In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

/pdf/understanding-the-warburg-effect-the-metabolic-requirements-t1cwrmjv80.pdf

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications

1. Introduction 20642. Synthesis of Magnetic Nanoparticles 20662.1. Classical Synthesis by Coprecipitation 20662.2. Reactions in Constrained Environments 20682.3. Hydrothermal and High-TemperatureReactions20692.4. Sol-Gel Reactions 20702.5. Polyol Methods 20712.6. Flow Injection Syntheses 20712.7. Electrochemical Methods 20712.8. Aerosol/Vapor Methods 20712.9. Sonolysis 20723. Stabilization of Magnetic Particles 20723.1. Monomeric Stabilizers 20723.1.1. Carboxylates 20733.1.2. Phosphates 20733.2. Inorganic Materials 20733.2.1. Silica 20733.2.2. Gold 20743.3. Polymer Stabilizers 20743.3.1. Dextran 20743.3.2. Polyethylene Glycol (PEG) 20753.3.3. Polyvinyl Alcohol (PVA) 20753.3.4. Alginate 20753.3.5. Chitosan 20753.3.6. Other Polymers 20753.4. Other Strategies for Stabilization 20764. Methods of Vectorization of the Particles 20765. Structural and Physicochemical Characterization 20785.1. Size, Polydispersity, Shape, and SurfaceCharacterization20795.2. Structure of Ferro- or FerrimagneticNanoparticles20805.2.1. Ferro- and Ferrimagnetic Nanoparticles 20805.3. Use of Nanoparticles as Contrast Agents forMRI20825.3.1. High Anisotropy Model 20845.3.2. Small Crystal and Low Anisotropy EnergyLimit20855.3.3. Practical Interests of Magnetic NuclearRelaxation for the Characterization ofSuperparamagnetic Colloid20855.3.4. Relaxation of Agglomerated Systems 20856. Applications 20866.1. MRI: Cellular Labeling, Molecular Imaging(Inﬂammation, Apoptose, etc.)20866.2.

Magnetic Iron Oxide Nanoparticles: Synthesis, Stabilization, Vectorization, Physicochemical Characterizations, and Biological Applications

One of the fastest moving and most exciting interfaces of nanotechnology is the use of quantum dots (QDs) in biology. The unique optical properties of QDs make them appealing as in vivo and in vitro fluorophores in a variety of biological investigations, in which traditional fluorescent labels based on organic molecules fall short of providing long-term stability and simultaneous detection of multiple signals. The ability to make QDs water soluble and target them to specific biomolecules has led to promising applications in cellular labelling, deep-tissue imaging, assay labelling and as efficient fluorescence resonance energy transfer donors. Despite recent progress, much work still needs to be done to achieve reproducible and robust surface functionalization and develop flexible bioconjugation techniques. In this review, we look at current methods for preparing QD bioconjugates as well as presenting an overview of applications. The potential of QDs in biology has just begun to be realized and new avenues will arise as our ability to manipulate these materials improves.

Quantum dot bioconjugates for imaging, labelling and sensing

2 Objectives Approximately 20%-25% of patients with colorectal cancer (CRC) have liver metastases at the time of diagnosis. The prognosis of CRC is dependent on accurate diagnosis at the time of biopsy as well as the efficiency of liver cytoreductive surgery. C-Met is a proto-oncogene overexpressing in 70-86 % of CRC and can be effectively used to detect metastatic foci of CRC to liver. Our aim was to assess whether optical imaging of c-Met using a targeted fluorescence probe, GE-137, can be used to delineate intrahepatic CRC metastasis and be effectively employed for intraoperative and minimally invasive interventions. Methods A focal model of CRC metastasis to liver was generated by injection of human CRC cells (HT-29) in the hepatic subcapsular space in nu/nu mice (n=8). Multispectral epifluorescence imaging was performed over 8 hours following GE-137 probe injection and uptake in the liver and tumor, and tumor to background ratio (TBR) were calculated. Biodistribution study was performed to evaluate NIR signal in different organs1 hour after probe injection. IHC evaluation of c-Met expression in human CRCs was performed using a tissue array. Results Surface epifluorescence imaging showed high uptake in subcapsularly grown tumors with the maximum intensity 1 hour after injection. While the signal intensity in both liver and xenograft tumor decreased afterwards, TBR increased constantly (1.41±0.14, 5 min vs. 5.29±1.59, 8 hours after injection). Tumor to background liver signal reached a peak of 15.28±0.9, 1 hour post-injection. Biodistribution study demonstrated low NIR signal in normal liver tissue. IHC confirmed elevated expression of c-MET in 81% of CRC samples. Conclusions High tumor to normal liver fluorescence ratios in our tumor model using GE-137 and overexpression of c-MET in most of human CRC tumors suggest that optical imaging of c-MET is a promising and translatable approach for early detection of liver metastases from CRC and for intraoperative and minimally invasive image-guided interventions.

Non-invasive imaging of C-MET receptor for delineation of liver metastasis of colorectal cancer

Oncology presentations at this meeting included 252 basic science reports and 276 clinical reports—far too many to review in the limited time allotted for these highlights. One of the highlights for me was listening to the Cassen Lecture, titled “What Have We Learned from the National Oncologic PET Registry,” delivered by this year’s Cassen awardee, Barry A. Siegel, MD, reviewing what we have done and can do as a community to advance patient care in cancer.

Scientific knowledge about cancer is accelerating in terms of understanding mechanisms of disease, cancer pathways, and the cell types involved. It is encouraging that the imaging sciences are keeping pace with this acceleration of discovery, and we saw many of these innovations highlighted at this SNMMI meeting.

It may seem a little trite in an overview of oncology to show slides from Hanahan and Weinberg’s “Hallmarks of cancer: the next generation” (Cell. 2011;144:646), but at this meeting we heard presentations on imaging of cells throughout the tumor microenvironment, including immune cells, cancer stem cells, endothelial cells, and invasive cancer cells as they change from epithelial to mesenchymal phenotypes. With increased specificity of therapeutic targeting of different cancers we are able to image receptor tyrosine kinases to help guide therapy choices, for example, guiding inhibition of epidermal growth factor receptor (EGFR) when it is overexpressed. We are looking at proliferation to study cyclin-dependent kinase inhibitors. We are looking at immune cell activation by imaging immune cells and at vascular changes by documenting vascular endothelial growth factor (VEGF) signaling. We are researching metabolic changes, for example, with aerobic glycolysis inhibitors. For all of these fundamental hallmarks of cancer, we are engaged in continuous enhancement of techniques and expansion of knowledge to improve imaging for diagnosis and to guide therapeutic decision making.

2014 SNMMI highlights lecture: Oncology.

https://jnm.snmjournals.org/content/50/11/15N.full.pdf

MICoE Task Force Looks to the Future

https://ieeexplore.ieee.org/iel5/51/29517/01337950.pdf

Near Infrared Optical Applications in Molecular Imaging Earlier, More Accurate Assessment of Disease Presence, Disease Course, and Efficacy of

1793 Objectives Distinguishing true progression of glioblastoma multiforme (GBM) from pseudoprogression after surgery with chemoradiation is quite challenging using current imaging techniques. EGFR is overexpressed on 40-60% of GBMs, and we hypothesized that targeted imaging could provide a novel mechanism for distinguishing recurrence from pseudoprogression. We developed and preclinically tested a novel PET probe, 64Cu-DOTA-EGFR F(ab)’2, for direct tumor imaging based on EGFR expression. Methods An EGFR-specific imaging probe, 64Cu-DOTA-EGFR F(ab)’2 was developed with F(ab)’2 fragmentation and chelator conjugation of a humanized monoclonal antibody to EGFR. Probe affinity was assessed using 67Ga labeling and saturation binding studies with EGFR positive A345 cells. For in-vivo studies, mice were intracranially injected with EGFR WT-expressing U87 or EGFR vIII expressing Gli-36vIII, n=3 for each group. PET-CT imaging of tumors was performed 24 hours after injection with 64Cu-DOTA-EGFR F(ab)’2 . Blocking studies were performed by injecting cetuximab 24h prior to imaging agent administration into the mice with intracranial U87 or Gli36vIII tumors, n=3 respectively. Results 67Ga-DOTA-EGFR F(ab)’2 was generated with radiochemical purity of >95%, and binds to EGFR with a Kd of 11.5 nM. PET-CT imaging of intracranially injected tumors (n=3 for each group) demonstrated SUV of 0.83 ± 0.13 for U87 tumors, and a SUV of 0.89 ± 0.07 for Gli36vIII tumors, demonstrating TBRs of 27.7 and 25.5, respectively. After blocking with cetuximab (n=3 for each group), uptake of imaging agent was reduced by 58% and 68% in U87 and Gli36vIII tumors, respectively, demonstrating probe specificity. Conclusions Specific PET imaging of EGFR-expressing GBMs is possible using the novel PET imaging agent 64Cu-DOTA-EGFR F(ab)’2.

Umar Mahmood

Papers

Non-invasive imaging of C-MET receptor for delineation of liver metastasis of colorectal cancer

2014 SNMMI highlights lecture: Oncology.

MICoE Task Force Looks to the Future

Near Infrared Optical Applications in Molecular Imaging Earlier, More Accurate Assessment of Disease Presence, Disease Course, and Efficacy of

A F(ab)′2-based EGFR targeted PET probe for glioma imaging