tbuckley/cabot-search huggingface dataset:
Baseline serum lactate dehydrogenase levels are highly predictive of superior outcomes in patients with advanced melanoma: Results from extended follow-up from the dacarbazine/oblimersen (Bcl-2 Antisense) multinational trial
Authors: A. C. Pavlick, A. Eggermont, F. Haluska, M. Millward, M. Gore, H. Pehamberger, P. Hersey, A. Y. Bedikian
Journal: Journal of Clinical Oncology (2006)

18001 Background: Bcl-2 inhibits apoptosis, confers resistance to chemotherapy in many cancers, is often over-expressed in advanced melanoma, and is a prime candidate for pro-apoptotic targeted therapy. Recent studies by the EORTC and others show that lactate dehydrogenase (LDH) is a powerful prognostic determinant in advanced melanoma patients (pts). The chief treatment effect of oblimersen (Obl) + dacarbazine (DTIC) was obtained from the largest cohort of normal LDH pts studied to date; detailed efficacy and safety data are reported. Methods: Previously untreated pts (N = 771) were randomized to receive DTIC 1000 mg/m 2 IV Q 3W alone or preceded by Obl (7 mg/kg/d × 5D). Pts were stratified pre-randomization by performance status, liver metastases, and visceral metastases and/or elevated LDH. Serum LDH was ≤ the cutoff of 1.1 × upper limit of normal in 508 pts. Treatment group characteristics were well matched. Results: Combining Obl and DTIC significantly increased all efficacy outcomes in pts with baseline (BL) nonelevated (NE) LDH, including overall survival (median 11.4 vs 9.7 mo; P = .018), progression-free survival (3.1 vs. 1.6 mo; P = .0007), objective response (17.2% vs 9.3%; P = .009), complete response (3.4% vs 0.8%; P = .041), and durable response ≥6 mo (9.6% vs 4.0%; P = .014). In contrast, there were no significant differences in outcomes for pts with elevated BL LDH (n = 252). BL LDH was the only stratification variable significantly associated with a treatment interaction effect. Compared with the entire study population, pts with NE LDH in both groups had a lower incidence of treatment-emergent adverse events (TEAEs) with an outcome of death, serious TEAEs, and discontinuations due to TEAEs. Conclusions: With extended follow-up, this large trial confirms that serum LDH (prospectively stratified pre-randomization) is probably the most important prognostic factor in advanced melanoma. Given the demonstrable lack of benefit and high potential to yield misleading evidence regarding therapeutic activity, pts with elevated LDH should probably be excluded from trials of new therapies until establishing efficacy in pts with nonelevated LDH. No significant financial relationships to disclose.
Curcumin and pancreatic cancer: Phase II clinical trial experience
Authors: N. Dhillon, B. B. Aggarwal, R. A. Newman, R. A. Wolff, A. B. Kunnumakkara, J. L. Abbruzzese, D. S. Hong, L. H. Camacho, C. Ng, R. Kurzrock
Journal: Journal of Clinical Oncology (2007)

4599 Background: Pancreatic cancer is virtually always lethal, and the only FDA-approved therapies–gemcitabine and erlotinib–produce objective responses in less than 10% of patients. Curcumin (diferuloyl methane) is a plant-derived dietary ingredient that suppresses NF-κB and numerous other pathways relevant to pancreatic cancer and has potent preclinical anti-tumor activity. Herein, we evaluated the safety and potential antitumor activity of curcumin against advanced pancreatic cancer, and its impact on biologic correlates. Methods: Patients received 8 grams of curcumin by mouth daily for two months and were then restaged. Maintenance therapy was continued at the same dose and schedule until disease progression. Results: Twenty-five patients were enrolled as of the date of analysis, with 21 evaluable for response. Circulating curcumin was detectable, albeit at low steady-state levels (about 31 ng/ml), suggesting poor oral bioavailability. To date, two patients have had prolonged stable disease (8 and 12+ months). Interestingly, one patient had a brief, but marked tumor regression (73%) (accompanied by significant increases (4–35-fold) in serum cytokine (interleukin-6 (IL-6), IL-8, IL-10, and IL-1 receptor antagonist (IL-1RA) levels). No toxicities have been observed. Curcumin down-regulated expression of NF-κB, COX-2 and phosphorylated STAT3 in peripheral blood mononuclear cells (PBMC) from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers)although the decrease did not reach statistical significance for p65. Curcumin was determined in patient plasma samples after enzymatic digestion with glucuronidase enzyme. While there was considerable variation in plasma curcumin levels from patient to patient, drug levels peaked at 22–41 ng/ml and remained relatively constant over the entire 4 week experimental period. Conclusions: We conclude that oral curcumin is well tolerated and, despite its limited absorption, has biologic activity in patients with pancreatic cancer. [Table: see text] No significant financial relationships to disclose.
Inorganic Phosphate Activates the AKT/mTORC1 Pathway and Shortens the Life Span of an α‑Klotho–Deficient Model
Authors: Masanobu Kawai, Saori Kinoshita, Keiichi Ozono, Toshimi Michigami
Journal: Journal of the American Society of Nephrology (2016)

Inorganic phosphate (Pi) has been implicated in the pathogenesis of accelerated aging; however, the underlying mechanisms remain elusive. Herein, we demonstrated in cultured cells and in vivo that increased levels of extracellular Pi activated the AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway by suppressing membrane-bound phosphatase and tensin homolog (PTEN) levels in a manner requiring the sodium-dependent Pi transporter PiT‑1. High levels of extracellular Pi also led to phosphorylation of Ser/Thr clusters in the C‑terminal tail of PTEN, which has been shown to dissociate PTEN from the membrane. Notably, blockade of mTORC1 activity by rapamycin treatment prolonged the life span of hyperphosphatemic α‑Klotho-deficient (Kl(-/-)) mice. Dietary correction of hyperphosphatemia or treatment with rapamycin also rescued the brown adipose tissue dysfunction and oxidative damage observed in Kl(-/-) mice. Furthermore, rapamycin treatment partially rescued these effects and extended the life span when Kl(-/-) mice were maintained on a high-phosphate diet. Finally, rapamycin reduced circulating Pi levels in Kl(-/-) mice, apparently by decreasing the localization of sodium-dependent Pi transport protein 2a at the renal brush border membrane. Therefore, the activation of mTORC1 may create a vicious loop that exacerbates the retention of Pi, which in turn may enhance oxidative damage and ultimately shorten the life span of Kl(-/-) mice. These results demonstrate that Pi has important roles in the aging process, and the blockade of mTORC1 may have therapeutic potential for premature aging-like symptoms associated with hyperphosphatemia.
Phase I trial of BAY 43–9006 (sorafenib) combined with dacarbazine (DTIC) in metastatic melanoma patients
Authors: T. Eisen, T. Ahmad, M. E. Gore, R. Marais, I. Gibbens, M. G. James, B. Schwartz, L. Bergamini
Journal: Journal of Clinical Oncology (2005)

7508 Background: BAY 43–9006 (BAY) prevents tumor cell proliferation and angiogenesis via blockade of the RAF/MEK/ERK pathway at the level of RAF (RAF-1, wild-type B-RAF, V599E B-RAF) kinase and inhibition of the receptor tyrosine kinases VEGFR-2 and PDGFR-β. In phase I/II trials, BAY was generally well tolerated as a single agent or with concomitant chemotherapy. Methods: This single-centre, open-label, phase I, dose-escalation study was performed to determine the safety profile and maximum tolerated dose (MTD) of BAY administered at 200 (cohort 1) or 400 (cohort 2) mg bid in combination with repeated 21-day cycles of DTIC 1000 mg/m2. In an extension phase (cohort 3), patients (pts) received the MTD of BAY plus DTIC 1000 mg/m2. Results: Pts with metastatic melanoma were enrolled (ECOG PS 0–1) into cohorts 1 (n=3) 2 (n=6) and 3 (n=3). 1 pt died due to PD. The most common drug-related AEs were dermatologic (rash, flushing, hand-foot skin reaction [HFS]); gastrointestinal (nausea, diarrhoea, constipation, vomiting), constitutional (fatigue/lethargy) or blood/bone-marrow-related, and were generally grade (gr) 1–2 in severity and transient. 1 pt in cohort 2 experienced dose-limiting toxicity of gr 3 HFS. No drug-related gr 3/4 AEs occurred in cohort 1. Gr 3/4 drug-related AEs in cohort 2 were mostly resolved and included gr 4 hypercalcemia; gr 3 low hemoglobin; gr 3 pancreatic hemorrhage; gr 3 pancreatitis; gr 3 leucopenia that occurred in 1 pt each and gr 3/4 neutropenia in 2 pts. Gr 3/4 laboratory abnormalities were rare. According to RECIST, of the 11 evaluable pts after cycle 2, 2 pts had PR; 2 pts had response not reaching PR; 1 pt had SD; and 6 pts had PD. Conclusions: Continuous BAY 400 mg bid is safe and well tolerated and shows preliminary anti-tumor activity in combination with DTIC 1000 mg/m2. The MTD of BAY is 400 mg bid in combination with DTIC 1000 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Bayer Healthcare Bayer, CFSB, Deutsche Bank, Medacorp AstraZeneca, Bayer AG Bayer Bayer
Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group study
Authors: VM Whitehead, MJ Vuchich, SJ Lauer, D Mahoney, AJ Carroll, JJ Shuster, DW Esseltine, C Payment, AT Look, J Akabutu
Journal: Blood (1992)
Abstract 16413: Molecular Imaging of Apelin on Enhancing Survival of Mesenchymal Stem Cells in Hindlimb Mice by Differential Regulation of Autophagy
Authors: Dong Liang, Ke Ma, Xiujuan Li, Yabin Wang, Feng Cao
Journal: Circulation (2013)

Introduction: Stem cell therapy has exerted a promising approach against ischemic vascular diseases in past decade. Nevertheless, somatic stem cells, especially mesenchymal stem cells, can hardly l...
Expression of Nm23-H1 in AML correlates with white cell count at diagnosis and in vitro acts as a survival factor for primary AMLs cells; evidence of a novel autocrine survival factor in AML.
Authors: Quang T. Luong, Robert Kerrin Hills, Mark T. Drayson, Keith Wheatley, Alan Kenneth Burnett, David C. Linch, Christopher M. Bunce
Journal: Blood (2003)
Effects of exposure to parental smoking on pulmonary function and symptoms in children with asthma
Authors: Polytimi Panaghiotopoulou-Gartagani, Panagiota Nikolaou, Efthimia Kalampouka, Emmanouel Karavitakis, George Kavadias, Maria Chatzisimeon, Athanasios Kaditis, Chryssa Bakoula, George Chrousos
Journal: European Respiratory Journal (2011)

Exposure to parental smoking (EPS) has been associated with increased asthma symptoms and airway hyperreactivity. Aim of the present study was to evaluate prospectively the effects of EPS on pulmonary function and symptoms in children with asthma.

Methods: Urine cotinine-to-creatinine ratio (UCCRR) was used as an indirect measure of EPS, while FEV1 and asthma exacerbations were the main outcome variables. Subjects were evaluated at baseline and 2 years after an intervention to eliminate EPS.

Results: 78 children (6-14 y.o.) were recruited. Subjects with history of EPS (n=38) had significantly lower FEV1 and higher UCCRR compared to those without such history (90.6±11.1 vs 96.4±12.6% predicted, p=0.046; and 25.3±21.3 vs. 14.1±11.7 ng/mg; p=0.005). Two years later, 31 children were re-evaluated; subjects with a decrease in UCCRR were similar regarding FEV1 compared to those with an increase in UCCRR (100.1±9.4 vs. 105.4±14.7% predicted, p=0.299). However, there was a trend for reduced frequency of asthma exacerbations: from 3.2±2.1/year to 0.7±1.1, p=0.073 in children with reduced UCCRR.

Conclusions: History of EPS is associated with decreased airway function. Reduction in urinary cotinine levels within 2 years is accompanied by a trend for improvement in asthma exacerbations but not in airway function.
Therapeutic resistance and tumor-initiation: Molecular pathways involved in breast cancer stem cell self-renewal
Authors: J. C. Chang, X. Li, H. Wong, C. Creighton, S. G. Hilsenbeck, C. K. Osborne, J. M. Rosen, M. T. Lewis
Journal: Journal of Clinical Oncology (2007)

528 Background: Recent evidence supports the existance of a rare subpopulation of ‘cancer stem cells‘ (CSCs) which is chemoresistant and capable of self-renewal and tumor-initiation, resulting in relapse and metastases. We hypothesized that residual breast tumors after conventional chemotherapy (CTx) are enriched for CSCs bearing CD44+/CD24- markers, and show increased self-renewal as demonstrated by mammosphere (MS) forming assays. Molecular pathways like Notch, Wnt, and the polycomb family that regulate normal mammary self-renewal may be in aberrant in CSCs. Methods: Paired breast cancer biopsies from 35 patients were obtained before and after 12 weeks of neoadjuvant CTx (docetaxel 100 mg/m 2 or Adriamycin/Cytoxan 60/600 mg/m 2 , 4 cycles, q3weeks), digested by collagenase, stained with CD24/CD44/lineage antibodies, and analyzed by flow cytometry. MS assays were performed to measure self-renewal ability. Gene expression, using the Affymetrix U133 GeneChip platform, of cancer cells bearing CD44+/CD24- markers vs. all other sorted cells, and between secondary cancer MS vs. the primary bulk invasive cancers were analyzed. Results: CD44+/CD24- cells increased from a median of 4.8% to 14.8% after CTx (p&lt;0.005). Increased self-renewal was demonstrated by an increase in MS capacity after CTx (p=0.03), with a positive correlation between the number of CD44+/24- cells and MS assays (R=0.8, p&lt;0.05). Common molecular pathways shared by CD44+/CD24- cells and MS show increased expression in normal self-renewal pathways - polycomb family (PCGF5), Notch (MAML2), FOXP1, and BBX. In addition, genes governing alternative splicing were increased, including a non-coding RNA (MALAT1) of unknown function, and RNA splicing factors (SFRS3, SFRS21P, SFRS4). Conclusions: Our results with an increase in cells bearing stem cell markers, and increased MS formation of residual tumors provide the first strong clinical evidence for the existance of therapy-resistant cancer stem cells. Post-transcriptional regulation may play a crucial role in modifying gene function involved in cancer stem cell self-renewal. Clinical trials targeting these newly identified pathways may eradicate residual disease and improved cure rates for many breast cancer patients. [Table: see text]
Autosomal recessive Alport syndrome
Authors: J Ding, J Stitzel, P Berry, E Hawkins, C E Kashtan
Journal: Journal of the American Society of Nephrology (1995)

Autosomal recessive Alport syndrome can arise from a mutation in either of the genes COL4A3 and COL4A4 on chromosome 2, which encode, respectively, the alpha 3 and alpha 4 chains of Type IV collagen. This report describes a mutation in COL4A3 in a girl who presented at age 5 with hematuria and proteinuria, lacking any family history of renal disease. Renal biopsy at age 8 showed immunoglobulin A nephropathy and Alport syndrome. Sensorineural deafness developed during adolescence, and the patient's renal disease progressed to terminal renal failure by age 20. She received a living related donor renal allograft at age 20 and developed antiglomerular basement membrane nephritis of the allograft 8 months after transplantation. Amplification and sequencing of exon 5 of COL4A3 (counting from the 3' end of the gene) revealed a 7-base-pair deletion, producing a shift of the reading frame and the creation of a premature stop codon. Each parent was heterozygous for the normal and mutant exon 5 sequences. This mutation in COL4A3 would result in the loss of 222 amino acids from the carboxy-terminal noncollagenous domain of the alpha 3(IV) chain. The mutant chain would be unable to form trimers with other Type IV collagen alpha chains. In addition, the mutant chain would lack the Goodpasture epitope, which resides in the carboxy-terminal noncollagenous domain of the alpha 3(IV) chain. The absence of this epitope may underly the subsequent development of anti-glomerular basement membrane nephritis in the allograft.
Systemic Therapy in Perivascular Epithelioid Cell Tumors (Pecoma)
Authors: N. Hindi, R. Sanfilippo, S. Stacchiotti, E. Fumagalli, M. Libertini, S. Provenzano, E. Palassini, R.M. Bertulli, A. Marrari, L. Galli, V. Formica, V.E. Chiuri, D. Natale, P. Collini, A.P. Dei Tos, P.G. Casali
Journal: Annals of Oncology (2014)
&lt;italic&gt;Brief Communication:&lt;/italic&gt; Matrical Inclusions Induced by Clofibrate in Hepatic Microbodies of Rats Fed 2-Acetylaminofluorene&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: H Tsukada, Y Mochizuki, M Gotoh
Journal: JNCI Journal of the National Cancer Institute (1975)

Abnormal inclusions in microbodies were induced by clofibrate in hepatocytes of hyperplastic liver nodules in rats fed 2-acetylaminofluorene. These were matrical tubules and plates, each with the same ultrastructural features as those reported previously by other investigators. A hyperplastic state of hepatocytes induced by hepatocarcinogens might be related to the formation of these inclusions in response to clofibrate.
Sugar tax could stop 3.7 million UK people becoming obese, claims report
Authors: Jacqui Wise
Journal: BMJ (2016)

A 20% tax on sugary drinks could reduce obesity by 5% over the next decade in the United Kingdom, claims a new report from Cancer Research UK and the UK Health Forum.1

The report says that if current trends were to continue, the prevalence of obesity in the UK could rise from 29% of the population in 2015 to 34% in 2025. It models the effect of a 20% excise tax on beverages sweetened with sugar and estimates that a tax could …
Association Between Glycemic Control and Morning Blood Pressure Surge With Vascular Endothelial Dysfunction in Type 2 Diabetic Patients
Authors: Koichiro Yoda, Masaaki Inaba, Kae Hamamoto, Maki Yoda, Akihiro Tsuda, Katsuhito Mori, Shinsuke Yamada, Masanori Emoto, Hidenori Koyama, Yasuo Imanishi
Journal: Diabetes Care (2013)

Morning blood pressure surge (MBPS) is an independent predictor of cardiovascular events. However, little is known about the association between glycemic control and MBPS, and its effect on vascular injury in patients with type 2 diabetes mellitus (T2DM). The current study examined the association between glycemic control and MBPS, and the involvement of MBPS in the development of vascular dysfunction in T2DM patients.We examined MBPS in T2DM patients (25 male patients/25 female patients; mean age, 60.1 ± 13.2 years; n = 50) using 24-h ambulatory blood pressure monitoring, and assessed vascular function by brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD).HbA1c (ρ = 0.373, P = 0.009) and triglyceride (TG) (ρ = 0.375, P = 0.009) levels correlated significantly and positively with MBPS. In multiple regression analysis, including TG and HbA1c levels in addition to age and 24-h systolic blood pressure (SBP) as independent variables, HbA1c (β = 0.328, P = 0.016) and TG (β = 0.358, P = 0.014) were associated significantly in a positive manner with MBPS. In a noninsulin user, when homeostasis model assessment ratio (HOMA-R) was included in place of TG, HOMA-R emerged as a significant factor. MBPS (ρ = -0.289, P = 0.043) and HbA1c (ρ = -0.301, P = 0.035) correlated significantly and negatively with FMD, whereas 24-h SBP correlated with both FMD (ρ = -0.359, P = 0.012) and NMD (ρ = -0.478, P = 0.004). In multiple regression analysis, including age, gender, 24-h SBP, MBPS, LDL cholesterol, and HbA1c, MBPS (β = -0.284, P = 0.044) alone associated significantly in a negative manner with FMD, but not with NMD.The current study demonstrated that poor glycemic control and insulin resistance are independently associated with the occurrence of MBPS in T2DM patients, which might be significantly associated with endothelial dysfunction.
Role of Interventional Radiology in the Treatment of Patients with Neuroendocrine Metastases in the Liver
Authors: Larry K. Kvols, Kiran K. Turaga, Jonathan Strosberg, Junsung Choi
Journal: Journal of the National Comprehensive Cancer Network (2009)

Management of liver metastasis from neuroendocrine tumors routinely includes an interventional radiologist. Hepatic artery embolization, either bland (transarterial embolization) or with chemotherapy (transarterial chemoembolization), has been shown to improve response rates in neuroendocrine metastases to the liver. Radiofrequency ablation, cryotherapy, and percutaneous alcohol ablation are important adjuncts or alternative treatments to surgical debulking. In this article, the authors examine important techniques in the armamentarium of the interventional radiologist.
Abstract 17658: The Impact of Elective Percutaneous Coronary Intervention on Coronary Microvascular Resistance
Authors: Tadashi Murai, Tetsumin Lee, Asami Suzuki, Yoshihisa Kanaji, Junji Matsuda, Makoto Araki, Takayuki NIida, Mitsuaki Isobe, Tsunekazu Kakuta
Journal: Circulation (2014)

Background: The influence of elective percutaneous coronary intervention (PCI) in patients with stable angina pectoris on coronary microvascular function has not been fully elucidated. We performed a prospective study to investigate serial changes of microvascular function in patients undergoing elective PCI. Methods and Results: The index of microcirculatory resistance (IMR) and fractional flow reserve (FFR) was measured before, after PCI, and at follow-up (10 months) in 52 patients treated with single vessel uncomplicated elective PCI (male 80.8%, age 66.5 ± 8.3). IMR was calculated by taking collateral flow into account. The median IMR values before, after PCI, and at follow-up were 24.2 (interquartile range (IQR) 13.1-31.3), 15.8 (IQR 11.8-21.6), and 14.7 (IQR 11.3-20.9), respectively. IMR values significantly decreased after PCI (P=0.006), and showed no further significant change at follow-up. There was no significant relationship between delta IMR (post-pre IMR) values and PCI-related cardiac troponin elevations that distributed in the range of (median: 0.50 ng/dL, IQR 0.22-1.02 ng/dL). Pre-PCI IMR was not correlated with pre-PCI FFR values. Post-PCI IMR was significantly correlated with pre-PCI IMR values (P=0.005). Periprocedural IMR decrease (Pre-Post) was inversely associated with pre-PCI FFR (P=0.008) and greater improvement of FFR values by PCI was significantly associated with greater reduction of IMR values at follow-up (P=0.03). Decrease in FFR values from immediately after PCI to follow-up was greater in patients with DM (P=0.01). Furthermore, IMR at follow-up was worse in patients with DM than those without (P=0.009). Conclusions: Removal of physiologically significant epicardial stenosis leads to a decrease in microvascular resistance in patients with stable angina undergoing electively performed uncomplicated PCI. The periprocedural decrease in microvascular resistance was influenced by the hemodynamic significance of the epicardial stenosis before PCI. The baseline status of microvascular function is a significant determinant of post-PCI and follow-up microvascular function in these patients, and diabetes has an impact on the serial changes in microvascular function after successful PCI.