tbuckley/cabot-search huggingface dataset:
A phase I, open-label study of the safety, tolerability and pharmacokinetics of lapatinib (GW572016) in combination with letrozole in cancer patients
Authors: Q. Chu, L. Goldstein, N. Murray, E. Rowinsky, M. Cianfrocca, M. Gale, P. Ho, E. Paul, J. Loftiss, L. Pandite
Journal: Journal of Clinical Oncology (2005)

3001 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases leading to cell growth arrest and/or apoptosis in ErbB1 and ErbB2 dependent tumor cell lines and xenografts. Co-expression of ErbB2 and ER is associated with a reduced response rate to hormone therapy in breast cancer. A rational approach to treatment may be to block simultaneously both ER and ErbB2 pathways. Methods: Patients (pts) with advanced breast cancer, ER or PR +, or other tumors (e.g., ovarian, endometrial) that would be likely to respond to the combination therapy were enrolled. Escalating doses of lapatinib (1250–1500 mg/d) were administered in combination with letrozole (2.5 mg/d). Three pts were treated at each dose level, with expansion to 6 in the event of dose-limiting toxicity (DLT). Once the optimally tolerated regimen (OTR) was determined, an additional 8 - 16 pts were to be enrolled to establish the pharmacokinetic profiles of lapatinib and letrozole when administered alone and in combination. Results: Thirty-six pts (35 F, 1 M, median age 55 yrs, median Karnofsky PS 90%) were enrolled at the 2 dose levels (1250 mg 4 pts, 1500 mg 32 pts). One hundred and twenty-three treatment periods (4 weeks = 1 treatment period) were completed: median 2. One DLT (Gr 3 diarrhea) was reported at the 1500 mg/d dose level. The optimally tolerated regimen was determined to be letrozole 2.5 mg + lapatinib 1500 mg/d. Gr 1–2 diarrhea, nausea, rash and fatigue were the common non-hematologic toxicities. Out of 36 evaluable pts, 4 pts experienced SD for > 5 mo. (breast 2 pts, ovarian 2 pts). One endometrial pt experienced a PR at treatment period 8. Conclusions: Lapatinib may be administered safely in combination with letrozole at known effective single agent doses for each. The pharmacokinetic portion of the study is enrolling pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Phase III trial of nilotinib versus imatinib as first-line targeted therapy of advanced gastrointestinal stromal tumors (GIST).
Authors: Jean-Yves Blay, Lin Shen, Yoon-Koo Kang, Piotr Rutkowski, Shukui Qin, Dmitry Nosov, Steven C. Novick, Lilia Taningco, Shuyuan Mo, Peter Reichardt, George D. Demetri
Journal: Journal of Clinical Oncology (2013)

10501^ Background: Nilotinib (N) is a Bcr-Abl, KIT, and PDGFR tyrosine kinase inhibitor. This Phase III trial compared N and imatinib (I) as first-line therapy of advanced GIST. Accrual was stopped when a futility boundary was crossed at interim analysis (IA). This final analysis of the core study examined the effect of mutation on outcomes. Methods: Patients (pts) with unresectable and/or metastatic GIST who had no prior antineoplastic therapy or had recurrence ≥6 months (mos) after adjuvant I were randomized 1:1 to open-label N 400 mg bid or I 400 mg qd (400 mg bid for KIT exon 9 mutants). The primary endpoint was progression-free survival (PFS) per adjudicated central review. Enrollment targeted 736 pts to observe 375 events, yielding 90% power to detect a hazard ratio (HR) of 0.71 (median, 28 [N] and 20 [I] mos) with two-sided 5% type I error. Prior to IA, crossover was allowed only for pts with progressive disease (PD); after IA, pts on N with or without PD were offered I. Results: At IA, the PFS HR for N vs I of &gt;1.111 suggested a low probability of N superiority to I. Final analysis was performed in 644 pts; both PFS and OS favored I. In subgroup analysis of 401 pts who had mutational data, there was a large PFS difference favoring I in KIT exon 9 mutants, but similar PFS in KIT exon 11 mutants (Table). Based on immature data, OS favored I in all mutants. Conclusions: The IA showed N could not be superior to I for PFS in the overall population as first-line targeted therapy for pts with advanced GIST. PFS of N and I differed according to molecular subtypes, with PFSfavoring Iin KIT exon 9 mutants but roughly similar in exon 11 mutants. Clinical trial information: NCT00785785. [Table: see text]
Immunoferritin and Immunofluorescent Studies With Epstein-Barr Virus and Herpes Simplex Virus by Use of Human Sera and Hyperimmune Rabbit Sera&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: B Hampar, P Gerber, K C Hsu, L M Martos, J L Walker, R F Sigüenza, G A Wells
Journal: JNCI Journal of the National Cancer Institute (1970)
In Vivo Selection and Long-Term Engraftment Of Hematopoietic Stem Cells Generated Via Vascular Niche Induction Of Nonhuman Primate Induced Pluripotent Stem Cells
Authors: Jennifer L Gori, Jason M Butler, Devikha Chandrasekaran, Brian C Beard, Daniel J Nolan, Michael Ginsberg, Jennifer E Adair, Shahin Rafii, Hans-Peter Kiem
Journal: Blood (2013)
Is tolerance really teaching?
Authors: Lisa G Rapaport
Journal: Behavioral and Brain Sciences (2015)

Abstract Kline succeeds in demonstrating the value of an approach that integrates information from various scientific and social disciplines, but her framework does not uniformly provide clarity. Specifically, inclusion of situations in which knowledgeable individuals do not actively donate information is misguided. Passive tolerance by demonstrators should continue to be excluded from definitions of teaching, in order to focus on situations in which selection has favored behaviors that are specifically geared to promoting learning in others.
Fluorescence imaging proteometry of thymosin β4 in single cells for detection of bladder transitional cell carcinoma
Authors: G. P. Hemstreet, N. K. Wehbi, G. P. Casale, D. Huang, J. Tian, L. M. Hutchinson
Journal: Journal of Clinical Oncology (2005)

4745 Background: Thymosin β4 (Tβ4), a ubiquitous 5 kDa peptide, functions both as an intracellular actin remodeling peptide that binds G-actin and an extracellular cytokine-like molecule that induces metalloproteinases and angiogenesis. Human transcriptome analyses have demonstrated increased expression of Tβ4 in renal-cell carcinoma, breast cancer, metastatic melanoma, and non-metastatic colon cancer. In this study, we developed fluorescence imaging proteometry (FIP) for analysis of single-cell Tβ4 as a potential biomarker of bladder transitional cell carcinoma (BTCC). Methods: Cancer cell lines and cells in urine and bladder-wash specimens were fixed and stored at -80o C. Specimens imprinted to slides were stoichiometrically labeled with anti-Tβ4 antibody (1o Ab) and fluorophore-tagged 2o Ab (Fl-Ab) or with 1o Ab, biotinylated 2o Ab and fluorophore-tagged streptavidin (Fl-SA), with a BioGenex i6000 Autostainer. Gray scale images were captured with an automated Leica microscope and a high-resolution CCD b/w camera that were benchmarked with standard fluorescent beads, before each image capture session. Fluorescence emission was quantified as mean fluorescence intensity (MFI) per cell, using Image-Pro Plus software. Average MFI (AMFI) was determined with 500-1000 cells. Results: Reliable Tβ4 FIP was achieved with optimized specimen fixation, storage, imprinting, labeling, and signal stabilization; inter-analysis normalization standards; and image analysis benchmarking. Thus, fixation with 0.5% formaldehyde, zinc-based S.T.F. Streck fixative, and 4% paraformaldehyde produced relative AMFIs of 100, 36, and 46, respectively. AMFI doubled with specimen exposure to 1o Ab for 15–20 hours at 4o C vs. 1 hour at 25o C, followed by Fl-Ab for 1 hour at 25o C. Tβ4 FIP provided intra- and inter-analysis reproducibility of ± 10% and routine resolution of a 20% difference in single-cell Tβ4. In an initial test, Tβ4 signal was present in normal bladder cells but absent from high-grade tumor cells. Conclusions: Sensitive and reproducible FIP has been established for analyzing Tβ4 expression in individual bladder cells, as a potential biomarker that may be decreased in BTCC. No significant financial relationships to disclose.
Abstract 13449: Insulin-Like Growth Factor I (IGF-1) Downregulates 12/15-lipoxygenase in Apoe-Deficient Mice and in Cultured Macrophages: Potential Mechanism Mediating IGF-1-Induced Atheroprotection
Authors: Sergiy Sukhanov, Charlotte Vaughn, Shaw-Yung Shai, Yusuke Higashi, Jean-Luc Delafontaine, Patricia Snarski, Patrick Delafontaine
Journal: Circulation (2012)
Compensating the Fitness Costs of Synonymous Mutations
Authors: Anna Knöppel, Joakim Näsvall, Dan I. Andersson
Journal: Molecular Biology and Evolution (2016)

Synonymous mutations do not change the sequence of the polypeptide but they may still influence fitness. We investigated in Salmonella enterica how four synonymous mutations in the rpsT gene (encoding ribosomal protein S20) reduce fitness (i.e., growth rate) and the mechanisms by which this cost can be genetically compensated. The reduced growth rates of the synonymous mutants were correlated with reduced levels of the rpsT transcript and S20 protein. In an adaptive evolution experiment, these fitness impairments could be compensated by mutations that either caused up-regulation of S20 through increased gene dosage (due to duplications), increased transcription of the rpsT gene (due to an rpoD mutation or mutations in rpsT), or increased translation from the rpsT transcript (due to rpsT mutations). We suggest that the reduced levels of S20 in the synonymous mutants result in production of a defective subpopulation of 30S subunits lacking S20 that reduce protein synthesis and bacterial growth and that the compensatory mutations restore S20 levels and the number of functional ribosomes. Our results demonstrate how specific synonymous mutations can cause substantial fitness reductions and that many different types of intra- and extragenic compensatory mutations can efficiently restore fitness. Furthermore, this study highlights that also synonymous sites can be under strong selection, which may have implications for the use of dN/dS ratios as signature for selection.
Massachusetts Medical Society
Authors: John P. Connelly
Journal: New England Journal of Medicine (1957)

With the increasing use of various drugs to control elevated blood pressure, the presence of antihypertensive medication in the family medicine cabinet is becoming ever more common. The following report concerns the toxic results of the accidental ingestion of such a drug by a child.One hour before admission, a 26-month-old girl was discovered to have ingested approximately 20 2-mg. tablets of alkavervir (Veriloid) prescribed for her grandfather's high blood pressure. The mother's attempts to induce vomiting by gagging were unsuccessful. Fifteen minutes later the child suddenly became unresponsive and fell to the floor, with generalized tonic muscular spasms, opisthotonos . . .
PF-00299804 (PF299) patient (pt)-reported outcomes (PROs) and efficacy in adenocarcinoma (adeno) and nonadeno non-small cell lung cancer (NSCLC): A phase (P) II trial in advanced NSCLC after failure of chemotherapy (CT) and erlotinib (E).
Authors: A. Campbell, K. L. Reckamp, D. R. Camidge, G. Giaccone, S. M. Gadgeel, F. R. Khuri, J. A. Engelman, L. J. Denis, J. P. O'Connell, P. A. Janne
Journal: Journal of Clinical Oncology (2010)

7596 Background: Treatment (tx) options are limited for pts with NSCLC after failure of CT and E. Cough, dyspnea, and pain (chest) are key pt-reported NSCLC symptoms (symp). PF299 is an oral, irreversible, small-molecule pan-human epidermal growth factor receptor (-1, -2, and -4) tyrosine kinase inhibitor. Methods: This open-label, single-stage, P2 trial evaluated PF299 efficacy in pts with KRAS wild-type advanced NSCLC after failure of ≥1 CT regimen and E. Pts (adeno and nonadeno) received 45 mg PF299 once daily (3-week [wk] cycles [C]). Endpoints included response (primary), safety/tolerability, and PROs assessed by the EORTC-QLQ-C30/LC13 on day (D) 1 of each C (improvement of > 5 points [p] indicates meaningful benefit). Results: 65 pts (37 female, 50 adeno) have enrolled. Of 62 evaluable pts, 3 had a partial response and 35 stable disease (SD) ≥ 6 wks. 28 pts remained on treatment (tx) at C4D1 and had complete PRO data. Common tx-related adverse events (TRAEs) included diarrhea (86%), fatigue (40%), rash (45%), and stomatitis/mucosal inflammation (23%); mainly grade 1/2 and manageable. Pts reported an increase in “diarrhea” and “sore mouth” symp after C1 then gradual improvement. Qualitatively, raw scores for these symp moved from “not at all” at baseline to “a little” at C4D1. Importantly, pts reported clinically meaningful improvements (CMIs; > 5 p) in NSCLC symp. Mean baseline QLQ-LC13 scores were: dyspnea (21.4 p), cough (28.6 p), chest pain (14.3 p), and arm/shoulder pain (20.2 p). Improvements were: dyspnea (wk 6, 8.5 p; wk 9, 5.1 p), cough (wk 3, 8.8 p; wk 6, 5.9 p), chest pain (wk 3, 6.0 p; wk 6, 5.3 p; wk 9, 10.7 p), and arm/shoulder pain (wk 6, 10 p; wk 9, 8.3 p). Conclusions: Pts with adeno or nonadeno refractory NSCLC receiving PF299 in this study experience clinical benefit despite prior erlotinib tx. Pts report relief of NSCLC symp, including CMIs in key symp of cough, dyspnea, and pain. TRAEs were manageable. PRO results suggest that diarrhea and mucositis, while present, were tolerable. These results support further evaluation; a P3 trial of PF299 in refractory NSCLC is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Gatekeeper Pharmaceuticals, Pfizer AVEO, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, MedImmune, Millennium, Novartis, OSI Pharmaceuticals, Pfizer, Roche, Schering-Plough, Syndax Pharmaceuticals Gatekeeper Pharmaceuticals, Pfizer Novartis, Pfizer Genzyme
Chemoanticoagulation versus chemotherapy in advanced pancreatic cancer (APC): Results of the interim analysis of the FRAGEM trial
Authors: A. Maraveyas, M. Holmes, F. Lofts, K. K. Garadi, E. Gardiner, J. Sgouros
Journal: Journal of Clinical Oncology (2007)

4583 Background: Randomised phase III studies in APC, reveal that many patients (pts) (∼20–25%) die within 3 months from randomisation [(Early Death Burden) (EDB)]. More compared to studies done in other cancers despite pts entered on similar ‘global’ clinical criteria (e.g. 7% in colorectal cancer). We hypothesised that EDB in APC is related to hyper-coagulability. Prevention of veno-thromboembolism (VTE) may result in reduction of EDB. To test this we initiated the randomised phase IIb FRAGEM study. Methods: Upon written informed consent pts with inoperable APC, are eligible for the study (MREC N° 07/02/129, UKCRN 1290). Concurrent VTE or anticoagulant therapy are exclusion criteria. Standard arm pts (arm A) receive gemcitabine 1gr/m 2 weekly (Burris schedule). Arm B also receives daily dalteparin injections for 12 weeks at therapeutic dose (CLOT schedule). Primary end point is the reduction of VTE, secondary endpoint the reduction of EDB. To detect a reduction of VTE from around 25% to 5% (odds ratio of 0.158), using a two-group chi-squared test with a two-sided 5% significance level and 80% power, a minimum of 59 pts per treatment group are required. Interim analysis was planned after the first 25 pts entered into arm B to exclude toxicity from dalteparin’s therapeutic, given prophylactically, dose. These results are presented here. Results: 26 pts (50% male, 61% with metastases) in arm A and 25 pts (60% male, 44% with metastases) in arm B have been treated so far. The incidence of VTE in arm A was 31% with 3 pts developing leg deep vein thrombosis (DVT) with pulmonary embolism (PE), 2pts DVT, 1 pt splanchnic vein thrombosis and PE, 1 pt PE without DVT and 1 patient a stroke. No VTE observed in arm B. Haemorrhagic events were 7.5% and 4% in arm A and B respectively. Within the first 12 weeks period 4 pts (15%) in arm A died, 2 from PE (autopsy- confirmed in one ‘sudden death’), 1 from stroke and one from progressive cancer. The VTE related mortality was 37%. In arm B the EDB was 4% as 1 pt died from sepsis. Conclusions: Results of the interim analysis indicate that the dose of dalteparin is safe. They also support our hypothesis that reduction of VTE may result in reduction of the EDB. The trial is on course to achieve its primary endpoint. No significant financial relationships to disclose.
Mitigation of goblet cell hyperplasia and gastrointestinal toxicity in rats with intermittent combination dosing of PF-03084014 (gamma secretase inhibitor) and dexamethasone.
Authors: B. Han, L. Liu, R. Denlinger, N. Hosea, L. Burns Naas, S. Randolph
Journal: Journal of Clinical Oncology (2010)

e13616 Background: Gamma-secretase inhibitors (GSIs), which block activation of the oncogenic protein Notch homolog-1 (NOTCH-1) are associated with severe gastrointestinal toxicity which potentially limits clinical application. While a combination treatment of GSI and dexamethasone (DEX) has been shown to reduce the gastrointestinal toxicity in mice by suppressing goblet cell hyperplasia, continuous concomitant treatment with GSI and DEX has limited clinical application due to the toxicity of DEX. Methods: In this study, rats were dosed orally with 100 mg/kg of PF-03084014 (a selective GSI that has demonstrated antitumor activity in Notch-driven tumors) for 4 weeks. During weeks 1 and 3, 1 mg/kg of DEX was given concomitantly by oral administration. The gastrointestinal tract was examined microscopically for goblet cell hyperplasia following week 1 (7 days of PF-03084014 and DEX in combination); following week 2 (7days of single agent PF-03084014); following week 3 (7 days of PF-03084014 and DEX in combination); and following week 4 (7 days of single agent PF-03084014). Results: Goblet cell hyperplasia was mitigated at all intervals, compared with controls, including weeks where rats received PF-03084014 alone. In addition, the suppression of goblet cell hyperplasia by intermittent combination dosing with DEX lasted up to 4 weeks. Conclusions: The data suggest that the protective effect of DEX lasts beyond its actual dosing period, and that intermittent combination therapy with PF-03084014 and DEX may be a viable dosing regimen in the clinic to minimize GSI-related GI toxicity while extending the treatment period of PF-03084014. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer
Clinical activity of pertuzumab (rhuMab 2C4) in advanced, refractory or recurrent ovarian cancer (OC), and the role of HER2 activation status
Authors: M. S. Gordon, D. Matei, C. Aghajanian, U. A. Matulonis, M. A. Brewer, G. F. Fleming, J. D. Hainsworth, A. A. Garcia, M. Pegram, B. Y. Karlan
Journal: Journal of Clinical Oncology (2005)

5051 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs) that inhibit dimerization of HER2 with EGFR, HER3 and HER4, and inhibit signaling through MAP and PI3 kinases. A phase I trial has demonstrated safety and activity in several tumors including ovarian cancer (OC). Interim data from a phase II trial with P in OC is presented. Methods: 65 pts with relapsed OC were enrolled with 61 receiving therapy with P. P was administered intravenously with a loading of 840mg followed by 420mg every 3 weeks. Tumor assessments were obtained after 2, 4, 6, 8, 12 and 16 cycles. Response rate (RR) by RECIST was the primary endpoint. Fresh tumor biopsies were mandatory in order to assay for HER2 phosphorylation (pHER2) status. Results: Median age was 59 years (range 35–78) and median ECOG PS was 1 (range 0–3). The median number of prior chemotherapy regimens was 5. 60 pts were evaluable for response. There were 2 objective partial responses (PRs) (RR=3%) and 24 (40%) of pts had stable disease (SD) per RECIST. CA125 RR of >50% reduction was 12%. 11 pts (15%) had SD for >18 weeks (range 18–36 weeks), with 4 pts >32 weeks. Of the 65 tumor biopsies, 31 were evaluable and 8 (26%) were positive for pHER2 by ELISA. Overall median time to progression (TTP) was 6.6 weeks (n=54); TTP for pHER2+ pts was 20.9 weeks (n=8), compared to 5.7 weeks for pHER2- (n=20), and 9.4 weeks for unknown pHER2 status (n=26). P was well tolerated with diarrhea in 57% of pts (grade 1–3). 1 pt had a drop in ejection fraction to < 50% (45%). Conclusions: As a single agent P is well tolerated. Clinical activity was demonstrated by PR’s and CA125 responses in 15%, and SD for > 4 months in 18% of pts with heavily pretreated OC. This study suggests P may be active in OC. Preliminary analysis suggests pHER2 status may be important for P activity. An update on this trial, as well as a 2nd cohort of pts treated with 1050mg single agent P will be reported. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech, Inc. for accrual patient costs only, Genentech
Aortic valve conduit implantation in the descending thoracic aorta in a sheep model: The outcomes of pre-seeded scaffold
Authors: Abdol-Mohammad Kajbafzadeh, Seyed Hossein Ahmadi Tafti, Mohammad-Reza Mokhber-Dezfooli, Reza Khorramirouz, Shabnam Sabetkish, Nastaran Sabetkish, Shahram Rabbani, Hamid Tavana, Mohammad Javad Mohseni
Journal: International Journal of Surgery (2016)
pVAX14 DNA, a Non-Specific DNA Vaccine, Improves Survival In An Acute Promyelocytic Leukemia (APL) Mouse Model Treated With All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO) and Targets Leukemia Initiating Cells (LICs)
Authors: Satyananda Patel, Laura Guerenne, Carole Le Pogam, Petra Gorombei, Patricia Krief, Marie-Helene Schlageter, Robert West, Vikram Mathews, Marika Pla, Pierre Fenaux, Christine Chomienne, Rose Ann Padua
Journal: Blood (2013)
Multiple primary cancers in patients with non-Hodgkin’s lymphoma
Authors: H. Song, Y. Do, W. Lee, J. Lee
Journal: Journal of Clinical Oncology (2006)

17562 Background: Multiple primary malignant tumors have been documented with increased frequency over the last two decades. An analysis of other primary cancers in individuals with non-Hodgkin’s lymphoma (NHL) can help to elucidate this cancer epidemics and etiology. Methods: The occurrence of multiple malignancy was studied in patients with NHL from 1985 to 2005. Results: One or more additional cancers were observed in 19 patients. Seven were diagnosed prior to, 5 concomitantly with, and 7 after the diagnosis of NHL. The diagnosis of 5 synchronous primary cancer were rectal cancer, squamous cell esophageal cancer, prostatic cancer, transitional cell bladder cancer, and non-small cell lung cancer. Each cases of colon cancer, breast cancer, hepatoma, small cell lung cancer, stomach cancer, cervical cancer, and rhabdomyosarcoma were diagnosed prior to NHL, and the second primary cancers were two squamous skin cancer and each cases of melanoma, colon cancer, thyroid cancer, adenocarcinoma of the salivary gland, and cholangiocarcinoma. The mean age of synchronous cases was 68.2 ± 4.8 years-old, and all 5 cases were primary extranodal NHL (2 gastric, 1 nasopharynx, 1 nasal, 1 rectal) and pathologic diagnosis were diffuse large cell in 4 cases and extranasal NK/T cell type in one case. The mean age of the second primary NHL was 57.6 ± 11.4 years-old, and 5 of 7 cases were extranodal origin (each one case of colon, tonsil, tongue, stomach, and CNS), and were diagnosed 11, 19, 24, 72, 73, 101, 168 months after the diagnosis of variable cancers. The mean age of the second primary cancer was 46.9 ± 15.9 years-old, and 3 of 7 cases were extranodal origin (2 gastric and 1 tonsil), and were diagnosed 55, 73, 75, 99, 144, 156, 161 months after the diagnosis of NHL. Conclusions: The synchronous cases of NHL were more older and more frequent extranodal manifestations than metachronous cases. No significant financial relationships to disclose.