27.59 ng/mL; range, 5.09-129.6 ng/mL) patients than in MDS patients (median, 4.54; range, 1.35-58.3 ng/mL) or healthy controls (median, 4.13 ng/mL; range, 1.75-13.6 ng/mL). Levels of cHSP70 showed a significant positive correlation with lactate dehydrogenase (LDH) level and white blood cells (WBC) count in AML and ALL patients, which suggests cHSP70 level reflects tumor load. Furthermore, patients with higher levels of cHSP70 had significantly shorter survival in AML (P=0.04) and ALL (P=0.05), which may suggest that in these two acute diseases cHSP70 is indicative of disease severity. Our data support the potential use cHSP70 as a biomarker in leukemias and possibly other types of cancer.
Seasonal variation of serum KL-6 levels in patients with interstitial lung diseases
Authors: Hiroshi Ohnishi, Shintaro Miyamoto, Shigeo Kawase, Tetsuya Kubota, Akihito Yokoyama
Journal: European Respiratory Journal (2014)

Background:  Krebs von den Lungen-6 (KL-6) in sera is a useful biomarker for the diagnosis of interstitial lung diseases (ILD). However, KL-6 cannot be applied to discriminate types of ILD. Some case reports demonstrated that serum KL-6 levels were changed depending on antigen exposure levels in patients with hypersensitivity pneumonitis (HP), however seasonal changes in serum KL-6 levels in ILD are unknown.   Aims and objectives:  The aim of this study was to determine seasonal variation of serum KL-6 levels in various ILD.   Methods:  Serum KL-6 levels in the summer (June-September) and the winter (November-February) were retrospectively analyzed in 93 patients with ILD including idiopathic pulmonary fibrosis (IPF, n=16), non-specific interstitial pneumonia (NSIP, n=16), collagen vascular disease-associated interstitial pneumonia (CVD-IP, n=33), house-related HP (House-HP, n=9), bird-related HP (Bird-HP, n=6), and combined pulmonary fibrosis and emphysema (CPFE, n=13).   Results:  CVD-IP and CPFE showed lower serum KL-6 levels than the other ILD throughout their clinical course regardless of the season. Bird-HP and House-HP showed greater seasonal variation in serum KL-6 levels compared with the other ILD. Serum KL-6 levels in Bird-HP were significantly increased in the winter. House-HP showed significant increases of serum KL-6 in the summer. Variations in serum KL-6 levels were significantly greater in acute form of HP than chronic form of HP.   Conclusions : HP should be considered in ILD with greater seasonal changes in serum KL-6 levels.
Allogeneic bone marrow transplantation for refractory and recurrent low-grade lymphoma: the case for aggressive management.
Authors: K W van Besien, I F Khouri, S A Giralt, P McCarthy, R Mehra, B S Andersson, D Przepiorka, J L Gajewski, N Bellare, R Nath
Journal: Journal of Clinical Oncology (1995)

PURPOSE To evaluate the role of allogeneic bone marrow transplantation (BMT) in recurrent low-grade lymphoma. PATIENTS AND METHODS Between 1989 and 1994, 10 patients with chemotherapy-refractory and recurrent low-grade lymphoma were treated with myeloablative therapy and allogeneic BMT. All patients had poor prognostic features and had been extensively pretreated. RESULTS Eight patients achieved a complete remission and none have relapsed at a median follow-up time of 816 days (range, 346 to 1,865). Two patients died of early complications. The actuarial survival and failure-free survival rates are both 80% +/- 12.6%. For surviving patients, the duration of the current remission exceeds that of any previous remission achieved. CONCLUSION These results compare favorably with those for autologous BMT. Allogeneic BMT offers considerable promise for the treatment of patients with poor-prognosis low-grade lymphoma. Its role should be further defined in prospective studies.
Homeless mentally ill or mentally ill homeless?
Authors: C I Cohen, K S Thompson
Journal: American Journal of Psychiatry (1992)

Mainstream psychiatry conceptualizes people who are homeless and mentally ill as distinct from other homeless persons because it is thought that their status stems from their mental disorder and the poor implementation of deinstitutionalization. The authors believe this dichotomy is illusory. They present data indicating that recent socioeconomic and political shifts contributed greatly to homelessness among all groups, regardless of mental illness; that those with and without mental illness have similar biographical and demographic profiles; that high levels of mental distress are common to all homeless persons; and that few mentally ill homeless persons require involuntary hospitalization. This perspective suggests novel responses that de-emphasize clinical solutions and focus on empowerment, consumerism, entitlement, community-level interventions, and closer alliances with other advocates for the homeless.
Influence of Biologic Factors and Anatomic Site in Completely Resected Liposarcoma
Authors: David C. Linehan, Jonathan J. Lewis, Denis Leung, Murray F. Brennan
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Soft tissue sarcoma (STS) encompasses a group of neoplasms that are anatomically and biologically diverse. Retroperitoneal/visceral (RP/V) tumors have a poorer prognosis than extremity/trunk (E/T) lesions, and this has been attributed to frequent presentation with tumors of large size and multiorgan involvement that precludes complete resection. The worse prognosis that is associated with RP/V tumors has also been thought to be histopathologically dependent and not necessarily related to anatomic site. The aim of this study was to determine the role of anatomic site and biologic features in prognosis and outcome in patients after complete resection by examining a large cohort of STS patients with a single histopathology, ie, liposarcoma. METHODS: All patients who were treated for liposarcoma from July 1, 1982, through July 1, 1998, were included. Univariate analyses were performed using log-rank test and Kaplan-Meier estimates, and multivariate analyses were performed using Cox regression. The three end points examined were local recurrence (LR), distant recurrence, and disease-specific survival (DSS). RESULTS: Seven hundred twenty patients with liposarcoma were evaluated, and of these, 460 had completely resected primary or completely resected locally recurrent disease. Breakdown of anatomic site was 65% E/T (n = 301) and 35% RP/V (n = 159). The median follow-up period for patients who underwent complete resection was 42 months (range, 1 to 194 months). We found that RP/V site is a poor prognosticator that is independent of patient sex and age; tumor size, grade, and margin; and recurrent presentation. Sixty-nine percent of patients with RP/V tumors who died had local disease only and no distant metastasis at the time of death. CONCLUSION: In liposarcoma, tumor location exerts as strong an influence on prognosis as biology. In contrast to extremity liposarcoma, LR without distant metastasis often results in death for patients with RP/V tumors. For these patients, local control accomplished by complete surgical resection ± adjuvant radiation therapy should impact strongly on DSS.
Diffuse pulmonary calcinosis without calcium metabolism abnormalities in a renal transplant recipient
Authors: M Romagnoli, G Mourad, I Serre, JP Senac, L Paradis, P Godard, P Chanez
Journal: European Respiratory Journal (1997)

Eighteen years after an uneventful renal transplantation, the chest radiograph of an asymptomatic 50 year old man showed diffuse bilateral infiltrations, predominately at the right apex. Computed tomography (CT) scan demonstrated a diffuse alveolar pattern, the alveoli being filled with a very dense material, with some tracheal calcifications. Bronchoalveolar lavage fluid analysis was normal, but bronchial and transbronchial biopsies revealed calcium deposits in the bronchial mucosa and in the alveolar septa. The diagnosis of diffuse pulmonary calcinosis was established, despite normal blood calcium, phosphorus and magnesium levels, based upon computed tomography scan and pathological findings at fibreoptic bronchoscopy, without the need for an open lung biopsy.
Isolation and characterization of putative human lung alveolar epithelial progenitor cell from tissue explants
Authors: Edward Ingenito, Shiva Tyagi, Julia Paxson, Andrew Hoffman
Journal: European Respiratory Journal (2013)

Introduction: Alveolar epithelial type II cells (AECII) are generally considered the stem/progenitor cells of the alveolar compartment. However, recent studies in rodents suggest that AECs may arise from primitive precursors.  Objective: Isolate and characterize alveolar progenitor cells (aEpiPCs) from human lung tissue.  Methods: Surgical biopsies from anonymous donors were obtained under an approved IRB protocol at Brigham and Women’s Hospital (Boston, USA). Explant cultures were established and epithelial progenitors were isolated using serum-free media. Outgrowth cells were characterized by flow cytometry, immunostaining, and qRT-PCR. Function and differentiation were assessed via scaffold re-cellularization and Matrigel® assays.  Results: Passage 0 aEpiPCs were uniformly EpCAM + , Itg β4α6 + , Pancytokeratin + , proSP-C - , and Aquaporin5 - . They were also c-kit - , CD45 - , CD90 -  and CD31 - , consistent with an undifferentiated epithelial phenotype. Cells were highly clonogenic (cfu efficiency = 12%), self-renewing out to passage 10, and displayed increased telomerase levels. On laminin and collagen I, aEpiPCs differentiated into AECI and II cells, expressing proSP-B, proSP-C, Aqp5 and ZO-1. Differentiation was also observed following seeding onto de-cellularized mouse lung and plating on Matrigel.  Conclusions: Undifferentiated human aEpiPCs isolated from biopsy specimens are highly proliferative, clonogenic, and demonstrate lineage-restricted multipotency in culture. These cells, which can be readily isolated from explants of human lung tissue, appear to represent precursors to AECI and II cells, and may play an important role in homeostasis and regeneration in the human lung.
Relationship between pulse transit time and blood pressure during cardiopulmonary exercise tests
Authors: Thomas Wibmer, Cornelia Kropf, Kathrin Stoiber, Stefan Ruediger, Martin Lanzinger, Wolfgang Rottbauer, Christian Schumann
Journal: European Respiratory Journal (2011)

Introduction:  Pulse transit time (PTT), the interval between ventricular electrical activity and peripheral pulse wave, is generally assumed to be a surrogate marker for blood pressure changes. Although recent studies have affirmed the potential use of PTT in the diagnostic of sleep disorders and the monitoring of psychophysiological stress, little work has been published on the effect of physical exercise on PTT and results have been inconsistant.   Aims:  To analyse PTT and its relation to blood pressure during cardiopulmonary exercise tests.   Methods:  In 20 patients (mean age 51, range 14-82) in a cardiopulmonary unit, ECG and finger-photoplethysmography were continuously recorded during routine cardiopulmonary cycle exercise tests. PTT was calculated for each R-wave in the ECG and the corresponding steepest upstroke in the plethysmogram. For each subject the resulting PTT-curve was averaged in order to compensate sample rate- and movement-associated variation, and values were compared to systolic (sBP) and diastolic blood pressure (dBP) in 9 predefined measuring points including measurements at rest, during increasing and maximum exercise as well as during the recovery period.   Results:  Mean sBP and PTT at rest were 127 mmHg and 372 ms respectively, 197 mmHg and 287 ms under maximum exercise, and 132 mmHg and 365 ms during recovery. All subjects showed a significant, strong negative correlation between PTT and sBP (mean r=-0.97, range -0.99 to -0.93, p=    Conclusions:  These results indicate that PTT is a good potential surrogate measure for sBP during exercise.
Association of Anti–<i>Porphyromonas gingivalis</i> Antibody Titers With Nonsmoking Status in Early Rheumatoid Arthritis: Results From the Prospective French Cohort of Patients With Early Rheumatoid Arthritis
Authors: Raphaèle Seror, Sandrine Le Gall‐David, Martine Bonnaure‐Mallet, Thierry Schaeverbeke, Alain Cantagrel, Jacques Minet, Jacques‐Eric Gottenberg, Philippe Chanson, Philippe Ravaud, Xavier Mariette
Journal: Arthritis & Rheumatology (2015)

To investigate the possible link between Porphyromonas gingivalis infection and rheumatoid arthritis (RA), according to antibody profile, genetic and environmental factors, and RA severity. For assessing P gingivalis infection, serum levels of antibodies directed against P gingivalis lipopolysaccharide were measured in 694 patients with early RA who were not exposed to steroids or disease-modifying antirheumatic drugs. Anti-P gingivalis antibody titers were compared between patients with early RA and various control groups, and according to various patient characteristics. Anti-P gingivalis antibody titers did not significantly differ between patients with RA and controls and did not significantly differ with anti-citrullinated protein antibody (ACPA), rheumatoid factor (RF), or HLA shared epitope status. Anti-P gingivalis antibody titers were significantly higher among patients who had never smoked compared to patients who had ever smoked (P = 0.0049). Among nonsmokers, high anti-P gingivalis antibody levels were associated with a higher prevalence of erosive change (47.5% versus 33.3% with modified Sharp/van der Heijde score erosion subscale ≥1; P = 0.0135). In this large early RA cohort, we did not detect any association of anti-P gingivalis antibodies with RA or with ACPA status. These results suggest that the association of periodontitis and RA could be linked to bacterial species other than P gingivalis or to a mechanism other than citrullination. Nevertheless, we found higher anti-P gingivalis antibody titers in nonsmokers. In addition, in this population of nonsmokers, high anti-P gingivalis antibody titers were associated with more severe disease. We hypothesize that the role of tobacco in RA pathogenesis is so high that the effect of P gingivalis could be revealed only in a population not exposed to tobacco.
Abdominal Tuberculosis: Still a Problem Today
Authors: A D Wells, J M A Northover, E R Howard
Journal: Journal of the Royal Society of Medicine (1986)

Thirty cases of abdominal tuberculosis were diagnosed over an 18-year period, 26 being in immigrants; the mean age at presentation was 33 years. There were 25 cases of tuberculous peritonitis, two of tuberculous mesenteric lymphadenitis, and one each of gastric tuberculosis, colonic tuberculosis and tuberculous ischiorectal abscess. The presenting symptoms were of vague ill-health and not diagnostic, and the most common findings were of pyrexia, abdominal tenderness and ascites. The most common haematological abnormalities were raised ESR (22 patients) and mild anaemia (15 patients). Most commonly, diagnosis was made by formal laparotomy (19 cases) with biopsy (18 cases); histological examination gave a positive diagnosis in all 18 cases, but bacteriological examination yielded the tubercle bacillus in only 10 (56%). There were 2 deaths in the series, not directly related to the abdominal tuberculosis. In view of its infrequent and vague presentation, care is required to avoid overlooking the diagnosis of abdominal tuberculosis, particularly in the immigrant population.