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Papers by David Flowers

Poster: "ECR 2012 / C-2093 / Is plain chest imaging being used appropriately in the pre-oper... more Poster: "ECR 2012 / C-2093 / Is plain chest imaging being used appropriately in the pre-operative staging of our breast cancer patients?" by: "D. E. S. Flowers1, O. Pearce2, J. Nash3, G. E. A. Beling4; 1Southampton/UK, 2Cosham/UK, 3Coventry/UK, 4Portsmouth/UK"

There al-e very few teenagers who are interested in politics or who even pay attention to them. W... more There al-e very few teenagers who are interested in politics or who even pay attention to them. What are the di fferences between the parties? Who are the candidates? Is their party united? These are questions which can be answered only by a minority of the teenagers. Some of them have not even thought about the questions; others do not have their minds made up as to what is the best solution. The minor would jump at the chance to vote, but very few would take the needed time and effort to prepare for voting. This country cloes not need voters who are making their decisions as they mark the ballots. It needs voters who have their minds made up and are ready to back their decisions with supporting evidence.

Journal for ImmunoTherapy of Cancer, 2021

BackgroundBispecific antibodies have shown significant promise as therapies for various cancers.1... more BackgroundBispecific antibodies have shown significant promise as therapies for various cancers.1 ATG101 is a bispecific antibody that crosslinks tumor-expressed PD-L1 to T-cell-expressed 4-1BB, thereby selectively activating tumor-infiltrating T-cells while inhibiting immune checkpoints. The pharmacologically active complex, which is a trimer consisting of drug bound to both PD-L1 and 4-1BB and is difficult to measure directly, was predicted using a semi-mechanistic pharmacological model by integrating and calibrating against data from multiple in vitro assays. The model was then used to predict both (1) the number of PD-L1:ATG101:4-1BB trimers formed per T-cell and (2) PD-L1 occupancy, allowing it to quantify 4-1BB-driven activation as well as checkpoint blockade along the PD-1:PD-L1 axis in vivo.MethodsModel structureA single-compartment in vitro model and a three-compartment in vivo model were built (figure 1). The bispecific molecules could first bind to either 4-1BB or PD-L1 a...

Blood, 1998

We examined the expression of two members of theNotch family, Notch-1 and Notch-2, and one Notch ... more We examined the expression of two members of theNotch family, Notch-1 and Notch-2, and one Notch ligand, Jagged-1, in hematopoietic cells. Both Notch-1 and Notch-2 were detected in murine marrow precursors (Lin−Sca-1+c-kit+). The Notch ligand, Jagged-1, was not detected in whole marrow or in precursors. However, Jagged-1 was seen in cultured primary murine fetal liver stroma, cultured primary murine bone marrow stroma, and in stromal cell lines. These results indicate a potential role for Notch-Notch ligand interactions in hematopoiesis. To further test this possibility, the effect of Jagged-1 on murine marrow precursor cells was assessed by coculturing sorted precursor cells (Lin−Sca-1+c-kit+) with a 3T3 cell layer that expressed human Jagged-1 or by incubating sorted precursors with beads coated with the purified extracellular domain of human Jagged-1 (Jagged-1ext). We found that Jagged-1, presented both on the cell surface and on beads, promoted a twofold to threefold increase in...

Blood, 2000

Notch signaling has been shown to play a key role in cell fate decisions in numerous developmenta... more Notch signaling has been shown to play a key role in cell fate decisions in numerous developmental systems. Using a reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we reported the expression of human Notch-1 in CD34+ progenitors. In this study, we evaluated the expression of human Notch-1 and Notch-2 protein by hematopoietic cells. In immunofluoresence study, we detected low amounts of Notch-1 and Notch-2 protein in both CD34+ and CD34+Lin− cells, high amounts in CD14+ monocytes as well as B and T cells, but no expression in CD15+ granulocytes. We further found that an immobilized truncated form of the Notch ligand, Delta-1, induced apoptosis in monocytes in the presence of macrophage colony-stimulating factor (M-CSF), but not granulocyte-macrophage colony-stimulating factor (GM-CSF). The widespread expressions of Notch proteins suggest multiple functions for this receptor during hematopoiesis. These studies further indicate a novel role for Notch in regulating monoc...

BMJ Case Reports, 2019

A 51-year-old man presented with a swollen left arm and unilateral pulsatile tinnitus 2 weeks aft... more A 51-year-old man presented with a swollen left arm and unilateral pulsatile tinnitus 2 weeks after a left upper arm polytetrafluoroethylene graft was created for haemodialysis access. A fistulogram of the left upper arm showed a central venous stenosis and significant retrograde flow up the left internal jugular vein. Percutaneous transluminal angioplasty was attempted unsuccessfully and fistula ligation was subsequently performed. This led to immediate resolution of the tinnitus. The venous stenosis was likely secondary to a cardiac resynchronisation therapy defibrillator, which had been removed 1 year previously. Central venous stenosis is a common but often asymptomatic complication of a cardiac device, with the exception of patients with upper extremity arteriovenous fistulas, who frequently develop symptomatic venous hypertension. This generally presents with ipsilateral arm swelling and/or high venous pressures during dialysis. To our knowledge, this is the first report of pu...

Nature Medicine, 2000

Hematopoietic stem cells give rise to progeny that either self-renew in an undifferentiated state... more Hematopoietic stem cells give rise to progeny that either self-renew in an undifferentiated state or lose self-renewal capabilities and commit to lymphoid or myeloid lineages. Here we evaluated whether hematopoietic stem cell self-renewal is affected by the Notch pathway. Notch signaling controls cell fate choices in both invertebrates and vertebrates by inhibiting certain differentiation pathways, thereby permitting cells to either differentiate along an alternative pathway or to self-renew. Notch receptors are present in hematopoietic precursors and Notch signaling enhances the in vitro generation of human and mouse hematopoietic precursors, determines T- or B-cell lineage specification from a common lymphoid precursor and promotes expansion of CD8(+) cells. Here, we demonstrate that constitutive Notch1 signaling in hematopoietic cells established immortalized, cytokine-dependent cell lines that generated progeny with either lymphoid or myeloid characteristics both in vitro and in vivo. These data support a role for Notch signaling in regulating hematopoietic stem cell self-renewal. Furthermore, the establishment of clonal, pluripotent cell lines provides the opportunity to assess mechanisms regulating stem cell commitment and demonstrates a general method for immortalizing stem cell populations for further analysis.

Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, Jan 7, 2015

Laparoscopic liver resection for lesions adjacent to major vasculature can be challenging, and ma... more Laparoscopic liver resection for lesions adjacent to major vasculature can be challenging, and many would consider it a contraindication. Recently, however, laparoscopic liver surgeons have been pushing boundaries and approached some of these lesions laparoscopically. We assessed feasibility, safety and oncological efficiency of this laparoscopic approach for these lesions. This is a monocenter study (2003-2013) describing technique and outcomes of laparoscopic liver resection for lesions adjacent to major vasculature: <2 cm from the portal vein (main trunk and first division), hepatic arteries or inferior vena cava. Thirty-seven patients underwent laparoscopic liver resection (LLR) for a lesion adjacent to major vasculature. Twenty-four (65 %) resections were for malignant disease and 92 % R0 resections. Conversion occurred in three patients (8 %). Mean operative time was 313 min (standard deviation (SD) ± 101) and intraoperative blood loss 400 ml (IQR 213-700). Clavien-Dindo co...

2008 51st Midwest Symposium on Circuits and Systems, 2008

A new calibration method applicable to pipelined analog-to-digital converters (ADCs) is introduce... more A new calibration method applicable to pipelined analog-to-digital converters (ADCs) is introduced. The concept of reference tapering is presented as a simplification of a previous method. Behavioral modeling results verify that this simple method is a viable alternative for increasing the performance of ADCs fabricated in deep-submicron processes. For low amplifier gains, simulations show an improvement of as much as

Journal of the American College of Cardiology, 1986

Epidemiology, 2005

Page 1. LETTERS Mobile Phone Use and Acoustic Neuromas To the Editor: Lönn et al1 state that a me... more Page 1. LETTERS Mobile Phone Use and Acoustic Neuromas To the Editor: Lönn et al1 state that a method of laterality analysis used in previous stud-ies of cellular telephones and brain tu-mors assumes that tumors are equally ...

Blood, 2001

Expression of multidrug resistance (MDR) features by acute myeloid leukemia (AML) cells predicts ... more Expression of multidrug resistance (MDR) features by acute myeloid leukemia (AML) cells predicts a poor response to many treatments. The MDR phenotype often correlates with expression of P-glycoprotein (Pgp), and Pgp antagonists such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtuzumab ozogamicin, an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, is effective monotherapy for CD33+ relapsed AML. However, the contribution of Pgp to gemtuzumab ozogamicin resistance is poorly defined. In this study, blast cell samples from relapsed AML patients eligible for gemtuzumab ozogamicin clinical trials were assayed for Pgp surface expression and Pgp function using a dye efflux assay. In most cases, surface expression of Pgp correlated with Pgp function, as indicated by elevated dye efflux that was inhibited by CSA. Among samples from patients who either failed to clear marrow blasts or failed to achieve remission, 72% or 52%, respectively, exhibi...

Blood, 2005

While gemtuzumab ozogamicin (GTMZ) is commonly used in the treatment of acute myeloid leukemia (A... more While gemtuzumab ozogamicin (GTMZ) is commonly used in the treatment of acute myeloid leukemia (AML) in combination with standard chemotherapy agents, the pediatric maximumtolerated dose (MTD) of GMTZ in combination with chemotherapy has not been determined. Patients and Methods The Children's Oncology Group AAML00P2 trial sought to define the MTD of GMTZ in combination with cytarabine and mitoxantrone and cytarabine and L-asparaginase chemotherapy regimens. Results The MTD for GMTZ in combination with cytarabine and mitoxantrone was 3 mg/m 2 while the MTD in combination with cytarabine and L-asparaginase was 2 mg/m 2. Toxicities observed in both treatment regimens were typical of those seen in the relapsed AML setting and consisted primarily of infectious complications. The overall remission response rate (mean Ϯ SE) was 45% Ϯ 15% and the 1 year event-free survival and overall survival estimates were 38% Ϯ 14% and 53% Ϯ 15%, respectively. Conclusion This trial determined the pediatric MTD for GMTZ with two commonly used AML chemotherapy combinations. Based on these results, an ongoing phase III trial conducted within the Children's Oncology Group is evaluating the effect of GMTZ when added to standard AML therapy.

Biotechnology Journal, 2013

Identifying multiple enzyme targets for metabolic engineering is very critical for redirecting ce... more Identifying multiple enzyme targets for metabolic engineering is very critical for redirecting cellular metabolism to achieve desirable phenotypes, e.g., overproduction of a target chemical. The challenge is to determine which enzymes and how much of these enzymes should be manipulated by adding, deleting, under‐, and/or over‐expressing associated genes. In this study, we report the development of a systematic multiple enzyme targeting method (SMET), to rationally design optimal strains for target chemical overproduction. The SMET method combines both elementary mode analysis and ensemble metabolic modeling to derive SMET metrics including l‐values and c‐values that can identify rate‐limiting reaction steps and suggest which enzymes and how much of these enzymes to manipulate to enhance product yields, titers, and productivities. We illustrated, tested, and validated the SMET method by analyzing two networks, a simple network for concept demonstration and an Escherichia coli metabol...

The American Journal of Cardiology, 1986

Twenty-nine patients with acute myocardial infarction (AMI) were studied in a randomized double-b... more Twenty-nine patients with acute myocardial infarction (AMI) were studied in a randomized double-blind trial of intravenous lidocaine and tocainide, followed by either oral tocainide or placebo without regard to previous therapy, for the prophylaxis of arrhythmias associated with acute infarction. No patient had symptomatic ventricular tachycardia or fibrillation, although 1 patient taking lidocaine was withdrawn from therapy because of breakthrough arrhythmias. One patient in each group died from mechanical complications of AMI. Tocainide was administered to 16 patients and lidocaine to 13. Seven of the 13 patients receiving lidocaine had ventricular tachycardia or accelerated idioventricular rhythm, compared with 2 of 16 receiving tocainide (p less than 0.05). Adverse effects were noted in 11 of the 13 patients receiving lidocaine and 6 of the 16 patients receiving tocainide. The infusions used provided therapeutic levels of lidocaine or tocainide and the transition to oral tocainide was accomplished safely with maintenance of therapeutic antiarrhythmic levels. Thus, tocainide appears to be at least as efficacious and may be safer than lidocaine for the prophylaxis of ventricular arrhythmias associated with AMI. The transition to oral tocainide is well tolerated and can be accomplished with minimal difficulty.

The American Journal of Cardiology, 1984

Studies were performed in 20 patients with symptomatic ventricular tachycardia (VT) to determine ... more Studies were performed in 20 patients with symptomatic ventricular tachycardia (VT) to determine the efficacy of bethanidine compared with procainamide in preventing VT induced by programmed electrical stimulation. Before administering bethanidine, 5 to 10 mg/kg, the patients received 15 mg of protriptyline orally 24 and 2 hours before electrophysiologic studies to prevent the orthostatic hypotensive effects of bethanidine. Sustained VT (VT not spontaneously stopping) was induced in 8 and nonsustained VT (10 beats or more, terminating spontaneously) was induced in 4 patients. Bethanidine, 5 mg/kg, protected in 7 patients, and 10 mg/kg protected 1 additional patient. Procainamide, 1,000 and 1,500 mg intravenously, protected 8 of 16 patients. Bethanidine prevented VT induction in 50% of the patients not protected by procainamide. Bethanidine facilitated VT induction in 3 patients, while procainamide facilitated VT induction in 1 patient. Four patients with symptomatic VT have received bethanidine therapy for an average of 11 +/- 1.3 months, without clinical recurrence of their VT. Concomitant administration of protriptyline attenuated the acute hemodynamic changes caused by bethanidine and chronic combined therapy of protriptyline and bethanidine abolished the severe orthostatic changes in blood pressure caused by bethanidine. These studies show that bethanidine is effective in preventing VT induction and, thus, its use may not be restricted only to cases of primary ventricular fibrillation.