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PubMed1996

Quality control of pharmaceuticals containing clenbuterol by thermal lens spectrometry.

An ultrasensitive absorptiometric procedure for the determination of clenbuterol in pharmaceutical preparations was developed. Clenbuterol was diazotized with nitrite and coupled with 1-(naphthyl)ethylenediamine, and the absorbance of the azo dye formed was measured by both spectrophotometry and ultrasensitive thermal lens spectrometry (TLS). The TLS limit of detection was 1.5 ppb, 14-fold lower than with a Hewlett-Packard diode array spectrophotometer. Thus, the TLS procedure can be advantageously applied to quality control of clenbuterol at the individual dose level and in small samples. Repeatability as relative standard deviation was 1.5% (50 ppb, n = 6).

Adrenergic beta-Agonists↗

PubMedDate not supplied

Emergency department approach to acute thoracolumbar spine injury.

This review provides a literature-based approach to the management of acute thoracolumbar spine (TLS) injury. The epidemiology of spinal cord injury and pertinent spinal cord anatomy are reviewed. A review of current TLS fracture/dislocation classification schemes is provided. The principal focus of this review is the immediate diagnostic and therapeutic interventions needed to maximize the recovery of patients with acute TLS injury.

Acute Disease↗

PubMed2004

Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage.

Most types of DNA damage block replication fork progression during DNA synthesis because replicative DNA polymerases are unable to accommodate altered DNA bases in their active sites. To overcome this block, eukaryotic cells employ specialized translesion synthesis (TLS) polymerases, which can insert nucleotides opposite damaged bases. In particular, TLS by DNA polymerase eta (poleta) is the major pathway for bypassing UV photoproducts. How the cell switches from replicative to TLS polymerase at the site of blocked forks is unknown. We show that, in human cells, PCNA becomes monoubiquitinated following UV irradiation of the cells and that this is dependent on the hRad18 protein. Monoubiquitinated PCNA but not unmodified PCNA specifically interacts with poleta, and we have identified two motifs in poleta that are involved in this interaction. Our findings provide an attractive mechanism by which monoubiquitination of PCNA might mediate the polymerase switch.

Chromatin↗

PubMed1986

Tourette-like syndrome following low dose short-term neuroleptic treatment.

A Tourette-like syndrome (TLS) may occur after long-term neuroleptic treatment. A review of 11 cases reported in the literature is given. We describe the onset of a TLS in a 13-year old boy with childhood schizophrenia after short term, low-dose treatment with thioridazine. The syndrome resolved 5 months after neuroleptic withdrawal. Subsequent exposure to neuroleptics (mainly perphenazine) induced a recurrence of motor tics and involuntary vocalizations which resolved on drug discontinuation. Awareness that neuroleptics may induce a TLS may lead to prompt recognition and avoidance of labelling the manifestations as symptoms of the underlying psychosis or attention-seeking behaviour.

Adolescent↗

PubMed2006

The management of tumor lysis syndrome.

The manifestation of tumor lysis syndrome (TLS) occurs when the destruction of tumor cells releases breakdown products that overwhelm the excretory mechanisms of the body. A cardinal sign is hyperuricemia, leading to uric acid nephropathy. Other signs are hyperkalemia, hyperphosphatemia and secondary hypocalcemia. Conventional management of TLS consists of aggressive intravenous hydration, diuretic therapy, urinary alkalization, and inhibition of urate production by high-dose allopurinol. Urate oxidase has been used in the management of patients at risk for TLS and recently the recombinant urate oxidase rasburicase was developed. Several data indicate that rasburicase is effective and well tolerated in the prevention and treatment of chemotherapy-induced hyperuricemia. Treatment options of hyperkalemia include sodium polystyrene sulfonate, hypertonic glucose and insulin, loop diuretics, and bicarbonate. Treatment of hyperphosphatemia reduces dietary phosphate intake and includes phosphate binders such as aluminum hydroxide and aluminum carbonate. When recurrent hypocalcemia is present, a continuous intravenous infusion of calcium gluconate can be initiated. Hemodialysis should be considered for every patient with excessively elevated uric acid, phosphate and/or potassium and in those patients with acute renal failure to control urinary volume and manage uremia.

Acute Kidney Injury↗

PubMed2003

Peracute onset of severe tumor lysis syndrome immediately after 4 Gy fractionated TBI as part of reduced intensity preparative regimen in a patient with T-ALL with high tumor burden.

We report a 30-year-old patient with therapy-refractory T-ALL undergoing unrelated allogeneic PBSCT. He developed severe tumor lysis syndrome (TLS) with extreme biochemical changes, cardiac and neurological symptoms and dialysis-dependent acute renal failure after TBI (4 Gy) on the first day of reduced intensity conditioning (RIC) for unrelated allogeneic PBSCT. The patient's clinical condition was stabilized after beginning daily hemodialysis and treatment for disturbed electrolytes, metabolic acidosis and plasma coagulation, as well as reduction of uric acid by rasburicase. The conditioning therapy and the allogenic PBSCT were scheduled according to the preparative regimen. According to our knowledge, severe TLS induced by 4 Gy TBI has not been reported so far. Regimen-related toxicity using RIC regimen was mild, allowing 30-50% of the patients to have an entirely outpatient transplantation. However, we would like to point out that severe TLS could also complicate PBSCT using RIC regimens in patients with relatively radiation-sensitive malignancies and high tumor burden.

Adult↗

PubMed2004

Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM.

Some of the restarting events of stalled replication forks lead to sister chromatid exchange (SCE) as a result of homologous recombination (HR) repair with crossing over. The rate of SCE is elevated by the loss of BLM helicase or by a defect in translesion synthesis (TLS). We found that spontaneous SCE levels were elevated approximately 2-fold in chicken DT40 cells deficient in Fanconi anemia (FA) gene FANCC. To investigate the mechanism of the elevated SCE, we deleted FANCC in cells lacking Rad51 paralog XRCC3, TLS factor RAD18, or BLM. The increased SCE in fancc cells required Xrcc3, whereas the fancc/rad18 double mutant exhibited higher SCE than either single mutant. Unexpectedly, SCE in the fancc/blm mutant was similar to that in blm cells, indicating functional linkage between FANCC and BLM. Furthermore, MMC-induced formation of GFP-BLM nuclear foci was severely compromised in both human and chicken fancc or fancd2 cells. Our cell survival data suggest that the FA proteins serve to facilitate HR, but not global TLS, during crosslink repair.

Adenosine Triphosphatases↗

PubMed2006

DNA interstrand crosslink repair during G1 involves nucleotide excision repair and DNA polymerase zeta.

The repair mechanisms acting on DNA interstrand crosslinks (ICLs) in eukaryotes are poorly understood. Here, we provide evidence for a pathway of ICL processing that uses components from both nucleotide excision repair (NER) and translesion synthesis (TLS) and predominates during the G1 phase of the yeast cell cycle. Our results suggest that repair is initiated by the NER apparatus and is followed by a thwarted attempt at gap-filling by the replicative Polymerase delta, which likely stalls at the site of the remaining crosslinked oligonucleotide. This in turn leads to ubiquitination of PCNA and recruitment of the damage-tolerant Polymerase zeta that can perform TLS. The ICL repair factor Pso2 acts downstream of the incision step and is not required for Polymerase zeta activation. We show that this combination of NER and TLS is the only pathway of ICL repair available to the cell in G1 phase and is essential for viability in the presence of DNA crosslinks.

Cross-Linking Reagents↗

PubMed2002

How DNA lesions are turned into mutations within cells?

Genomes of all living organisms are constantly injured by endogenous and exogenous agents that modify the chemical integrity of DNA and in turn challenge its informational content. Despite the efficient action of numerous repair systems that remove lesions in DNA in an error-free manner, some lesions, that escape these repair mechanisms, are present when DNA is being replicated. Although replicative DNA polymerases are usually unable to copy past such lesions, it was recently discovered that cells are equipped with specialized DNA polymerases that will assist the replicative polymerase during the process of Translesion Synthesis (TLS). These TLS polymerases exhibit relaxed fidelity that allows them to copy past lesions in DNA with an inherent risk of generating mutations at high frequency. We present recent aspects related to the genetics and biochemistry of TLS and highlight some of the remaining hot topics of this field.

Animals↗

PubMed2004

Acute tumour lysis syndrome after oral fludarabine in a patient with chronic lymphocytic leukaemia.

Acute tumour lysis syndrome (TLS) is a very rare complication of cytotoxic therapy in patients with chronic lymphocytic leukaemia (CLL). We report a patient with CLL who developed tumour lysis syndrome twice after oral fludarabine therapy. Both times TLS developed more than 2 weeks after the initiation of therapy. To our knowledge this is the first reported case of TLS in CLL precipitated by oral fludarabine.

Acute Kidney Injury↗

PubMed2002

Molecular analysis of mutations in DNA polymerase eta in xeroderma pigmentosum-variant patients.

Xeroderma pigmentosum variant (XP-V) cells are deficient in their ability to synthesize intact daughter DNA strands after UV irradiation. This deficiency results from mutations in the gene encoding DNA polymerase eta, which is required for effecting translesion synthesis (TLS) past UV photoproducts. We have developed a simple cellular procedure to identify XP-V cell strains, and have subsequently analyzed the mutations in 21 patients with XP-V. The 16 mutations that we have identified fall into three categories. Many of them result in severe truncations of the protein and are effectively null alleles. However, we have also identified five missense mutations located in the conserved catalytic domain of the protein. Extracts of cells falling into these two categories are defective in the ability to carry out TLS past sites of DNA damage. Three mutations cause truncations at the C terminus such that the catalytic domains are intact, and extracts from these cells are able to carry out TLS. From our previous work, however, we anticipate that protein in these cells will not be localized in the nucleus nor will it be relocalized into replication foci during DNA replication. The spectrum of both missense and truncating mutations is markedly skewed toward the N-terminal half of the protein. Two of the missense mutations are predicted to affect the interaction with DNA, the others are likely to disrupt the three-dimensional structure of the protein. There is a wide variability in clinical features among patients, which is not obviously related to the site or type of mutation.

Cell Line↗

PubMed2006

Interplay between replication and recombination in Escherichia coli: impact of the alternative DNA polymerases.

Homologous recombination (HR) and translesion synthesis (TLS) are two pathways involved in the tolerance of lesions that block the replicative DNA polymerase. However, whereas TLS is frequently error-prone and, therefore, can be deleterious, HR is generally error-free. Furthermore, because the recombination enzymes and alternative DNA polymerases that perform TLS may use the same substrate, their coordination might be important to assure cell fitness and survival. This study aimed to determine whether and how these pathways are coordinated in Escherichia coli cells by using conjugational replication and recombination as a model system. The role of the three alternative DNA polymerases that are regulated by the SOS system was tested in DNA polymerase III holoenzyme-proficient and -deficient mutants. When PolIII is inactive, the alternative DNA polymerases copy DNA in the following order: PolII, PolIV, and PolV. The observed hierarchy corresponds to the selective constraints imposed on the genes coding for alternative DNA polymerases observed in natural populations of E. coli, suggesting that this hierarchy depends on the frequency of specific damages encountered during the evolutionary history of E. coli. We also found that DNA replication and HR are in competition and that they can precede each other. Our results suggest that there is probably not an active choice of which pathway to use, but, rather, the nature and concentration of lesions that lead to formation of ssDNA and the level of SOS induction that they engender might determine the outcome of the competition between HR and alternative DNA polymerases.

Chromosomes, Bacterial↗

PubMed2003

The efficiency and specificity of apurinic/apyrimidinic site bypass by human DNA polymerase eta and Sulfolobus solfataricus Dpo4.

One of the most common DNA lesions arising in cells is an apurinic/apyrimidinic (AP) site resulting from base loss. Although a template strand AP site impedes DNA synthesis, translesion synthesis (TLS) DNA polymerases can bypass an AP site. Because this bypass is expected to be highly mutagenic because of loss of base coding potential, here we quantify the efficiency and the specificity of AP site bypass by two Y family TLS enzymes, Sulfolobus solfataricus DNA polymerase 4 (Dpo4) and human DNA polymerase eta (Pol eta). During a single cycle of processive DNA synthesis, Dpo4 and Pol eta bypass synthetic AP sites with 13-30 and 10-13%, respectively, of the bypass efficiency for undamaged bases in the same sequence contexts. These efficiencies are higher than for the A family, exonuclease-deficient Klenow fragment of Escherichia coli DNA polymerase I. We then determined AP site bypass specificity for complete bypass, requiring insertion or misalignment at the AP site followed by multiple incorporations using the aberrant primer templates. Although Dpo4, Pol eta, and Klenow polymerase have different fidelity when copying undamaged DNA, bypass of AP sites lacking A or G by all three polymerases is nearly 100% mutagenic. The majority (70-80%) of bypass events made by all three polymerases are insertion of dAMP opposite the AP site. Single base deletion errors comprise 10-25% of bypass events, with other base insertions observed at lower rates. Given that mammalian cells contain five polymerases implicated in TLS, and given that a large number of AP sites are generated per mammalian cell per day, even moderately efficient AP site bypass could be a source of substitution and frameshift mutagenesis in vivo.

Base Sequence↗

PubMed2006

The Mycobacterium tuberculosis cell-surface glycoprotein apa as a potential adhesin to colonize target cells via the innate immune system pulmonary C-type lectin surfactant protein A.

Tuberculosis is still a major health problem, and understanding the mechanism by which Mycobacterium tuberculosis (Mtb) invades and colonizes its host target cells remains an important issue for the control of infection. The innate immune system C-type lectins (C-TLs), including the human pulmonary surfactant protein A (PSP-A), have been recently identified as determinant players in the early recognition of the invading pathogen and in mounting the host defense response. Although the antigenic lipoglycan mannosylated lipoarabinomannan is currently considered to be the major C-TL target on the mycobacterial surface, the recognition by some C-TLs of the only mycobacterial species composing the "Mtb complex" indicates that mannosylated lipoarabinomannan cannot account alone for this specificity. Thus, we searched for the mycobacterial molecules targeted by human PSP-A, focusing our attention on the Mtb surface glycoproteins. We developed an original functional proteomic approach based on a lectin blot assay using crude human bronchoalveolar lavage fluid as a source of physiological PSP-A. Combined with selective cell-surface protein extraction and mass spectrometry peptide mapping, this strategy allowed us to identify the Apa (alanine- and proline-rich antigenic) glycoprotein as new potential target for PSP-A. This result was supported by direct binding of PSP-A to purified Apa. Moreover, EDTA addition or deglycosylation of purified Apa samples completely abolished the interaction, demonstrating that the interaction is calcium- and mannose-dependent, as expected. Finally, we provide convincing evidence that Apa, formerly considered as mainly secreted, is associated with the cell wall for a sufficiently long time to aid in the attachment of PSP-A. Because, to date, Apa seems to be restricted to the Mtb complex strains, we propose that it may account for the selective recognition of those strains by PSP-A and other immune system C-TLs containing homologous functional domains.

Adhesins, Bacterial↗

PubMed2000

The role of partial laryngeal resection in current management of laryngeal cancer: a collective review.

A spectrum of treatment plans and surgical procedures is available for management of early and moderately advanced laryngeal cancer. While the approach of chemotherapy and irradiation, or irradiation alone, followed by total laryngectomy for failure is often employed in practice by present day clinicians, the options of conventional conservation surgery (CCS), transoral endoscopic laser surgery (TLS) and supracricoid partial laryngectomy (SCPL) provide a wide choice of treatments that may help attain the goal of cure with preservation of laryngeal function and integrity of the airway. While CCS has been supplanted for many early-stage lesions by TLS and for more advanced stages by SCPL, centres throughout the world have reported favourable results with CCS, which is often modified to include resection of more extensive tumours than was previously possible. During the past decade a number of extended CCS procedures have been developed for management of glottic tumours involving both vocal cords and the anterior commissure, the paraglottic space and with vocal cord fixation, and for supraglottic tumours involving the glottis or hypopharynx. TLS has proved an effective, minimally invasive and functionally satisfactory procedure for management of suitable T1 and T2 glottic cancers, and stage I-III supraglottic cancers. The procedure may be effectively employed in combination with neck dissection and postoperative radiotherapy when necessary, particularly for moderately advanced supraglottic carcinomas. SCPL has proven effective in management of glottic and supraglottic cancers of all stages, even with involvement of paraglottic space and thyroid cartilage, provided at least one arytenoid unit can be preserved with clear margins. Invasion of cricoid cartilage is the most significant limitation for this procedure. All three surgical approaches have been employed for irradiation failure, but with greatly increased failure and complication rates compared with the results of treatment of non-irradiated patients. Thus a decision to treat laryngeal cancer initially with irradiation may preclude a satisfactory result from partial laryngectomy should radiation fail. The treatment of laryngeal cancer should be individualized according to the size and extent of the tumour, the age and physical condition of the patient, and the skill and experience of the surgeon with various treatment modalities and surgical procedures.

Combined Modality Therapy↗

PubMed2000

All three SOS-inducible DNA polymerases (Pol II, Pol IV and Pol V) are involved in induced mutagenesis.

Most organisms contain several members of a recently discovered class of DNA polymerases (umuC/dinB superfamily) potentially involved in replication of damaged DNA. In Escherichia coli, only Pol V (umuDC) was known to be essential for base substitution mutagenesis induced by UV light or abasic sites. Here we show that, depending upon the nature of the DNA damage and its sequence context, the two additional SOS-inducible DNA polymerases, Pol II (polB) and Pol IV (dinB), are also involved in error-free and mutagenic translesion synthesis (TLS). For example, bypass of N:-2-acetylaminofluorene (AAF) guanine adducts located within the NAR:I mutation hot spot requires Pol II for -2 frameshifts but Pol V for error-free TLS. On the other hand, error-free and -1 frameshift TLS at a benzo(a)pyrene adduct requires both Pol IV and Pol V. Therefore, in response to the vast diversity of existing DNA damage, the cell uses a pool of 'translesional' DNA polymerases in order to bypass the various DNA lesions.

2-Acetylaminofluorene↗

PubMed2003

Multiple roles of Rev3, the catalytic subunit of polzeta in maintaining genome stability in vertebrates.

Translesion DNA synthesis (TLS) and homologous DNA recombination (HR) are two major postreplicational repair (PRR) pathways. The REV3 gene of Saccharomyces cerevisiae encodes the catalytic subunit of DNA polymerase zeta, which is involved in mutagenic TLS. To investigate the role of REV3 in vertebrates, we disruped the gene in chicken DT40 cells. REV3(-/-) cells are sensitive to various DNA-damaging agents, including UV, methyl methanesulphonate (MMS), cisplatin and ionizing radiation (IR), consistent with its role in TLS. Interestingly, REV3(-/-) cells showed reduced gene targeting efficiencies and significant increase in the level of chromosomal breaks in the subsequent M phase after IR in the G(2) phase, suggesting the involvement of Rev3 in HR-mediated double-strand break repair. REV3(-/-) cells showed significant increase in sister chromatid exchange events and chromosomal breaks even in the absence of exogenous genotoxic stress. Furthermore, double mutants of REV3 and RAD54, genes involved in HR, are synthetic lethal. In conclusion, Rev3 plays critical roles in PRR, which accounts for survival on naturally occurring endogenous as well as induced damages during replication.

Animals↗

PubMed2004

O-acetylserine (thiol) lyase: an enigmatic enzyme of plant cysteine biosynthesis revisited in Arabidopsis thaliana.

The synthesis of cysteine is positioned at a decisive stage of assimilatory sulphate reduction, marking the fixation of inorganic sulphide into a carbon skeleton. O-acetylserine (thiol) lyase (OAS-TL) catalyses the reaction of inorganic sulphide with O-acetylserine (OAS). Despite its prominent position in the pathway OAS-TL is generally regarded as a non-limiting enzyme without regulatory function, due to low substrate affinities and semi-constitutive expression patterns. To resolve this apparent contradiction, the kinetic properties of three OAS-TLs from Arabidopsis thaliana, localized in the cytosol (A), plastids (B), and mitochondria (C), were analysed. The recombinant expressed OAS-TLs were purified to apparent homogeneity without any fusion tag to maintain their native forms. The proteins displayed high specific activities of 550-900 micromol min(-1) mg(-1). Using an improved and highly sensitive assay method for cysteine determination, the apparent K(m)(sulphide) was 3-6 microM for OAS-TL A, B, and C and thus 10-100 times lower than previously reported for plant OAS-TLs. K(m)(OAS) was between 310 microM and 690 microM for OAS-TL isoform A, B, and C, whereas the apparent dissociation binding constant for OAS was much lower (K(d)<1 microM OAS). A HPLC method was developed for OAS quantification that revealed fast increases of the cellular OAS concentration in response to sulphate deprivation. The observed fluctuations of intracellular OAS concentrations, combined with the OAS dissociation constant and the catalytic properties of OAS-TL, support the model of a dynamic cysteine synthesis system with regulatory function as can be expected from the position of the reaction in the sulphur assimilation pathway.

Arabidopsis↗