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PubMed1984

Relative biological effectiveness of modulated proton beams in various murine tissues.

The relative biological effectiveness (RBE) of proton beams produced by Harvard University 160 MeV synchrocyclotron was studied in various murine tissues. Reference radiation was Cobalt-60 gamma-rays from a teletherapy unit at the Massachusetts General Hospital. Animals were C3Hf/Sed mice derived from our defined flora mouse colony. Test tissues are: lens, lung, testes and tail vertebrae. The RBE of the third generation isotransplants of a spontaneous mouse mammary carcinoma was also investigated. The proton and Cobalt-60 irradiations were carried out simultaneously by 2 teams. The dose response curves obtained for testes weight loss and growth stunting of tail vertebrae indicated that the RBE for our protons was independent of radiation dose in the range of 0.4 to 16 Gy. This finding was identical to our previous studies of the murine fibrosarcoma, skin and small intestine. The RBE values for lens and lung tissues were obtained by determining radiation dose to result in a complete cataract in half the irradiated eyes in 210 days and a 50% mortality in 180 days respectively. We have studied proton RBE in 7 normal tissues and 2 tumors including previously reported results. The RBE values for these tissues were found to fall between 1.09 and 1.32. No significant differences in the proton RBE were found between the several normal and tumor tissues studied.

Animals↗
PubMed2005

Detecting proton flux across chromatophores driven by F0F1-ATPase using N-(fluorescein-5-thiocarbamoyl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt.

N-(Fluorescein-5-thiocarbamoyl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt (F-DHPE) is a lipid fluorescence dye sensitive to pH changes and is used in this study for detecting proton flux through F0F1-ATPase within chromatophores driven by ATP hydrolysis. F-DHPE is easily labeled to the outer surface of chromatophores. In the range of pH 7.0 to 9.0, fluorescence intensity is sensitive to pH changes. The sensitivity is especially great in the range of pH 8.2 to 9.0, so pH 8.6 was chosen as the appropriate experimental condition. It is shown that added ATP not only acts as a fluorescence quencher but also can be hydrolyzed by F0F1-ATPase to pump protons into chromatophores, resulting in fluorescence restoration. A stimulator (NaSO3) and various types of inhibitors (NaN3, 5'-adenylyl imidodiphosphate [AMP-PNP], and N,N'-dicyclohexylcarbodiimide [DCCD]) of F0F1 confirmed that fluorescence restoration is caused by ATP-driven proton flux. When loaded with one antibody (anti-beta antibody) or two antibodies (anti-beta antibody and sheep to rabbit second antibody), F0F1-ATPase exhibits lower proton pumping activities, as indicated by fluorescence restoration. The possible mechanism of the inhibition of antibodies on proton pumping activity is discussed.

Antibodies↗
PubMed2005

[Chordomas of the base of the skull and upper cervical spine. 100 patients irradiated by a 3D conformal technique combining photon and proton beams].

OBJECTIVE: To define prognostic factors for local control and survival in 100 consecutive patients treated by fractionated photon and proton radiation for chordoma of the skull base and upper cervical spine. PATIENTS AND METHODS: Between December 1995 and August 2002, 100 patients (median age: 53 years, range: 8-85, M/F sex-ratio: 3/2), were treated by a combination of high-energy photons and protons. The proton component was delivered by the 201 MeV proton beam of the Centre de Protonthérapie d'Orsay (CPO). The median total dose delivered to the gross tumour volume was 67 Cobalt Gray Equivalent (CGE) (range: 60-71). A complete surgery, incomplete surgery or a biopsy was performed before the radiotherapy in 16, 75 and 9 cases, respectively. RESULTS: With a median follow-up of 31 months (range: 1-87), 25 tumours failed locally. The 2 and 4-year local control rates were 86.3% (+/-3.9%) and 53.8% (+/-7.5%), respectively. According to multivariate analysis, less than 95% of the tumour volume encompassed by the 95% isodose line (P=0.048; RR: 3.4 IC95% [1.01-11.8]) and a minimal dose less than 56 CGE (p=0.042; RR: 2.3 IC95% [1.03-5.2]) were independent prognostic factors of local control. Ten patients died. The 2 and 5-year overall survival rates were 94.3% (+/-2.5%) and 80.5% (+/-7.2%). According to multivariate analysis, a controlled tumour (P=0.005; RR: 21 IC95% [2.2-200]) was the lonely independent favourable prognostic factor for overall survival. CONCLUSION: In chordomas of the skull base and upper cervical spine treated by surgical resection followed by high-dose photon and proton irradiation, local control is mainly dependent on the quality of radiation, especially dose-uniformity within the gross tumour volume. Special attention must be paid to minimise underdosed areas due to the close proximity of critical structures and possibly escalate dose-constraints to tumour targets in future studies, in view of the low toxicity observed to date.

Adolescent↗
PubMed2005

A COOH-terminal domain regulates the activity of Leishmania proton pumps LDH1A and LDH1B.

Leishmania donovani requires actively transporting proton efflux pumps to survive the acidic environment of macrophage phagolysosomal vacuoles and to maintain an electrogenic H(+) gradient for nutrient uptake. The L. donovani genome contains a differentially expressed pair of genes, LDH1A and LDH1B, with homology to yeast H(+)-ATPases that are 98% identical in sequence with amino acid differences concentrated at the COOH-terminus (15 of last 37 differ), a region implicated in regulation of yeast and plant proton pumps. Functional complementation of a Saccharomyces cerevisiae strain deficient in endogenous H(+)-ATPase activity, support of yeast growth at low pH, and ability to acidify media demonstrate that LDH1A and LDH1B encode proton pumps. LDH1A and LDH1B encode a COOH-terminal autoinhibitory domain as COOH-truncated peptides support increased rates of growth in yeast, enhanced media acidification, increased enzyme activity (V(max)) and decreased K(m). This regulatory domain mediates differing function properties; LDH1A, but not LDH1B, supports yeast growth at pH 3 and LDH1A shows a greater ability to acidify media. Deletion of the last eight amino acids from LDH1B permits growth at pH 3 and increases media acidification, swapping of the COOH-tails between LDH1A and LDH1B results in LDH1A (with LDH1B tail) unable to support yeast growth at pH 3 and LDH1B (with LDH1A tail) now able to support growth at pH 3. Replacement of the COOH-terminal eight amino acids of LDH1B with those from LDH1A also confers the ability to support growth at pH 3. The complementation system for the Leishmania proton pumps in yeast described here provides a means to dissect the functional properties of the two isoforms, a convenient supply of protein for structural analysis and a model amenable to screening proton pump inhibitors for potential anti-leishmanial therapeutics.

Animals↗
PubMed2005

Results of spot-scanning proton radiation therapy for chordoma and chondrosarcoma of the skull base: the Paul Scherrer Institut experience.

PURPOSE: To assess the clinical results of spot scanning proton beam radiation therapy (PT) in the treatment of skull base chordomas and low-grade chondrosarcomas (CS). METHODS AND MATERIALS: Between October 1998 and October 2003, 29 patients (median age, 39 years) with chordomas (n = 18) and CS (n = 11) were treated at the Paul Scherrer Institut (PSI) with protons using the main 510-MeV cyclotron. Tumor conformal application of proton beams was realized by spot scanning technology. The median chordoma and CS dose was 74 and 68 cobalt Gy equivalent, respectively (cobalt Gy equivalent = proton Gy x 1.1). Median gross tumor volumes (GTV) were 16.4 mL (range, 1.8-48.1 mL) and 15.2 mL (range, 2.3-57.3 mL) for chordoma and CS, respectively. Late toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v3.0) grading system. The median follow-up time was 29 months (range, 6-68 months). RESULTS: Actuarial 3-year local control rates were 87.5% and 100% for chordoma and CS, respectively. We observed one surgical pathway and one marginal failure in patients with chordomas. No regional failure or distant metastasis was observed. At 3 years, actuarial PFS and OS for the entire cohort was 90% and 93.8%, respectively. Actuarial 3-year complication-free survival was 82.2%. Radiation-induced pituitary dysfunction was observed in 4 (14%) patients (CTCAE Grade 2). No patient presented with post-PT brainstem or optic pathways necrosis or dysfunction. In univariate analysis, age < or =40 years at the time of PT affected favorably on PFS (p = 0.09). CONCLUSION: Spot-scanning PT offers high tumor control rates of skull base chordoma and CS. These results compare favorably to other combined proton-photon or carbon ion irradiation series. Observed toxicity was acceptable. Younger age (< or =40 years) was a favorable prognostic factor of PFS. These preliminary results are encouraging but should be confirmed during a longer follow-up.

Adult↗
PubMed2000

The mechanism of the proton transfer: an outline.

A brief summary of the principal notions of the quantum-mechanical theory of the charge transfer reactions has been presented. In the framework of this theory, the mechanism of the proton transfer consists in the classical medium reorganization that equalizes the proton energy levels in the initial and final states, and a consequent proton transfer via a quantum-mechanical underbarrier transition. On the basis of this mechanism, factors influencing the proton transfer probability, and hence kinetic isotope effect, have been discussed; among them are the optimum tunneling distance, the involvement of the excited vibrational states, etc. Semi-classical and quantum-mechanical treatments of the Swain-Schaad relations have been compared. Some applications to enzymatic proton-transfer reactions have been described.

Energy Metabolism↗
PubMed2000

Hydrogen bonds and proton transfer in general-catalytic transition-state stabilization in enzyme catalysis.

The question of the nature of the proton bridge involved in general acid-base catalysis in both enzymic and non-enzymic systems is considered in the light of long-known but insufficiently appreciated work of Jencks and his coworkers and of more recent results from neutron-diffraction crystallography and NMR spectroscopic studies, as well as results from isotope-effect investigations. These lines of inquiry lead toward the view that the bridging proton, when between electronegative atoms, is in a stable potential at the transition state, not participating strongly in the reaction-coordinate motion. Furthermore they suggest that bond order is well-conserved at unity for bridging protons, and give rough estimates of the degree to which the proton will respond to structural changes in its bonding partners. Thus if a center involved in general-catalytic bridging becomes more basic, the proton is expected to move toward it while maintaining a unit total bond order. For a unit increase in the pK of a bridging partner, the other partner is expected to acquire about 0.06 units of negative charge. The implications are considered for charge distribution in enzymic transition states as the basicity of catalytic residues changes in the course of molecular evolution or during progress along a catalytic pathway.

Catalysis↗
PubMed2000

Marcus rate theory applied to enzymatic proton transfer.

The hydration of CO(2) and the dehydration of HCO(3)(-) catalyzed by the carbonic anhydrases is accompanied by the transfer of protons between solution and the zinc-bound water molecule in the active site. This transfer is facilitated by amino acid residues of the enzyme which act as intramolecular proton shuttles; variants of carbonic anhydrase lacking such shuttle residues are enhanced or rescued in catalysis by intermolecular proton transfer from donors such as imidazole in solution. The resulting rate constants for proton transfer when compared with the values of the pK(a) of the donor and acceptor give Bronsted plots of high curvature. These data are described by Marcus theory which shows an intrinsic barrier for proton transfer from 1 to 2 kcal/mol and work terms or thermodynamic contributions to the free energy of reaction from 4 to10 kcal/mol. The interpretation of these Marcus parameters is discussed in terms of the well-studied pathway of the catalysis and structure of the enzymes.

Animals↗
PubMed2002

Cardiolipin: a proton trap for oxidative phosphorylation.

The role of specific lipid structures in biological membranes has been elusive. There are hundreds of them in nature. Why has nature made them? How do they aid in the functioning of membrane proteins? Genetics with its 'knock out' organisms declares that functions persist in the absence of any particular lipid. Nonetheless some lipids, such as cardiolipin (CL), are associated with particular functions in the cell. It may merely expand the variety of culture conditions (pH, temperature, etc.) under which the wild-type organism survives. This article explores a unique role of CL as a proton trap within membranes that conduct oxidative phosphorylation and therefore the synthesis of ATP. CL's pK(2) (above 8.0) provides a role for it as a headgroup proton trap for oxidative phosphorylation. It suggests why CL is found in membranes that pump protons. The high pK(2) also indicates that the headgroup has but one negative charge in the neutral pH range. Data on the binding of CL to all of the oxidative phosphorylation proteins suggest that the CL may aggregate the oxidative phosphorylation proteins into a patch while it restricts pumped protons within its headgroup domain - supplying protons to the ATP synthase with minimal changes in the bulk phase pH.

Cardiolipins↗
PubMed2001

Combination of photon and proton radiation therapy for chordomas and chondrosarcomas of the skull base: the Centre de Protonthérapie D'Orsay experience.

PURPOSE: Prospective analysis of local tumor control, survival, and treatment complications in 44 consecutive patients treated with fractionated photon and proton radiation for a chordoma or chondrosarcoma of the skull base. METHODS AND MATERIALS: Between December 1995 and December 1998, 45 patients with a median age of 55 years (14-85) were treated using a 201-MeV proton beam at the Centre de Protonthérapie d'Orsay, 34 for a chordoma and 11 for a chondrosarcoma. Irradiation combined high-energy photons and protons. Photons represented two-thirds of the total dose and protons one-third. The median total dose delivered within the gross tumor volume was 67 cobalt Gray equivalent (CGE) (range: 60-70). RESULTS: With a mean follow-up of 30.5 months (range: 2-56), the 3-year local control rates for chordomas and chondrosarcomas were 83.1% and 90%, respectively, and 3-year overall survival rates were 91% and 90%, respectively. Eight patients (18%) failed locally (7 within the clinical tumor volume and 1 unknown). Four patients died of tumor and 2 others of intercurrent disease. In univariate analysis, young age at time of radiotherapy influenced local control positively (p < 0.03), but not in multivariate analysis. Only 2 patients presented Grade 3 or 4 complications. CONCLUSION: In skull-base chordomas and chondrosarcomas, the combination of photons with a proton boost of one-third the total dose offers an excellent chance of cure at the price of an acceptable toxicity. These results should be confirmed with a longer follow-up.

Adolescent↗
PubMed2004

Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma.

PURPOSE: To determine the potential improvements in patients with paranasal sinus carcinoma by comparing proton and intensity-modulated radiotherapy (IMRT) with conventional and conformal photon treatment planning techniques. METHODS AND MATERIALS: In 5 patients, comparative treatment planning was performed by comparing proton plans and related conventional, conformal, and IMRT photon plans. The evaluations analyzed dose-volume histogram findings of the target volumes and organs at risk (OARs, i.e., pituitary gland, optical pathway structures, brain, nontarget tissue). RESULTS: The mean and maximal doses, dose inhomogeneities, and conformity indexes for the planning target volumes were comparable for all techniques. Photon plans resulted in greater volumes of irradiated nontarget tissues at the 10-70% dose level compared with the corresponding proton plans. The volumes thereby increased by a factor of 1.3-3.1 for conventional, 1.1-3.8 for conformal, and 1.1-3.7 for IMRT. Compared with conventional techniques, conformal and IMRT photon treatment planning options similarly reduced the mean dose to the OARs. The use of protons further reduced the mean dose to the OARs by up to 65% and 62% compared with the conformal and IMRT technique, respectively. CONCLUSION: Compared with conventional treatment techniques, conformal RT and IMRT similarly enabled dose reductions to the OARs. Additional improvements were obtained using proton-based treatment planning modalities.

Humans↗
PubMed2001

Exocytosed protons feedback to suppress the Ca2+ current in mammalian cone photoreceptors.

A proton pump acidifies synaptic vesicles and provides the electrochemical gradient for transmitter uptake. Although external protons can modulate membrane voltage- and ligand-gated conductances, the fate of the protons released when vesicles fuse with the plasma membrane is unclear. In the dark, the glutamate-laden vesicles of cone photoreceptors fuse continuously with the plasma membrane. I now show that vesicular protons feed back to block the nearby calcium channels that mediate release. This local proton-mediated feedback is a novel mechanism through which neurons may regulate the release of transmitter.

Acids↗
PubMed2001

On the mechanism of sodium-proton exchange in crayfish.

In salt depleted crayfish net sodium and proton fluxes were coupled 1:1 as required by the frog skin-turtle bladder model. In addition, three proton pump inhibitors produced equal reductions of both fluxes. It is concluded that the model operates in these animals. Net Na+ and H+ fluxes were very small in tap water adapted animals, but regression analysis clearly showed that they were coupled, though perhaps not 1:1. Proton pump inhibitors, at concentrations that suppressed fluxes in salt-depleted crayfish, had no measureable effect on proton movement in tap water-adapted animals. Two of them (dicyclocarbodiimide and N-ethyl maleimide), caused a small reduction in Na+ influx without affecting proton efflux. These experiments provide no support for operation of the frog-turtle system in adult crayfish adapted to tap water. A 2Na+-H+ exchanger is considered from an energetic point of view. Such a system might be able to couple Na+ and H+ fluxes in dilute, near neutral solutions ([Na+] approximately 1-2 mM; pH 7).

Animals↗
PubMed2002

Abundant proton pumping in Plasmodium falciparum, but why?

Intraerythrocytic Plasmodium parasites depend on glycolysis for energy production. The stoichiometric amounts of lactate and protons produced are efficiently removed by a lactate:H(+) symporter. However, inhibition of recently identified plasma-membrane proton pumps result in acidification, suggesting additional mechanism(s) for proton generation. This article attempts to integrate the knowledge on the metabolic generation of protons and their disposal in the regulation of parasite cytosolic pH, and suggests additional roles for the various proton pumps that act in the parasite membrane.

Animals↗
PubMed1989

The sodium ion translocating adenosinetriphosphatase of Propionigenium modestum pumps protons at low sodium ion concentrations.

The purified ATPase (F1F0) of Propionigenium modestum has its pH optimum at pH 7.0 or at pH 6.0 in the presence or absence of 5 mM NaCl, respectively. The activation by 5 mM NaCl was 12-fold at pH 7.0, 3.5-fold at pH 6.0, and 1.5-fold at pH 5.0. In addition to its function as a primary Na+ pump, the ATPase was capable of pumping protons. This activity was demonstrated with reconstituted proteoliposomes by the ATP-dependent quenching of the fluorescence of 9-amino-6-chloro-2-methoxyacridine. No delta pH was formed in the presence of the uncoupler carbonyl cyanide m-chlorophenylhydrazone or by blocking the ATPase with dicyclohexylcarbodiimide. In the presence of valinomycin and K+, the delta pH increased, in accord with the operation of an electrogenic proton pump. The proton pump was only operative at low Na+ concentrations (less than 1 mM), and its activity increased as the Na+ concentration decreased. Parallel to the decrease of H+ pumping, the velocity of the Na+ transport increased about 6-fold from 0.1 to 4 mM NaCl, indicating a switch from H+ to Na+ pumping, as the Na+ concentration increases. Due to proton leaks in the proteoliposomal membranes, fluorescence quenching was released after blocking the ATPase with dicyclohexylcarbodiimide, by trapping residual ATP with glucose and hexokinase, or by the Na+-induced conversion of the proton pump onto a Na+ pump. Amiloride, an inhibitor of various Na+-coupled transport systems, was without effect on the kinetics of Na+ transport by the P. modestum ATPase.

Amiloride↗
PubMed1998

Relevance of divalent cations to ATP-driven proton pumping in beef heart mitochondrial F0F1-ATPase.

The ATP hydrolysis rate and the ATP hydrolysis-linked proton translocation by the F0F1-ATPase of beef heart submitochondrial particles were examined in the presence of several divalent metal cations. All Me-ATP complexes tested sustained ATP hydrolysis, although to a different extent. However, only Mg- and Mn-ATP-dependent hydrolysis could sustain a high level of proton pumping activity, as determined by acridine fluorescence quenching. Moreover, the Km of the Me-ATP hydrolysis-induced proton pumping activity was very similar to the Km value of Me-ATP hydrolysis. Both oligomycin and DCCD caused the full recovery of the fluorescence, providing clear evidence for the association of Mg-ATP hydrolysis with proton translocation through the F0F1-ATPase complex. In contrast, with other Me-ATP complexes, including Ca-ATP as substrate, the proton pumping activity was undetectable, implicating an uncoupling nature for these substrates. Attempts to demonstrate the involvement of the epsilon subunit of the enzyme in the coupling mechanism failed, suggesting that the participation of at least the N-terminal segment of the subunit in the coupling mechanism of the mitochondrial enzyme is unlikely.

Adenosine Triphosphate↗
PubMed2000

Proton beam irradiation of subfoveal choroidal neovascularisation in age-related macular degeneration.

PURPOSE: To assess the safety and potential toxicity of proton beam radiation in the treatment of subfoveal choroidal neovascular membrane (CNVM) due to age-related manner degeneration (ARMD) in a prospective, non-randomised study. METHODS: Forty-eight eyes of 46 consecutive patients with subfoveal CNVM due to ARMD, not amenable to laser photocoagulation, were treated prospectively with a single proton beam exposure. Two dose regimens were evaluated: 8 CGE (Cobalt Gray Equivalent) and 14 CGE. Patients were followed for an average of 22.1 months after proton beam treatment. RESULTS: At the 12 month follow-up, 44% of eyes in the 8 CGE group and 75% of the eyes in the 14 CGE group had stabilized or improved visual acuity. Complex size in the 8 CGE group as measured on standard fluorescein angiography (FA), decreased or had no change initially but showed less effect over time, while the eyes treated with 14 CGE maintained decreased leakage over the follow-up period of 12 months. However, 11 eyes in the 14 CGE group experienced radiation retinopathy, with the onset between 3 and 30 months. Seven of these 11 eyes have demonstrated some visual loss but only 1 eye developed severe visual loss at 15 months after proton treatment. CONCLUSIONS: To date, 14 CGE has suggested a favourable influence on visual function and growth inhibition of CNVM. Proton beam irradiation appears to inhibit CNVM growth. The 14 CGE dose regimen appears to have a longer effect of CNVM growth than does 8 CGE, with overall stabilisation of visual function and growth inhibition. Radiation retinopathy has developed over time, but severe visual loss has been limited. On the basis of the incidence of radiation retinopathy, adjustments in the total radiation dosage and/or fractionation of the dosage should be considered.

Aged↗
PubMed1998

Gastro-oesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors.

BACKGROUND: Nocturnal gastric acid breakthrough, defined as intragastric pH < 4 for more than 1 h in the overnight period, is observed in up to 70% of normal subjects on proton pump inhibitors taken twice daily. The frequency of this breakthrough in patients with gastro-oesophageal reflux and accompanying oesophageal reflux during this period has not been studied. AIM: To examine the frequency of nocturnal break-through and accompanying oesophageal acid exposure in patients with gastro-oesophageal reflux treated with proton pump inhibitors twice daily. METHODS: Prolonged ambulatory pH records from 76 patients on twice daily proton pump inhibitors between January 1991 and July 1997 were analysed for the presence of nocturnal gastric acid breakthrough and accompanying oesophageal pH < 4. Studies from 31 normal subjects on twice daily proton pump inhibitors constituted the control group. RESULTS: Nocturnal gastric acid breakthrough was seen in 70% of 61 patients with gastro-oesophageal reflux, 80% of 15 patients with Barrett's oesophagus and 67% of normal controls (P=N.S.). Oesophageal acid exposure was seen in 33% of gastro-oesophageal reflux patients, 50% of Barrett's oesophagus patients and 8% of normal controls (P < 0.03). No difference was found between patients taking omeprazole or lansoprazole. CONCLUSION: Nocturnal acid breakthrough is frequently seen on proton pump inhibitors twice daily and is often accompanied by oesophageal reflux. This has important implications for medical therapy in patients with severe gastro-oesophageal reflux and Barrett's oesophagus.

2-Pyridinylmethylsulfinylbenzimidazoles↗