A bipartite NLS motif mediates the nuclear import of Drosophila moesin.

The ERM protein family, which consists of three closely related proteins in vertebrates, ezrin, radixin, and moesin (ERM), is an ancient and important group of cytoplasmic actin-binding and organizing proteins. With their FERM domain, ERMs bind various transmembrane proteins and anchor them to the actin cortex through their C-terminal F-actin binding domain, thus they are major regulators of actin dynamics in the cell. ERMs participate in many fundamental cellular processes, such as phagocytosis, microvilli formation, T-cell activation and tumor metastasis. We have previously shown that, besides its cytoplasmic activities, the single ERM protein of Drosophila melanogaster, moesin, is also present in the cell nucleus, where it participates in gene expression and mRNA export. Here we study the mechanism by which moesin enters the nucleus. We show that the nuclear import of moesin is an NLS-mediated, active process. The nuclear localization sequence of the moesin protein is an evolutionarily highly conserved, conventional bipartite motif located on the surface of the FERM domain. Our experiments also reveal that the nuclear import of moesin does not require PIP2 binding or protein activation, and occurs in monomeric form. We propose, that the balance between the phosphorylated and non-phosphorylated protein pools determines the degree of nuclear import of moesin.

TEMPO-conjugated tobacco mosaic virus as a magnetic resonance imaging contrast agent for detection of superoxide production in the inflamed liver.

Superoxide, an anionic dioxygen molecule, plays a crucial role in redox regulation within the body but is implicated in various pathological conditions when produced excessively. Efforts to develop superoxide detection strategies have led to the exploration of organic-based contrast agents for magnetic resonance imaging (MRI). This study compares the effectiveness of two such agents, nTMV-TEMPO and kTMV-TEMPO, for detecting superoxide in a mouse liver model with lipopolysaccharide (LPS)-induced inflammation. The study demonstrates that kTMV-TEMPO, with a strategically positioned lysine residue for TEMPO attachment, outperforms nTMV-TEMPO as an MRI contrast agent. The enhanced sensitivity of kTMV-TEMPO is attributed to its more exposed TEMPO attachment site, facilitating stronger interactions with water protons and superoxide radicals. EPR kinetics experiments confirm kTMV-TEMPO's faster oxidation and reduction rates, making it a promising sensor for superoxide in inflamed liver tissue. In vivo experiments using healthy and LPS-induced inflamed mice reveal that reduced kTMV-TEMPO remains MRI-inactive in healthy mice but becomes MRI-active in inflamed livers. The contrast enhancement in inflamed livers is substantial, validating the potential of kTMV-TEMPO for detecting superoxide in vivo. This research underscores the importance of optimizing contrast agents for in vivo imaging applications. The enhanced sensitivity and biocompatibility of kTMV-TEMPO make it a promising candidate for further studies in the realm of medical imaging, particularly in the context of monitoring oxidative stress-related diseases.

2,3-Dihydroferroceno[3,4]pyrrolo[2,1-b]thiazol-5(8b)-ones: Synthesis, Structure and DFT Study on the Mechanism of Chemo- and Diastereoslective Annulations of (Sp)-2-Formylferrocenecarbonyl Fluoride and (Sp)-2-Formylferrocenecarboxylic Acid.

By means of the annulation of easy-to-handle yet sufficiently reactive (Sp)-2-formylferrocenecar- bonyl fluoride with the hydrochlorides of cysteamine and the methyl esters of enentiomer cysteines conducted in dichloromethane at room temperature in the presence of pyridine, the first members of 2,3-dihydroferroceno[3,4]pyrrolo[2,1-b]thiazol-5(8bH)-ones with the elements of planar- and central chirality were prepared as single enantiomers. An atom economic procedure was also elaborated for the synthesis of these organometallic heterocycles directly exploring (Sp)-2-formylferrocenecarboxylic acid in situ activated by CDI and TFA, sequentially added to the reaction mixture. The relative and consequently, the absolute, configuration of the isolated diastereomers was determined by NMR measurements supported by DFT structural optimization. On the basis of the results of synthetic control experiments and a series of further DFT modelling studies, including energetic and MO analysis of the iminium intermediates, we propose a mechanism for the thiazolidine-forming annulations that proceed via primary N-acylation followed by proton-mediated cyclocondensation and subsequent diastereoselective sulfhydryl-attack on the resulting iminium center.

Hyperpolarized 15N-labeled, deuterated tris (2-pyridylmethyl)amine as an MRI sensor of freely available Zn2.

Dynamic nuclear polarization (DNP) coupled with 15N magnetic resonance imaging (MRI) provides an opportunity to image quantitative levels of biologically important metal ions such as Zn2+, Mg2+ or Ca2+ using appropriately designed 15N enriched probes. For example, a Zn-specific probe could prove particularly valuable for imaging the tissue distribution of freely available Zn2+ ions, an important known metal ion biomarker in the pancreas, in prostate cancer, and in several neurodegenerative diseases. In the present study, we prepare the cell-permeable, 15N-enriched, d6-deuterated version of the well-known Zn2+ chelator, tris(2-pyridylmethyl)amine (TPA) and demonstrate that the polarized ligand had favorable T1 and linewidth characteristics for 15N MRI. Examples of how polarized TPA can be used to quantify freely available Zn2+ in homogenized human prostate tissue and intact cells are presented.

The modified vaccination technique designed to prevent and cure acute and chronic disorders.

In spite of enormous efforts there have been no solutions to date for preventing/terminating certain acute and chronic disorders of humans by vaccination or drugs. Yet it is well understood that if the target antigen (ag) could be presented appropriately to the cells of the immune system then solutions could be found. Recently, the Barabas research group has introduced and described the third vaccination method - called modified vaccination technique (MVT) - which has the ability to provide a corrective immune response in experimental animals with an autoimmune kidney disease. Injections of immune complexes - made up of the target ag and specific non-pathogenic IgM antibodies directed against the target ag - achieved downregulation of pathogenic immune responses and tolerance to self was regained. Utilizing the immune system's natural abilities to respond to corrective information, the MVT technique was able to prevent an autoimmune kidney disease from occurring (prophylactic effect) in experimental animals, and when present, terminating it (therapeutic effect) specifically and without measurable side effects.It is predicted that the application of the MVT will have the potential in the future to revolutionize the preventative and therapeutic options for dealing with chronic disorders in humans (such as autoimmune disease, cancer and acute chronic infections) and achieve cures.

[The effect of palliative neural therapy on the improvement of chronic pain]. / A palliatív jellegu neurálterápia hatása idült fájdalmak csökkentésében.

Background and purpose: To assess the extent to which pain therapy can improve chronic pain in a heterogeneous group of patients, its impact on their quality of life and the correlation of the changes with their age and the underlying disease. The investigation has its actuality by its impact on public health. Methods: a prospective, non-randomized, interventional, clinical cohort study was conducted under real-life conditions in a general pain clinic, which lasted for 6 months. Changes in pain intensity (VAS) and related quality of life changes (SF-36 HRQoL) were measured using validated internationally accepted questionnaires. The questionnaires were filled out by all patients on their own, so they provided information of self-esteem on their own. All patient post-treatment results were compared to pre-treatment results. The general quality of life changes found in our patients were compared to the representative norms of healthy population in Hungary. Subjects - patients participated voluntarily at their own decision in the survey. The underlying disease of chronic pain, age and gender of the patients did not limit the inclusion into the study. Results: Data of 231 patients were evaluated. After pain therapy, the decrease in intensity of pain was confirmed by VAS at p=0.002. This was linked to a quality of life change that has been shown to be p=0.003 for men, with p=0.002 in women with SF-36 HRQoL. Based on the correlation coefficients, the changes in quality of life improved regardless of the age of the patients and the nature of the underlying conditions causing the pain. Conclusion: Although analgesia is basicly a symptomatic therapy, our findings suggest that the reduction of pain improves the quality of life of patients independently from their, and the curability of the underlying and accompanying diseases.

Celiac plexus block increases quality of life in patients with pancreatic cancer.

BACKGROUND: Pancreatic cancer is a malignant disease with a high mortality rate and severe pain that is challenging to manage. To reduce the excruciating abdominal pain, opioids and adjuvant agents are conventionally used. OBJECTIVES: PRNCPB is a treatment of neural therapy. The number of studies assessing the effect on patients' QoL is limited and inconsistent. With this study, we intended to address this issue. STUDY DESIGN: A prospective nonrandomized study with a series of cases of unresectable pancreatic cancer was conducted. SETTING: The study was performed at our pain clinic under real life conditions. MATERIALS AND METHODS: A total number of 16 patients with severe abdominal pain were enrolled in the study all of whom had responded to combined systemic analgesic therapy inadequately and had intolerable side effects contraindicating further increase in dose. The efficacy of this invasive, palliative analgesic procedure was evaluated 35 days after PRNCPB was performed. Primary outcomes were changed in pain intensity using the VAS questionnaire. Secondary outcomes were improved in QoL using the SF-36 questionnaire. Changes in pain medications and adverse reactions were monitored. RESULTS: After PRNCPB patients experienced a significant decrease (P=0.002) in pain intensity as shown by the VAS score, and a decreased opiate demand. Their QoL scores considering effect sizes also improved (P<0.001). No complications attributable to PRNCPB were observed during the study period. Additionally, no adverse drug reactions were observed. LIMITATIONS: Detection, observation, and reporting bias can be estimated as moderate. Selection bias was not detected. CONCLUSION: Our results give preliminary evidence that PRNCPB might be helpful as an additional treatment to conventional pain management in end-stage pancreatic cancer patients. PRNCPB seems to improve QoL in these patients in a time frame of at least 5 weeks after intervention.

Probing carbohydrate metabolism using hyperpolarized 13 C-labeled molecules.

Glycolysis is a fundamental metabolic process in all organisms. Anomalies in glucose metabolism are linked to various pathological conditions. In particular, elevated aerobic glycolysis is a characteristic feature of rapidly growing cells. Glycolysis and the closely related pentose phosphate pathway can be monitored in real time by hyperpolarized 13 C-labeled metabolic substrates such as 13 C-enriched, deuterated D-glucose derivatives, [2-13 C]-D-fructose, [2-13 C] dihydroxyacetone, [1-13 C]-D-glycerate, [1-13 C]-D-glucono-δ-lactone and [1-13 C] pyruvate in healthy and diseased tissues. Elevated glycolysis in tumors (the Warburg effect) was also successfully imaged using hyperpolarized [U-13 C6 , U-2 H7 ]-D-glucose, while the size of the preexisting lactate pool can be measured by 13 C MRS and/or MRI with hyperpolarized [1-13 C]pyruvate. This review summarizes the application of various hyperpolarized 13 C-labeled metabolites to the real-time monitoring of glycolysis and related metabolic processes in normal and diseased tissues.

Improved Efficacy of Synthesizing *MIII-Labeled DOTA Complexes in Binary Mixtures of Water and Organic Solvents. A Combined Radio- and Physicochemical Study.

Typically, the synthesis of radiometal-based radiopharmaceuticals is performed in buffered aqueous solutions. We found that the presence of organic solvents like ethanol increased the radiolabeling yields of [68Ga]Ga-DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacatic acid). In the present study, the effect of organic cosolvents [ethanol (EtOH), isopropyl alcohol, and acetonitrile] on the radiolabeling yields of the macrocyclic chelator DOTA with several trivalent radiometals (gallium-68, scandium-44, and lutetium-177) was systematically investigated. Various binary water (H2O)/organic solvent mixtures allowed the radiolabeling of DOTA at a significantly lower temperature than 95 °C, which is relevant for the labeling of sensitive biological molecules. Simultaneously, much lower amounts of the chelators were required. This strategy may have a fundamental impact on the formulation of trivalent radiometal-based radiopharmaceuticals. The equilibrium properties and formation kinetics of [M(DOTA)]- (MIII= GaIII, CeIII, EuIII, YIII, and LuIII) complexes were investigated in H2O/EtOH mixtures (up to 70 vol % EtOH). The protonation constants of DOTA were determined by pH potentiometry in H2O/EtOH mixtures (0-70 vol % EtOH, 0.15 M NaCl, 25 °C). The log K1H and log K2H values associated with protonation of the ring N atoms decreased with an increase of the EtOH content. The formation rates of [M(DOTA)]- complexes increase with an increase of the pH and [EtOH]. Complexation occurs through rapid formation of the diprotonated [M(H2DOTA)]+ intermediates, which are in equilibrium with the kinetically active monoprotonated [M(HDOTA)] intermediates. The rate-controlling step is deprotonation (and rearrangement) of the monoprotonated intermediate, which occurs through H2O (*M(HL) kH2O) and OH- (*M(HL) kOH) assisted reaction pathways. The rate constants are essentially independent of the EtOH concentration, but the M(HL) kH2O values increase from CeIII to LuIII. However, the log KM(HL)H protonation constants, analogous to the log KH2 value, decrease with increasing [EtOH], which increases the concentration of the monoprotonated M(HDOTA) intermediate and accelerates formation of the final complexes. The overall rates of complex formation calculated by the obtained rate constants at different EtOH concentrations show a trend similar to that of the complexation rates determined with the use of radioactive isotopes.

Engineering a pH-Sensitive Liposomal MRI Agent by Modification of a Bacterial Channel.

MscL is a bacterial mechanosensitive channel that serves as a cellular emergency release valve, protecting the cell from lysis upon a drop in external osmolarity. The channel has an extremely large pore (30 Å) and can be purified and reconstituted into artificial membranes. Moreover, MscL is modified to open in response to alternative external stimuli including changes in pH. These properties suggest this channel's potential as a triggered "nanopore" for localized release of vesicular contents such as magnetic resonance imaging (MRI) contrast agents and drugs. Toward this end, several variants of pH-triggered MscL nanovalves are engineered. Stealth vesicles previously been shown to evade normal in vivo clearance and passively accumulate in inflamed and malignant tissues are reconstituted. These vesicles are loaded with 1,4,7,10-tetraazacyclododecane tetraacetic acid gadolinium complex (Gd-DOTA), an MRI contrast reagent, and the resulting nanodevices tested for their ability to release Gd-DOTA as evidenced by enhancement of the longitudinal relaxation rate (R1 ) of the bulk water proton spins. Nanovalves that are responsive to physiological pH changes are identified, but differ in sensitivity and efficacy, thus giving an array of nanovalves that could potentially be useful in different settings. These triggered nanodevices may be useful in delivering both diagnostic and therapeutic agents.

Hyperpolarized δ-[1-13 C]gluconolactone as a probe of the pentose phosphate pathway.

The pentose phosphate pathway (PPP) is thought to be upregulated in trauma (to produce excess NADPH) and in cancer (to provide ribose for nucleotide biosynthesis), but simple methods for detecting changes in flux through this pathway are not available. MRI of hyperpolarized 13 C-enriched metabolites offers considerable potential as a rapid, non-invasive tool for detecting changes in metabolic fluxes. In this study, hyperpolarized δ-[1-13 C]gluconolactone was used as a probe to detect flux through the oxidative portion of the pentose phosphate pathway (PPPox ) in isolated perfused mouse livers. The appearance of hyperpolarized (HP) H13 CO3- within seconds after exposure of livers to HP-δ-[1-13 C]gluconolactone demonstrates that this probe rapidly enters hepatocytes, becomes phosphorylated, and enters the PPPox pathway to produce HP-H13 CO3- after three enzyme catalyzed steps (6P-gluconolactonase, 6-phosphogluconate dehydrogenase, and carbonic anhydrase). Livers perfused with octanoate as their sole energy source show no change in production of H13 CO3- after exposure to low levels of H2 O2 , while livers perfused with glucose and insulin showed a twofold increase in H13 CO3- after exposure to peroxide. This indicates that flux through the PPPox is stimulated by H2 O2 in glucose perfused livers but not in livers perfused with octanoate alone. Subsequent perfusion of livers with non-polarized [1,2-13 C]glucose followed by 1 H NMR analysis of lactate in the perfusate verified that flux through the PPPox is indeed low in healthy livers and modestly higher in peroxide damaged livers. We conclude that hyperpolarized δ-[1-13 C]gluconolactone has the potential to serve as a metabolic imaging probe of this important biological pathway.

Charting the chemical space around the (iso)indoline scaffold, a comprehensive approach towards multitarget directed ligands.

Within the framework of orthosteric G protein coupled receptor (GPCR) polypharmacology herein we report the systematic elaboration and thorough evaluation of a data matrix generated by sampling the chemical space around a common 5,6-fused bicyclic heteroaromatic template applying characteristic pharmacophore elements of central nervous system (CNS) relevant aminergic GPCR ligands.

Smart Sensing System for the Prognostic Monitoring of Bone Health.

The objective of this paper is to report a novel non-invasive, real-time, and label-free smart assay technique for the prognostic detection of bone loss by electrochemical impedance spectroscopy (EIS). The proposed system incorporated an antibody-antigen-based sensor functionalization to induce selectivity for the C-terminal telopeptide type one collagen (CTx-I) molecules-a bone loss biomarker. Streptavidin agarose was immobilized on the sensing area of a silicon substrate-based planar sensor, patterned with gold interdigital electrodes, to capture the antibody-antigen complex. Calibration experiments were conducted with various known CTx-I concentrations in a buffer solution to obtain a reference curve that was used to quantify the concentration of an analyte in the unknown serum samples. Multivariate chemometric analyses were done to determine the performance viability of the developed system. The analyses suggested that a frequency of 710 Hz is the most discriminating regarding the system sensitivity. A detection limit of 0.147 ng/mL was achieved for the proposed sensor and the corresponding reference curve was linear in the range of 0.147 ng/mL to 2.669 ng/mL. Two sheep blood samples were tested by the developed technique and the results were validated using enzyme-linked immunosorbent assay (ELISA). The results from the proposed technique match those from the ELISA.

Hepatic gluconeogenesis influences (13)C enrichment in lactate in human brain tumors during metabolism of [1,2-(13)C]acetate.

(13)C-enriched compounds are readily metabolized in human malignancies. Fragments of the tumor, acquired by biopsy or surgical resection, may be acid-extracted and (13)C NMR spectroscopy of metabolites such as glutamate, glutamine, 2-hydroxyglutarate, lactate and others provide a rich source of information about tumor metabolism in situ. Recently we observed (13)C-(13)C spin-spin coupling in (13)C NMR spectra of lactate in brain tumors removed from patients who were infused with [1,2-(13)C]acetate prior to the surgery. We found, in four patients, that infusion of (13)C-enriched acetate was associated with synthesis of (13)C-enriched glucose, detectable in plasma. (13)C labeled glucose derived from [1,2-(13)C]acetate metabolism in the liver and the brain pyruvate recycling in the tumor together lead to the production of the (13)C labeled lactate pool in the brain tumor. Their combined contribution to acetate metabolism in the brain tumors was less than 4.0%, significantly lower than the direct oxidation of acetate in the citric acid cycle in tumors.

Suppression of tumor growth by a heterologous antibody directed against multiple myeloma dominant CD38 antigen in SCID mice injected with multiple myeloma cells.

Employing passive immunization - using a heterologous anti-CD38 IgG antibody containing serum - in SCID mice injected subcutaneously with human multiple myeloma cells, we have shown that treatments with the antiserum - especially in the presence of complement - significantly decreased cancer growth. However, administered antibody and complement was not sufficient in amount to prevent cancer cell multiplication and cancer growth expansion to a satisfactory degree. Larger volumes of the same components more than likely would have further reduced cancer growth and prolonged the life of mice. In control mice, cancer growth progressed faster proving that lytic immune response against multiple myeloma cells is necessary for cancer cell kill.

NMDA-receptor associated encephalitis in a woman with mature cystic ovarian teratoma.

Introduction - N-methyl-D-aspartate receptor (NMDA-R) antibody-associated encephalitis has been reported in the international neurological literature to be associated with mature or immature ovarian teratomas (OTs). However, few cases of encephalitis were diagnosed in Hungary. In 2011 Hollody et al. described the first case of anti-NMDA receptor associated encephalitis in Hungary. Objective - Our aim was to present a case of NMDA-R antibody-mediated encephalitis in a woman with OT thereby providing information facilitating diagnosis of OT in women, who present with symptoms of encephalitis. Case - We report the case of a 25 year-old women, who developed NMDA-R -antibody associated autoimmune encephalitis and who displayed confusion, disorientation, a behavioural disturbance with agitation and features of paranoia and at least one reported generalized tonic clonic seizure and orofacial dyskinesia. Magnetic resonance imaging revealed a functional ovarian cyst measuring 3.3 cm, which was removed surgically and demonstrated histologically to be a mature cystic OT. The serum was positive for antibodies to NMDA receptors. Following intravenous immunoglobulin treatment, oophorectomy and a 5-day course of plasma exchange, followed by corticosteroid and azathioprine immunosuppressive therapy, the patient displayed a significant clinical improvement. Conclusion - Cystic teratomas are common benign ovarian lesions in women of reproductive age. Although the association of OTs and NMDA-R antibody-associated encephalitis has been described in the international neurological literature, this relationship needs to be considered from on the interdisciplinary aspect by the health care providers.

Conditions for (13)C NMR detection of 2-hydroxyglutarate in tissue extracts from isocitrate dehydrogenase-mutated gliomas.

(13)C NMR (nuclear magnetic resonance) spectroscopy of extracts from patient tumor samples provides rich information about metabolism. However, in isocitrate dehydrogenase (IDH)-mutant gliomas, (13)C labeling is obscured in oncometabolite 2-hydroxyglutaric acid (2 HG) by glutamate and glutamine, prompting development of a simple method to resolve the metabolites. J-coupled multiplets in 2 HG were similar to glutamate and glutamine and could be clearly resolved at pH 6. A cryogenically cooled (13)C probe, but not J-resolved heteronuclear single quantum coherence spectroscopy, significantly improved detection of 2 HG. These methods enable the monitoring of (13)C-(13)C spin-spin couplings in 2 HG expressing IDH-mutant gliomas.

Molecular platform for design and synthesis of targeted dual-modality imaging probes.

We report a versatile dendritic structure based platform for construction of targeted dual-modality imaging probes. The platform contains multiple copies of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) branching out from a 1,4,7-triazacyclononane-N,N',N″-triacetic acid (NOTA) core. The specific coordination chemistries of the NOTA and DOTA moieties offer specific loading of (68/67)Ga(3+) and Gd(3+), respectively, into a common molecular scaffold. The platform also contains three amino groups which can potentiate targeted dual-modality imaging of PET/MRI or SPECT/MRI (PET: positron emission tomography; SPECT: single photon emission computed tomography; MRI: magnetic resonance imaging) when further functionalized by targeting vectors of interest. To validate this design concept, a bimetallic complex was synthesized with six peripheral Gd-DOTA units and one Ga-NOTA core at the center, whose ion T1 relaxivity per gadolinium atom was measured to be 15.99 mM(-1) s(-1) at 20 MHz. Further, the bimetallic agent demonstrated its anticipated in vivo stability, tissue distribution, and pharmacokinetic profile when labeled with (67)Ga. When conjugated with a model targeting peptide sequence, the trivalent construct was able to visualize tumors in a mouse xenograft model by both PET and MRI via a single dose injection.

A comparative study of trans- and cis-isomers of a bone-seeking agent, DO2A2P.

The macrocyclic bone-seeking agent, DO2A2P, bears a cyclen core and two pairs of peripheral phosphonate and carboxylate groups. The geometric disposition of the peripheral functionalities gives arise to a pair of geometric isomers: cis-DO2A2P and trans-DO2A2P. In order to compare the biological behavior of the isomer pair, cis-DO2A2P was synthesized. Both isomers were successfully radiolabeled with (177)Lu, which might potentiate their applications in both radiotherapy and imaging of bone diseases. Through a set of biological assays including the hydroxyapatite binding, in vitro stability, and in vivo distribution, we demonstrated that the geometric pair of DO2A2P had virtually identical biological properties.

Acetate is a bioenergetic substrate for human glioblastoma and brain metastases.

Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using (13)C-NMR analysis of brain tumors resected from patients during infusion of (13)C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-(13)C]acetate and can do so while simultaneously oxidizing [1,6-(13)C]glucose. The tumors do not oxidize [U-(13)C]glutamine. In vivo oxidation of [1,2-(13)C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth.