86 research outputs found
Biochemical basis of 5-aminolaevulinic acid-induced protoporphyrin IX accumulation: a study in patients with (pre)malignant lesions of the oesophagus.
Administration of 5-aminolaevulinic acid (ALA) leads to porphyrin accumulation in malignant and premalignant tissues, and ALA is used as a prodrug in photodynamic therapy (PDT). To understand the mechanism of porphyrin accumulation after the administration of ALA and to investigate whether ALA-induced protoporphyrin IX might be a suitable photosensitizer in Barrett's oesophagus and adenocarcinoma, we determined the activities of porphobilinogen deaminase (PBG-D) and ferrochelatase (FC) in various malignant and premalignant as well as in normal tissues of the human oesophagus. A PDT power index for ALA-induced porphyrin accumulation, the ratio of PBG-D to FC normalized for the normal squamous epithelium of the oesophagus, was calculated to evaluate intertissue variation in the ability to accumulate porphyrins. In malignant and premalignant tissue a twofold increased PBG-D activity and a marginally increased FC activity was seen compared with normal squamous epithelium. A significantly increased PDT power index in Barrett's epithelium and adenocarcinoma was found. Our results suggest that, after the administration of ALA, porphyrins will accumulate in a greater amount in Barrett's epithelium and adenocarcinoma of the oesophagus because of an imbalance between PBG-D and FC activities. The PDT power index here defined might be a useful indicative parameter for predicting the susceptibility of these tissues to ALA-PDT
Porphyrin biosynthesis in human Barrett's oesophagus and adenocarcinoma after ingestion of 5-aminolaevulinic acid
5-Aminolaevulinic acid (ALA)-induced porphyrin biosynthesis, which is used for ALA-based photodynamic therapy (ALA-PDT), was studied in tissues of 10 patients with Barrett’s oesophagus (BE) and adenocarcinoma of the oesophagus (AC) undergoing oesophagectomy at a mean time interval of 6.7 h after the ingestion of ALA (60 mg kg–1). In BE, AC, squamous epithelium (SQ) and gastric cardia, the activities of the haem biosynthetic enzymes porphobilinogen deaminase (PBG-D) and ferrochelatase (FC) and the PDT power index – the ratio between PBG-D and FC in BE and AC in comparison with SQ – were determined before ALA ingestion. Following ALA administration, ALA, porphobilinogen, uroporphyrin I and PPIX were determined in tissues and plasma. The PDT power index did not predict the level of intracellular accumulation of PPIX found at 6.7 h. In BE, there was no selectivity of PPIX accumulation compared to SQ, whereas in half of patients with AC selectivity was found. Higher haem biosynthetic enzyme activities (i.e. PBG-D) and lower PPIX precursor concentrations were found in BE and AC compared to SQ. It is therefore possible that PPIX levels will peak at earlier time intervals in BE and AC compared to SQ. © 2000 Cancer Research Campaig
cGMP stimulation of cystic fibrosis transmembrane conductance regulator Cl- channels co-expressed with cGMP-dependent protein kinase type II but not type Ibeta
In order to investigate the involvement of cGMP-dependent protein kinase
(cGK) type II in cGMP-provoked intestinal Cl- secretion, cGMP-dependent
activation and phosphorylation of cystic fibrosis transmembrane
conductance regulator (CFTR) Cl- channels was analyzed after expression of
cGK II or cGK Ibeta in intact cells. An intestinal cell line which stably
expresses CFTR (IEC-CF7) but contains no detectable endogenous cGK II was
infected with a recombinant adenoviral vector containing the cGK II coding
region (Ad-cGK II) resulting in co-expression of active cGK II. In these
cells, CFTR was activated by membrane-permeant analogs of cGMP or by the
cGMP-elevating hormone atrial natriuretic peptide as measured by 125I-
efflux assays and whole-cell patch clamp analysis. In contrast, infection
with recombinant adenoviruses expressing cGK Ibeta or luciferase did not
convey cGMP sensitivity to CFTR in IEC-CF7 cells. Concordant with the
activation of CFTR by only cGK II, infection with Ad-cGK II but not Ad-cGK
Ibeta enabled cGMP analogs to increase CFTR phosphorylation in intact
cells. These and other data provide evidence that endogenous cGK II is a
key mediator of cGMP-provoked activation of CFTR in cells where both
proteins are co-localized, e. g. intestinal epithelial cells. Furthermore,
they demonstrate that neither the soluble cGK Ibeta nor cAMP-dependent
protein kinase are able to substitute for cGK II in this cGMP-regulated
function
Key Rotation for Authenticated Encryption
A common requirement in practice is to periodically rotate the keys used to
encrypt stored data. Systems used by Amazon and Google do so using a hybrid
encryption technique which is eminently practical but has questionable
security in the face of key compromises and does not provide full key
rotation. Meanwhile, symmetric updatable encryption schemes (introduced by
Boneh et al. CRYPTO 2013) support full key rotation without performing
decryption: ciphertexts created under one key can be rotated to ciphertexts
created under a different key with the help of a re-encryption token. By
design, the tokens do not leak information about keys or plaintexts and so
can be given to storage providers without compromising security. But the
prior work of Boneh et al. addresses relatively weak confidentiality goals
and does not consider integrity at all. Moreover, as we show, a subtle issue
with their concrete scheme obviates a security proof even for confidentiality
against passive attacks.
This paper presents a systematic study of updatable Authenticated Encryption
(AE). We provide a set of security notions that strengthen those in prior
work. These notions enable us to tease out real-world security requirements
of different strengths and build schemes that satisfy them efficiently. We
show that the hybrid approach currently used in industry achieves relatively
weak forms of confidentiality and integrity, but can be modified at low cost
to meet our stronger confidentiality and integrity goals. This leads to a
practical scheme that has negligible overhead beyond conventional AE. We then
introduce re-encryption indistinguishability, a security notion that formally
captures the idea of fully refreshing keys upon rotation. We show how to
repair the scheme of Boneh et al., attaining our stronger confidentiality
notion. We also show how to extend the scheme to provide integrity, and we
prove that it meets our re- encryption indistinguishability notion. Finally,
we discuss how to instantiate our scheme efficiently using off-the-shelf
cryptographic components (AE, hashing, elliptic curves). We report on the
performance of a prototype implementation, showing that fully secure key
rotations can be performed at a throughput of approximately 116 kB/s
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