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PubMed2000

Optimizing radiotherapy of orbital and paraorbital tumors: intensity-modulated X-ray beams vs. intensity-modulated proton beams.

PURPOSE: This study presents a dosimetric optimization effort aiming to compare intensity-modulated (IM) X-rays and IM protons in 4 different orbital and paraorbital tumors. These are most challenging targets for standard radiotherapy due to their close relationship with the eyes and related structures. METHODS AND MATERIALS: A primary orbital lymphoma, an optic nerve meningioma, a sphenoidal ridge meningioma protruding into the orbit, and a pediatric parameningeal paraorbital rhabdomyosarcoma were selected for the purpose of this study. Planning target volumes (PTVs) and organs at risk (OAR) were defined in each patient CT data set for each tumor site. IM X-ray and IM proton three-dimensional treatment plans were implemented. The following total tumor doses were prescribed: 30 Gy for the orbital lymphoma, 54 Gy for both meningiomas, and 50.4 Gy for the rhabdomyosarcoma case. Dose-volume histograms (DVHs) were obtained for all targets and OAR with both treatment techniques. DVHs were used to predict normal tissue complication probabilities (NTCPs) for the OAR in the vicinity of the tumor. RESULTS: The PTV coverage was optimal and equally homogeneous with both IM X-rays and IM proton plans in the 4 tumor sites. DVHs for most OAR were better with IM proton beams especially in the low- to mid-dose range region. The integral nontarget dose was lower with IM protons in every case (factor ranging from 1.5 to 1.9). However, predicted NTCPs (for severe late effects) were equally low for both treatment techniques in every tumor site. CONCLUSION: Although IM proton plans optimally decreased the dose to the OAR in all tumor sites, both optimized X-ray and proton beams equally succeeded to reduce severe-toxicity prediction risks to less than 5% while optimally treating the PTV.

Humans↗
PubMed2001

A comparison of dose distributions of proton and photon beams in stereotactic conformal radiotherapy of brain lesions.

PURPOSE: Micromultileaf collimators (mMLC) have recently been introduced to conform photon beams in stereotactic irradiation of brain lesions. Proton beams and stereotactic conformal radiotherapy (SCRT) can be used to tailor the dose to nonspherical targets, as most tumors of the brain are irregularly shaped. Comparative planning of brain lesions using either proton or stereotactically guided photon beams was done to assess the institution's clinically available modality for three-dimensional conformal radiotherapy. METHODS AND MATERIALS: For the photon treatment, multiple stereotactically guided uniform intensity beams from a linear accelerator were used, each conformed to a projection of the planning target volume (PTV) by a mMLC. Proton beams were delivered from an isocentrically mounted gantry, using the spot-scanning technique and energy modulation. Seven patients were scanned in a stereotactic frame; target volumes and organs at risk (OAR) were delineated with the help of MR images. Four different lesions were selected: (1) concave, (2) ellipsoid isolated, (3) superficial and close to an organ at risk, and (4) irregular complex. Dose distributions in the PTV and critical structures were calculated using three-dimensional treatment-planning systems, followed by both a quantitative (by dose--volume histogram and conformity index) and qualitative (visual inspection) assessment of the plans. RESULTS: A high degree of conformation was achieved with a mMLC and stereotactic uniform intensity beams with comparable conformity indices to protons for 5 out of 7 plans, especially for superficial or spherical lesions. In the cases studied, the conformity index was better for protons than for photons for complex or concave lesions, or when the PTV was in the neighborhood of critical structures. CONCLUSION: The results for the cases studied, show that for simple geometries or for superficial lesions, there is no advantage in using protons. However, for complex PTV shapes, or when the PTV is in the vicinity of critical structures, protons seem to be potentially better than the fixed-field photon technique.

Brain Neoplasms↗
PubMed2002

Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors.

PURPOSE: To assess the potential influence of improved dose distribution with proton beams compared to conventional or intensity-modulated (IM) X-ray beams on the incidence of treatment-induced secondary cancers in pediatric oncology. METHODS AND MATERIALS: Two children, one with a parameningeal rhabdomyosarcoma (RMS) and a second with a medulloblastoma, were used as models for the purpose of this study. After defining the target and critical structures, treatment plans were calculated and optimized, four for the RMS case (conventional X-ray, IM X-rays, protons, and IM protons) and three for the irradiation of the spinal axis in medulloblastoma (conventional X-ray, IM X-rays, protons). Secondary cancer incidence was estimated using a model based on Publication No. 60 of the International Commission on Radiologic Protection. This model allowed estimation of absolute risks of secondary cancer for each treatment plan based on dose-volume distributions for the nontarget organs. RESULTS: Proton beams reduced the expected incidence of radiation-induced secondary cancers for the RMS patient by a factor of >or=2 and for the medulloblastoma case by a factor of 8 to 15 when compared with either IM or conventional X-ray plans. CONCLUSIONS: The potential for a significant reduction in secondary cancers with pediatric cancers after using proton beams (forward planned or IM) in the treatment of RMS and MBD in children and adolescents represents an additional argument supporting the development of proton therapy for most radiotherapy indications in pediatric oncology.

Child↗
PubMed2004

Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma.

PURPOSE: To compare treatment plans from standard photon therapy to intensity modulated X-rays (IMRT) and protons for craniospinal axis irradiation and posterior fossa boost in a patient with medulloblastoma. METHODS: Proton planning was accomplished using an in-house 3D planning system. IMRT plans were developed using the KonRad treatment planning system with 6-MV photons. RESULTS: Substantial normal-tissue dose sparing was realized with IMRT and proton treatment of the posterior fossa and spinal column. For example, the dose to 90% of the cochlea was reduced from 101.2% of the prescribed posterior fossa boost dose from conventional X-rays to 33.4% and 2.4% from IMRT and protons, respectively. Dose to 50% of the heart volume was reduced from 72.2% for conventional X-rays to 29.5% for IMRT and 0.5% for protons. Long-term toxicity with emphasis on hearing and endocrine and cardiac function should be substantially improved secondary to nontarget tissue sparing achieved with protons. CONCLUSION: The present study clearly demonstrates the advantage of conformal radiation methods for the treatment of posterior fossa and spinal column in children with medulloblastoma, when compared to conventional X-rays. Of the two conformal treatment methods evaluated, protons were found to be superior to IMRT.

Cerebellar Neoplasms↗
PubMed2000

Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors.

Proton pump inhibitors have dramatically influenced the management of acid-peptic disorders in recent years. They all have a broadly similar mechanism of action and are extensively metabolized in the liver via cytochromes P450 2C19 and 3A4. There is some variation in their potential for drug interactions due to differences in enzyme inhibition. Relatively few serious adverse effects have been reported for the proton pump inhibitors. Comparative studies of acid suppression suggest that lansoprazole and pantoprazole have a potency similar to that of omeprazole on a mg for mg basis; however, rabeprazole may have a greater potency than omeprazole. Lansoprazole and rabeprazole display a more rapid onset of maximal acid suppression than the other proton pump inhibitors. Comparative studies using proton pump inhibitors for the treatment of reflux oesophagitis, duodenal ulcer healing and Helicobacter pylori eradication show little overall difference in outcome between the proton pump inhibitors when used in their standard doses. Lansoprazole and rabeprazole provide earlier and better symptom relief than the other proton pump inhibitors in some studies of peptic ulcer treatment. The few studies of gastric ulcer treatment suggest that there is an advantage in using the proton pump inhibitors that have a higher standard daily dose.

Duodenal Ulcer↗
PubMed2003

Low yield of endoscopy in patients with persistent dyspepsia taking proton pump inhibitors.

BACKGROUND: Options for the evaluation of dyspepsia include a Helicobacter pylori test-and-treat strategy, empiric acid suppression, and initial endoscopy. The aim of this study was to determine the yield of endoscopy in patients in whom empiric therapy is unsuccessful compared with patients who received no empiric therapy and to identify factors associated with endoscopic findings. METHODS: A total of 100 patients with dyspepsia referred for endoscopy completed a questionnaire that included a query concerning response to therapy. EGD findings were compared in patients taking an H2-receptor antagonist, patients taking a proton pump inhibitor, and those not receiving empiric therapy. RESULTS: There were fewer endoscopic findings in patients being treated with a proton pump inhibitor compared with those taking an H2-receptor antagonist or those not receiving therapy (p < 0.01). Fewer proton pump inhibitor recipients had esophagitis or ulcer compared with patients in the no therapy group. Lack of symptom relief (<20%) by acid suppression was highly associated with a normal endoscopy (17/17). CONCLUSIONS: Patients with persistent dyspepsia being treated with a proton pump inhibitor have fewer endoscopic abnormalities compared with patients with dyspepsia taking an H2-receptor antagonist and those receiving no therapy. For patients with partial symptom relief, proton pump inhibitor therapy may mask endoscopic findings, particularly esophagitis. Interruption of proton pump inhibitors before endoscopy may increase diagnostic yield. Endoscopy is unlikely to yield a positive finding in patients who experience no symptom relief while taking a proton pump inhibitor or H2-receptor antagonist.

Adult↗
PubMed1997

On the role of Arg-210 and Glu-219 of subunit a in proton translocation by the Escherichia coli F0F1-ATP synthase.

A strain of Escherichia coli was constructed which had a complete deletion of the chromosomal uncB gene encoding subunit a of the F0F1-ATP synthase. Gene replacement was facilitated by a selection protocol that utilized the sacB gene of Bacillus subtilis cloned in a kanamycin resistance cartridge (Ried, J. L., and Collmer, A. (1987) Gene (Amst.) 57, 239-246). F0 subunits b and c inserted normally into the membrane in the DeltauncB strain. This observation confirms a previous report (Hermolin, J., and Fillingame, R. H. (1995) J. Biol. Chem. 270, 2815-2817) that subunit a is not required for the insertion of subunits b and c. The DeltauncB strain has been used to characterize mutations in Arg-210 and Glu-219 of subunit a, residues previously postulated to be essential in proton translocation. The aE219G and aE219K mutants grew on a succinate carbon source via oxidative phosphorylation and membranes from these mutants exhibited ATPase-coupled proton translocation (i.e. ATP driven 9-amino-6-chloromethoxyacridine quenching responses that were 60-80% of wild type membranes). We conclude that the aGlu-219 residue cannot play a critical role in proton translocation. The aR210A mutant did not grow on succinate and membranes exhibited no ATPase-coupled proton translocation. However, on removal of F1 from membrane, the aR210A mutant F0 was active in passive proton translocation, i.e. in dissipating the DeltapH normally established by NADH oxidation with these membrane vesicles. aR210A membranes with F1 bound were also proton permeable. Arg-210 of subunit a may play a critical role in active H+ transport that is coupled to ATP synthesis or hydrolysis, but is not essential for the translocation of protons across the membranes.

Arginine↗
PubMed2005

Proton therapy of cancer: potential clinical advantages and cost-effectiveness.

Proton therapy may offer potential clinical advantages compared with conventional radiation therapy for many cancer patients. Due to the large investment costs for building a proton therapy facility, however, the treatment cost with proton radiation is higher than with conventional radiation. It is therefore important to evaluate whether the medical benefits of proton therapy are large enough to motivate the higher costs. We assessed the cost-effectiveness of proton therapy in the treatment of four different cancers: left-sided breast cancer, prostate cancer, head and neck cancer, and childhood medulloblastoma. A Markov cohort simulation model was created for each cancer type and used to simulate the life of patients treated with radiation. Cost and quality adjusted life years (QALYs) were used as primary outcome measures. The results indicated that proton therapy was cost-effective if appropriate risk groups were chosen. The average cost per QALY gained for the four types of cancer assessed was about pounds 10,130. If the value of a QALY was set to pounds 55,000, the total yearly net benefit of treating 925 cancer patients with the four types of cancer was about pounds 20.8 million. Investment in a proton facility may thus be cost-effective. The results must be interpreted with caution, since there is a lack of data, and consequently large uncertainties in the assumptions used.

Aged↗
PubMed2003

The H+/K+-ATPase (proton) pump is expressed in human laryngeal submucosal glands.

OBJECTIVES/HYPOTHESIS: Diagnosis and treatment of gastroesophageal and laryngopharyngeal reflux disease has significantly increased over recent years. The larynx is highly sensitive to the effects of LPRD and is similarly responsive to proton pump inhibitor pharmacotherapy. The hypothesis of the study was that proton pump activity exists in the human larynx and plays a functional role in normal and/or pathological laryngeal tissue. STUDY DESIGN: Pathological investigation. METHODS: Two fresh human cadaveric larynges (one male and one female larynx) were obtained as part of an exempt protocol from the Human Subjects Committee and were formalin fixed and paraffin embedded. Banked human stomach tissue was also obtained for use as comparative positive and negative control specimens. Sections were immunostained with monoclonal antibodies reactive with both alpha and beta subunits of the H+/K+-ATPase (proton) pump. Specimens were reviewed for staining pattern and intensity. RESULTS: Stomach parietal cells (known to produce gastric acid) exhibited strongly positive staining for both the alpha and beta subunits of the proton pump. There was no staining in stomach cells that were not morphologically consistent with the parietal cell. In the human larynx there were strong focal and identical staining patterns in the serous cells and ducts of the minor seromucinous glands by both alpha and beta monoclonals to the proton pump. There was variable staining in the laryngeal epithelium that was thought to be consistent with artifact staining resulting from tissue processing. CONCLUSION: The H+/K+-ATPase (proton) pump is present in serous cells and ducts of submucosal glands in the human larynx. Proton pump inhibitor pharmacotherapy may have a site of action in seromucinous glands of the human larynx, with possible relevance for patients treated for chronic laryngitis with or without laryngopharyngeal reflux disease.

Adenosine Triphosphatases↗
PubMed2006

Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy.

BACKGROUND: It is controversial whether proton pump inhibitor use leads to fundic gland polyp development. AIM: To determine whether fundic gland polyp development is due to proton pump inhibitor use and to investigate mechanisms involved. METHODS: Proton pump inhibitor use and the presence of fundic gland polyps were assessed in consecutive patients undergoing oesophagogastroduodenoscopy. Biopsies from fundic gland polyps and gastric mucosa were taken. Dysplasia was graded as negative, low or high grade. Prevalence of parietal cell hyperplasia and parietal cell protrusions and the proportional cystic area were assessed. RESULTS: 599 patients participated, 322 used proton pump inhibitors, 107 had fundic gland polyps. Long-term proton pump inhibitor use was associated with an increased risk of fundic gland polyps (1-4.9 years use: OR 2.2, 95% CI: 1.3-3.8; > or =5 years: OR 3.8, 95% CI: 2.2-6.7) while short-term therapy (<1 year) was not (OR 1.0, 95% CI: 0.5-1.8). Low-grade dysplasia was found in one fundic gland polyp. Fundic gland polyps associated with long-term proton pump inhibitor use had a larger proportional cystic area and higher frequency of parietal cell hyperplasia and parietal cell protrusion. CONCLUSIONS: Long-term proton pump inhibitor use is associated with an up to fourfold increase in the risk of fundic gland polyps. Risk of dysplasia is negligible. Aetiologically, these polyps seem to arise because of parietal cell hyperplasia and parietal cell protrusions resulting from acid suppression.

Adolescent↗
PubMed2007

Systematic review: Rebound acid hypersecretion after therapy with proton pump inhibitors.

BACKGROUND: The occurrence and the clinical relevance of rebound acid hypersecretion after discontinuation of proton pump inhibitors is unclear. AIM: To perform a systematic review of rebound acid hypersecretion after discontinuation of proton pump inhibitors. METHODS: PubMed, Embase and Central were searched up to October 2005 with indexed terms. RESULTS: Eight studies were included, sample size was 6-32. The studies used both basal and stimulated acid output as parameters to study rebound acid hypersecretion and assessed these at different time points and with variable methods. Five studies (including four randomized studies) did not find any evidence for rebound acid hypersecretion after proton pump inhibitor therapy. Of the remaining three studies, the duration of proton pump inhibitor therapy was the longest and two of these studies were the only to assess Helicobacter pylori status of their study subjects. These two studies suggested that rebound acid hypersecretion may occur in H. pylori-negatives after 8 weeks of proton pump inhibitors. CONCLUSIONS: Studies that have investigated rebound acid hypersecretion after cessation of proton pump inhibitor treatment are heterogenic in design, methods and outcome. There is some evidence from uncontrolled trials for an increased capacity to secrete acid in H. pylori-negative subjects after 8 weeks of treatment. There is no strong evidence for a clinically relevant increased acid production after withdrawal of proton pump inhibitor therapy.

Female↗
PubMed1982

Effect of thiol reagents on the proton conductivity of the H+-ATPase of mitochondria.

The role of thiol groups in the proton conduction by the H+-ATPase of mitochondria is examined. A detailed kinetic analysis of the effect of arsenite and N-ethylmaleimide on the anaerobic relaxation of the proton gradient set up by respiration in 'inside-out' submitochondrial particles from beef-heart has been carried out. Arsenite, which reacts with vicinal dithiols, is shown to enhance the proton conductivity of the H+-ATPase. This effect is exerted on the F0 moiety of the complex and apparently mimics and is, in fact, favoured by a state of high proton conductivity induced in the complex by the respiratory delta mu H+. N-Ethylmaleimide (MalNEt), which is a permeant monothiol blocking reagent, appears to attack critical -SH groups in a reaction leading to inhibition of the proton conductivity of the H+-ATPase. Also the inhibitory action of MalNEt on proton conduction is exerted on the F0 moiety of the H+-ATPase. Whilst the stimulatory effect of arsenite develops rapidly, the inhibitory action of MalNEt is sluggish and takes more than 10 min to fully develop. This and other kinetic characteristics, as well a partial additivity of the inhibition by MalNEt with that by oligomycin, indicate that the inhibitory action of MalNEt is associated to a substantial conformational transition in F0. Differences in the mechanism of inhibition of proton conduction by MalNEt and triphenyltin are also presented.

Adenosine Triphosphatases↗
PubMed2004

Proton pump inhibitors and the time trends for esophageal dilation.

AIM: Little is known about the impact of widespread proton pump inhibitor use on the need for dilation of esophageal strictures. To determine the time trends for upper endoscopy and stricture dilation before and after the availability of proton pump inhibitors. METHODS: The computerized databases of two large community hospitals were analyzed. Annual data on dilation procedures (by all methods) and upper endoscopy were obtained and analyzed in quartiles from 1986 to 2001 to determine if the relative or absolute need for dilation changed following the introduction of proton pump inhibitors in the United States. The number of prescriptions for acid suppressive agents (H2 receptor antagonists and proton pump inhibitors) for the corresponding time period was obtained from the IMS health database. RESULTS: A total of 57,496 upper GI endoscopies and 2,868 esophageal dilations were performed. The proportion of patients undergoing esophageal dilation increased from 4% in 1986-1989 to 6% in 1990-1993 (p < 0.001), remained unchanged (5.8%) in the period from 1994 to 1997 but declined significantly to 3.9% (p < 0.001) in the next quartile (1998-2001). Absolute numbers of dilation procedures declined significantly in the last quartile (1998-2001) and the proton pump inhibitor prescriptions in the United States increased markedly from 1995 onward. CONCLUSIONS: The need for stricture dilation peaked in 1994 and has declined thereafter, corresponding to an increase in the use of proton pump inhibitors. The widespread use of proton pump inhibitors has not, however, abolished the need for esophageal dilation.

Adult↗
PubMed1999

Proton-beam radiotherapy for early-stage lung cancer.

STUDY OBJECTIVE: A prospective study was undertaken to assess the efficacy and toxicity of conformal proton-beam radiotherapy for early-stage, medically inoperable non-small cell lung cancer. DESIGN: Eligible patients had clinical stage I to IIIa non-small cell lung cancer and were not candidates for surgical resection for medical reasons or because of patient refusal. Patients with adequate cardiopulmonary function received 45 Gy to the mediastinum and gross tumor volume with photons with a concurrent proton boost to the gross tumor volume of an additional 28.8 cobalt gray equivalents (CGE). Total tumor dose was 73.8 CGE given over 5 weeks. Patients with poor cardiopulmonary function received proton-beam radiotherapy to the gross tumor volume only, with 51 CGE given in 10 fractions over a 2-week period. RESULTS: Thirty-seven patients were treated in the study from July 1994 to March 1998. Clinical staging of patients was as follows: stage I, 27 patients; stage II, 2 patients; and stage IIIa, 8 patients. Eighteen patients received a combination of protons and x rays, while 19 patients received proton-beam radiation only. Follow-up of evaluable patients ranged from 3 to 45 months, with a median of 14 months. Two patients in the proton and photon arm developed pneumonitis that resolved with oral steroids; otherwise, no significant toxicities were encountered. The actuarial disease-free survival at 2 years for the entire group was 63%; for stage I patients, disease-free survival at 2 years was 86%. Local disease control was 87%. CONCLUSION: Preliminary results from this study indicate that proton-beam radiotherapy can be used safely in this group of patients. Disease-free survival and local control appear to be good and compare favorably with published reports utilizing conventional photon irradiation.

Aged↗
PubMed1987

Inhibition of the coated vesicle proton pump and labeling of a 17,000-dalton polypeptide by N,N'-dicyclohexylcarbodiimide.

N,N'-Dicyclohexylcarbodiimide (DCCD) inhibits 100% of proton transport and 80-85% of (Mg2+)-ATPase activity in clathrin-coated vesicles. Half-maximum inhibition of proton transport is observed at 10 microM DCCD after 30 min. Although treatment of the coated vesicle (H+)-ATPase with DCCD has no effect on ATP hydrolysis in the detergent-solubilized state, sensitivity of proton transport and ATPase activity to DCCD is restored following reconstitution into phospholipid vesicles. In addition, treatment of the detergent-solubilized enzyme with DCCD followed by reconstitution gives a preparation that is blocked in both proton transport and ATP hydrolysis. These results suggest that although the coated vesicle (H+)-ATPase can react with DCCD in either a membrane-bound or detergent-solubilized state, inhibition of ATPase activity is only manifested when the pump is present in sealed membrane vesicles. To identify the subunit responsible for inhibition of the coated vesicle (H+)-ATPase by DCCD, we have labeled the partially purified enzyme with [14C]DCCD. A single polypeptide of molecular weight 17,000 is labeled. The extremely hydrophobic nature of this polypeptide is indicated by its extraction with chloroform:methanol. The 17,000-dalton protein can be labeled to a maximum stoichiometry of 0.99 mol of DCCD/mol of protein with 100% inhibition of proton transport occurring at a stoichiometry of 0.15-0.20 mol of DCCD/mol of protein. Amino acid analysis of the chloroform:methanol extracted 17,000-dalton polypeptide reveals a high percentage of nonpolar amino acids. The similarity in properties of this protein and the DCCD-binding subunit of the coupling factor (H+)-ATPases suggests that the 17,000-dalton polypeptide may function as part of a proton channel in the coated vesicle proton pump.

Animals↗
PubMed1988

Partial resolution and reconstitution of the subunits of the clathrin-coated vesicle proton ATPase responsible for Ca2+-activated ATP hydrolysis.

The clathrin-coated vesicle proton-translocating complex is composed of a maximum of eight major polypeptides. Of these potential subunits, only the 17-kDa component, which is a proton pore, has been defined functionally (Sun, S.Z., Xie, X. S., and Stone, D. K. (1987) J. Biol. Chem. 262, 14790-14794). ATPase-and proton-pumping activities of the 200-fold purified proton-translocating complex are supported by Mg2+, whereas Ca2+ will only activate ATP hydrolysis. Like Mg2+-activated ATPase activity, Ca2+-supported ATP hydrolysis is inhibited by N-ethylmaleimide, NO3-, and an inhibitory antibody and is stimulated by Cl- and phosphatidylserine. Thus, Ca2+ prevents coupling of ATPase activity to vectoral proton movement, and Ca2+-activated ATPase activity is a partial reaction useful for analyzing the subunit structure required for ATP hydrolysis. The 530-kDa holoenzyme was dissociated with 3 M urea and subcomplexes, and isolated subunits were partially resolved by glycerol gradient centrifugation. No combination of these components yielded Mg2+-activated ATPase or proton pumping. Ca2+-activated ATP hydrolysis was not catalyzed by a subcomplex containing the 70- and 58-kDa subunits but was restored by recombination of the 70-, 58-, 40-, and 33-kDa polypeptides, indicating that these are subunits of the clathrin-coated vesicle proton pump which are necessary for ATP hydrolysis.

Adenosine Triphosphate↗
PubMed1988

Delta subunit of chloroplast coupling factor 1 inhibits proton leakage through coupling factor O.

The ATP synthase of chloroplasts consists of a proton-conducting portion, CF0, and a catalytic portion, CF1. The smaller subunits of CF1, in particular delta, may play a key role in the coupling of proton transport to ATP synthesis. Purified subunit delta, when added to partially CF1-depleted thylakoid membranes, can restore photophosphorylation (Engelbrecht, S., and Junge, W. (1987) Eur. J. Biochem. 172, 213-218). We report here that it does so by blocking proton conduction through CF0. Thylakoids were CF1-depleted by incubation in hypoosmolar NaCl/EDTA solutions. Variation of the NaCl concentrations and of the incubation times not only changed the overall degree of CF1 depletion but also the subunit composition of solubilized CF1, namely CF1 containing delta and CF1(-delta). This was quantified by immunoelectrophoresis and by fast protein liquid chromatography. Proton conduction was measured by flash spectrophotometry by using standard electrochromic and pH-indicating absorption changes. The removal of integral CF1 was correlated with high electric conductance of thylakoid membranes, an increased extent of rapid proton leakage, and loss of ATP synthesis activity, which exceeded the percentual loss of CF1. The removal of predominantly CF1(-delta) resulted in comparatively lesser effects on the loss of ATP synthesis and on the extent and velocity of proton leakage. On the same line, addition of integral CF1 and of purified delta diminished the electric leak in CF1-depleted thylakoids. Both approaches, the controlled removal of CF1 and CF1(-delta), respectively, and addition of delta and CF1 showed that delta can act as a "stopcock" to the exposed proton channel CF0.

Adenosine Triphosphate↗
PubMed1995

[Dose-volume histogram analysis of patients with hepatocellular carcinoma regarding changes in liver function after proton therapy].

Seventy-five patients with hepatocellular carcinoma were treated with proton beams from 1983-1993 at the Proton Medical Research Center, University of Tsukuba. For the purpose of confirming the feasibility of proton therapy for hepatocellular carcinoma, we investigated the influence of proton therapy on liver function and also tried to evaluate the possibility of optimization using dose-volume histogram (DVH) analysis. The results indicated that proton therapy did not cause clinically symptomatic damage in liver function and the only notable change after proton therapy was the transient increase of transminase. DVH analysis showed that this transient increase of transaminase was well correlated to the normal tissue complication probability (NTCP). These results indicate that localized high dose radiation using proton beams is feasible for the treatment of liver cancers and optimization of this treatment may be possible using DVH analysis.

Adult↗