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PubMed2005

The role of p53 and anaplastic lymphoma kinase genes in the progression of cutaneous CD30(+) lymphoproliferative diseases.

BACKGROUND AND OBJECTIVES: Molecular events that precede transformations from lymphomatoid palulosis (LyP) to mycosis fungoides (MF) or to cutaneous anaplastic large cell lymphoma (ALCL) in the CD 30(+) cutaneous lymphoproliferative diseases (LPDs) are not known. Altered p(53) gene may be responsible since overexpression of the p(53) gene product has been reported in higher, but not in lower grades of cutaneous lymphomas. Expression of the anaplastic lymphoma kinase (ALK) gene product has also been described as an important prognostic indicator in ALCL. ALK positive systemic nodal ALCL are associated with a good prognosis. However, primary cutaneous ALCL that are ALK negative have a better overall survival. The current study was done to see if mutated p(53) gene or ALK reactivity were poor prognostic indicators in those patients with CD 30(+) cutaneous LPD who showed progression of the disease. METHODS: Mutations of the p(53) gene and expression of the ALK gene product were analysed in 36 patients (23 of LyP and 13 of CD30(+) cutaneous ALCL). Follow up data were available up till 5 yr in all patients. RESULTS: Clinical progression or histological transformation in sequential biopsy specimens was found in 9 of 36 patients. Transformation occurred in 5 patients (4 from LyP to ALCL and 1 from MF to ALCL) and clinical progression in 4 patients with ALCL. Mutations of the p(53) gene were found in two biopsy specimens of LyP. ALK gene products were not detected in any of the biopsy specimens of LyP and primary cutaneous ALCL. INTERPRETATION AND CONCLUSION: Although 9 of 36 patients with cutaneous CD30(+) LPDs had progression of their disease, neither mutations of the p(53) gene nor ALK immunoreactivity were found in any of these biopsies. The two cases of LyP that had mutated p(53) gene in their biopsy specimens showed no progression of their disease in the 5 yr follow up period. It appears that these molecular events may not play any significant role in the pathogenesis, progression or transformation of cutaneous CD30(+) LPD.

Anaplastic Lymphoma Kinase↗
PubMed2025

Novel strategies for rare oncogenic drivers in non-small-cell lung cancer: An update from the 2024 Annual ESMO meeting.

Across the landscape of oncogene-addicted non-small-cell lung cancer (NSCLC), various tyrosine kinase inhibitors (TKIs) have been introduced in the last twenty years. During the 2024 Annual ESMO meeting new therapeutic options were presented for EGFR exon 20 insertion mutation, ALK fusion and ROS1 fusion positive advanced stage NSCLC. For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI. The vast majority of these patients also received platinum-doublet chemotherapy. For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib. The median number of prior anticancer therapies was 3. Intracranial responses were seen in lorlatinib naïve- and lorlatinib pretreated patients and toxicity was manageable. In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib. Iruplinalkib showed a superior median PFS (36.8 versus 14.55 months for crizotinib), but no difference in 36-month overall survival (OS) rate. Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in patients that were pretreated with crizotinib and an ORR of 38% in patients pretreated with repotrectinib. In this review, we will discuss the relevant study results presented at ESMO 2024 for these three genomic drivers and hypothesize on their respective place in the sequence of treatment options.

Humans↗
PubMed1999

Immunohistochemical screening for oncogenic tyrosine kinase activation.

Tyrosine kinases causing the abnormal phosphorylation of intracellular proteins have been shown to contribute to oncogenic transformation in a number of human neoplasms. Immunohistological staining of routine biopsy sections for increased levels of phosphotyrosine may therefore provide a simple means of screening for tumours containing activated tyrosine kinases. In this study, monoclonal antibodies to phosphotyrosine were used to immunostain a cell line and tumour biopsies from lymphomas known to contain the activated anaplastic-lymphoma-kinase (ALK) tyrosine kinase. A range of normal and other neoplastic tissues were also immunostained for comparison. An anaplastic large cell lymphoma (ALCL) cell line carrying the (2;5) translocation, which creates the activated nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase, was strongly labelled. Routine tissue biopsies from five cases of ALK-positive ALCL were also strongly positive for phosphotyrosine. The characteristic granular cytoplasmic labelling pattern for phosphotyrosine observed in a B-cell lymphoma (expressing full length ALK kinase) was identical to that obtained using an ALK-specific antibody, thus confirming that labelling for phosphotyrosine in lymphoma cells reflects the presence of an activated kinase. When normal lymphoid tissues were stained, there was little or no labelling for phosphotyrosine, but stronger labelling was seen in other cells and tissues; for example, endothelial cells and some carcinoma samples. Whilst the strong labelling for phosphotyrosine observed in the lymphoma cells is due to the presence of activated ALK, the strong staining of some normal cells presumably represents physiologically active kinases and this should be taken into account when interpreting the immunostaining of non-lymphoid tumours. The simplicity of this method, however, means that it offers a new rapid approach to the screening of large numbers of tumours for the presence of aberrant tyrosine kinase activation, particularly if they arise from tissues which normally contain only background levels of phosphotyrosine.

Antibodies, Monoclonal↗
PubMed2000

Transforming growth factor beta2, but not beta1 and beta3, is critical for early rat lung branching.

Mesenchymal-epithelial tissue interactions are critical for lung branching morphogenesis, and polypeptide growth factors are likely involved in these tissue interactions. Transforming growth factorbetas (TGFbetas) have been implicated in lung development, but their involvement in early lung branching morphogenesis is unclear. In the present study, we investigated the role of the three mammalian TGFbeta subtypes (beta1, beta2, and beta3) and their receptors (type III (TbetaR-III), type II (TbetaR-II), and two types I (TbetaR-I), ALK-1 and ALK-5) in early rat lung organogenesis by using an embryonic rat lung explant culture. Transcripts and proteins for all three TGFbetas and their receptors were detected during the embryonic period of fetal rat lung development. Inhibition of TGFbeta2, but not beta1 and beta3, with antisense oligonucleotides and neutralizing antibodies resulted in significant inhibition of early lung branching in culture. Addition of minute amounts (</=1 ng/ml) of exogenous TGFbeta2, but not beta1 and beta3, restored the branching of TGFbeta2 antisense-treated explants. Higher concentrations of TGFbeta2 were inhibitory. BrdU labeling of lung explants was not altered by antisense TGFbeta2 treatment, but low concentrations of TGFbeta2 increased thymidine uptake by isolated epithelial cells. Fibronectin and metallogelatinase activities of embryonic lung cells were not affected by any TGFbeta isoform but TGFbeta2 specifically decreased mesenchymal hyaluronan synthesis. Antisense inhibition of ALK-5 and TbetaR-II showed a similar reduction in early lung branching as observed with antisense TGFbeta2. Incubation of lung explants with soluble TbetaR-II receptors also abrogated lung branching. ALK-1 antisense treatment did not affect early branching. Administration of neither activin A, which can act via ALK-1, nor follistatin, the natural inhibitor of activin, to the explants cultures had any significant effect on lung branching. Antisense inhibition of the activin receptor-II (Act-RII) also did not affect lung branching. These results are consistent with TGFbeta2, but not beta1 and beta3, regulating pattern formation during early rat lung organogenesis. This TGFbeta signaling in rat lung branching in vitro appears to be predominantly mediated via the TbetaR-I(ALK-5)/TbetaR-II heteromeric complex.

Activin Receptors, Type I↗
PubMed1998

C112R, W323S, N317K mutations in the vasopressin V2 receptor gene in patients with nephrogenic diabetes insipidus. Mutations in brief no. 165. Online.

Nephrogenic diabetes insipidus (NDI) is a rare, mostly X-linked recessive disorder characterized by renal tubular resistance to the antidiuretic effect of arginine vasopressin. The gene responsible for the X-linked NDI, the G-protein-coupled vasopressin V2 receptor, has been localized on the Xq28 region. In this study we present three NDI families from Hungary with three different missense mutations in the vasopressin V2 receptor gene. After the mutations in the affected probands in each family had been characterized, other family members were screened by restriction enzyme analysis. The N317K and W323S mutations have not been detected previously. The C112R is an already known mutation. The N317K was a de novo mutation in the patient. The C112R and the W323S were found in the mothers of the patients as carriers and in all other patients, but not in the unaffected members of the families. Segregation of the mutations was consistent with the clinically observed symptoms as well as their severity. As conclusion, these findings further evidence that X-linked NDI results from defects in the V2 receptor gene.

Diabetes Insipidus, Nephrogenic↗
PubMed1979

The distribution of alkaline phosphatase activity in normal and cross-species regenerated rat and mouse taste buds.

Alkaline phosphatase (ALK Pase) activity can be detected histochemically in the taste buds of rats but not mice. Since taste buds develop, regenerate and are maintained under the influence(s) of the sensory nerve it was decided to study cross-species regenerated buds of these two animals to determine whether the nerve also regulated ALK Pase development in taste cells. Grafts of rats sensory ganglion and mouse tongue or mouse ganglion and rat tongue were combined in the anterior chamber of the eyes of immunologically-deficient nude mice and the cross-species buds that developed at 35 days were examined histochemically for ALK Pase. The results revealed that the rat nerve did not cause ALK Pase to appear in any buds found in mouse tongue grafts and that mouse nerve could support buds containing ALK Pase in rat tongue tissue. Because the cross-species regenerated buds were histochemically characteristic of those normally found in rat or mouse tongue, there is no evidence that the foreign nerve altered gene expression for ALK Pase in the target organ, and the action of the nerve on gustatory epithelium appears to be that of activation and maintenance.

Alkaline Phosphatase↗
PubMed2003

Detection of a subset of CD30+ anaplastic large cell lymphoma by interphase fluorescence in situ hybridization.

T/null-cell anaplastic large cell lymphoma (ALCL) is a morphologically and clinically heterogeneous group of non-Hodgkin's lymphoma; to date several morphologic variants have been described on histologic specimens. However, the cytologic features of these variants in the fine-needle aspiration (FNA) specimens have not been well evaluated. The t(2;5)(p23;q35) has been identified in a subset of T/null-ALCL and is known to be associated with a favorable prognosis. We reviewed the cytomorphologic characteristics in 24 FNA specimens of ALCL. In all cases, the diagnosis was confirmed on histologic specimens, and immunohistochemical studies for anaplastic lymphoma kinase (ALK) protein expression were performed on the aspirates. The presence of ALK breakpoints were evaluated in nine cases, using a DNA break-apart probe on chromosome 2 covering the ALK gene by fluorescence in situ hybridization (FISH) techniques. Two hundred cells per case were examined. The results were expressed as the percentage of cells containing more than two signals of chromosome 2 to the total number of cells counted. FNA sites included lymph nodes (20), lung (2), breast (1), and soft tissue (1). The median age of the patients was 56 yr (range, 17-75 yr). Twenty cases had systemic involvement; in four cases, skin was the primary site with secondary involvement of the lymph nodes. All cases were CD30(+) by immunohistochemistry; 20 were of T-cell phenotype and 4 were null cell type. The cytologic evaluation revealed typical anaplastic morphology (common type) with many "hallmark cells" in 16 (67%) cases. Other morphologic variants identified were small cell pattern in five cases, monomorphic pattern in two cases, and lymphohistiocytic pattern in one case. FISH studies showed that six (66.7%) of nine cases had at least two signals of chromosome 2, consistent with ALK breakpoints. With careful cytomorphologic evaluation in conjunction with appropriate immunohistochemical studies, a diagnosis of ALCL can be confidently made in the FNA specimens in the cellular aspirates and its morphologic variants also can be recognized. Furthermore, the FNA specimen is suitable in detecting ALK breakpoints by FISH study, permitting rapid identification of a subset of patients with ALCL, who may have a favorable prognosis. Using a commercially available probe, detection of ALK breakpoints in the FNA specimens is simple and can be a useful diagnostic adjunct in cases where distinction from other lymphomas or lymphoid lesions is morphologically difficult.

Activin Receptors, Type I↗
PubMed1998

The conventional transforming growth factor-beta (TGF-beta) receptor type I is not required for TGF-beta 1 signaling in a human prostate cancer cell line, LNCaP.

LNCaP is an androgen-responsive human prostate cancer cell line that has a defective gene for ALK-5, the conventional TGF-beta receptor type I. Yet, these cells respond to exogenous TGF-beta 1 under appropriate concentrations of dihydrotestosterone (DHT). Because a heteromeric complex composed of type I and type II receptor is required for TGF-beta signaling, the expression of these receptors was investigated in LNCaP cells at following concentrations of DHT-0, 0.1, and 100 nM. These concentrations were selected because they represent the zero DHT control in which LNCaP cells are not sensitive to TGF-beta 1, the proliferative dose of DHT in which these cells are sensitive to exogenous TGF-beta 1, and the growth-arrest dose of DHT in which LNCaP exhibits signs of TGF-beta signaling but are insensitive to exogenous TGF-beta 1, respectively. Results of Western blot analysis showed that LNCaP cells express an increased level of type II receptor at 0.1 nM DHT, the TGF-beta 1-sensitive dose. However, results of competitive quantitative RT-PCR demonstrated that DHT did not significantly change the level of type II receptor mRNA, suggesting that DHT modulates the level of type II receptor at the posttranscriptional level. In contrast, ALK-5 was not detected in these cells by either Western blot analysis or RT-PCR at all concentrations of DHT used in this study. Subsequently, the expression of ALK-1, -2, and -4 in LNCaP cells was examined because these proteins have been shown to bind TGF-beta 1 in vitro. ALK-1 and -2 were detected in these cells. Further analysis by competitive quantitative RT-PCR and Western blot demonstrated that DHT did not affect the level of expression of ALK-1 and -2 in LNCaP cells. These observations, taken together, demonstrate that ALK-5 is not required for TGF-beta 1 signaling and that there may be alternative mechanism(s) for TGF-beta 1 signal transduction in some systems.

Activin Receptors, Type I↗
PubMed2000

A case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting with spontaneous splenic rupture: an extremely unusual presentation.

In a 22-year-old male with a 10-day history of fever, painful swelling in the left groin, and abdominal complaints, emergency surgery was performed because of spontaneous splenic rupture. At histology, a cellular infiltrate of intermediate-sized atypical lymphocytes was seen in the splenic white pulp, staining for T-cell markers. In addition, CD30 and anaplastic lymphoma kinase 1 (ALK) were diffusely positive, thus, representing a case of anaplastic large cell lymphoma (ALCL), T-cell, ALK-positive, small cell monomorphic variant. ALK-positive ALCL patients generally bear a much better prognosis than patients with T-cell lymphomas, unspecified, or ALK-negative ALCL. Therefore, besides the very unusual clinical presentation, this case highlights the importance of immunostaining for CD30 and ALK in all T-cell lymphomas. This report is the first extensive description of ALK-positive ALCL involvement of the spleen.

Adult↗
PubMed2006

The status of biochemical parameters in varying degrees of vitamin D deficiency.

Vitamin D (Vit D) is an essential element for the regulation of serum calcium, phosphate, and alkaline phosphatase (Alk Ph). Because the Vit D serum level is not usually measured directly, Vit D deficiency is diagnosed indirectly by changes in serum calcium, phosphate, and Alk Ph leves. The current study assessed the status of these biochemical parameters in subjects with different degrees of Vit D deficiency. We selected 1,210 subjects, between 20 and 69 years old, randomly from the Tehran population. Subjects with diseases or medications that modified bone metabolism were excluded from the study. Serum 25(OH) D, calcium, phosphate, Alk Ph, and parathyroid hormone (PTH) levels were measured and the status of these biochemical parameters was compared in subjects with different degrees of Vit D deficiency. Vit D deficiency was diagnosed in 79.6% of the subjects. Different degrees of Vit D deficiency were classified as follows: group 1, severe; group 2, moderate; and group 3, mild. Serum PTH levels in the Vit D-deficient groups were significantly higher than that in group 4 (normal Vit D). Serum calcium and phosphate levels in groups 1 and 2 were significantly lower than those in groups 3 and 4. No significant difference was seen in serum Alk Ph in the groups with different degrees of Vit D deficiency. The sensivity for at least one biochemical variable (calcium, phosphorus, or Alk Ph) for the detection of severe, moderate, and mild Vit D deficiency was 24.2%, 13.8%, and 6%, respectively. When the serum 25(OH) D level was reduced to less than 25 nmol/l (groups 1 and 2), the effects of Vit D deficiency on calcium and phosphate levels were obvious. Therefore, the usual biochemical parameters (calcium, phosphate, Alk Ph) alone do not have sufficient sensitivity to detect mild deficiency of Vit D.

Adult↗
PubMed1999

Biochemical detection of novel anaplastic lymphoma kinase proteins in tissue sections of anaplastic large cell lymphoma.

The (2;5) translocation, found in many T-cell and null cell anaplastic large cell lymphomas (ALCLs), creates a hybrid gene encoding the 80-kd NPM-ALK protein. Typically neoplastic cells show labeling of both nucleus and cytoplasm for anaplastic lymphoma kinase (ALK) and for the N-terminus of nucleophosmin (NPM). However, 10-20% of cases exhibit cytoplasmic labeling only for ALK, indicating the probable presence of variants of the classical (2;5) translocation that do not involve the NPM gene. We report the detection (using Western blotting and an in vitro kinase assay) in seven such ALCL cases, of ALK proteins with molecular masses of 85 kd, 97 kd (one case exhibiting a (2;3)(p23;q21) translocation), 104 kd (one case carried a (1;2)(q21;p23) translocation), and 113 kd. Tyrosine kinase activity was detected in four of these proteins, but the N-terminal portion of NPM could not be detected. These results show how ALCL cases that express ALK proteins other than NPM-ALK can be detected by sensitive biochemical techniques using routine cryostat sections.

Animals↗
PubMed1988

1-O-hexadec-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine and its biological activity.

1-O-Alk-1'-enyl analog of platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, alkylacetyl-GPC) was prepared semi-synthetically from choline plasmalogens of beef heart muscle. The main compound was identified mass spectrometrically as 1-hexadec-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine (16:O alk-1'-enylacetyl-GPC, 16:O vinyl form of PAF) and its platelet aggregation activity was about one-fifth of that of the corresponding 16:O alkylacetyl-GPC. The irreversible platelet aggregation activity induced by 5X10(-10) M 16:O alk-1'-enylacetyl-GPC was completely inhibited by 5X10(-7) M CV-3988 and 1X10(-7) M L-652, 731, specific PAF antagonists, and more than 99% of the activity was also lost by acid treatment. The hydrogenated product, alkylacetyl analog, showed quite same activity as that of authentic 16:O alkylacetyl-GPC. The platelets desensitized with 16:O alkylacetyl-GPC and with 16:O alk-1'-enylacetyl-GPC were not aggregated with 5X10(-10) M 16:O alk-1'-enylacetyl-GPC, suggesting that alk-1'-enylacetyl-GPC occupied the same receptor site of alkylacetyl-GPC.

Animals↗
PubMed1998

Inhibitory effects of tranilast on expression of transforming growth factor-beta isoforms and receptors in injured arteries.

Tranilast (N(3,4-dimethoxycinnamoyl)anthranilic acid), an agent which in cell culture inhibits transforming growth factor-beta (TGF-beta) secretion and antagonises the effects of TGF-beta and platelet-derived growth factor (PDGF) on cell migration and proliferation, has been reported to reduce the incidence of restenosis after angioplasty in angiographically validated human clinical trials. We investigated in a rat model of balloon angioplasty whether tranilast's effects in vivo could be attributed to inhibition of expression of TGF-beta and/or its receptor types. Using a standardised reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we examined the effects of three doses of tranilast (25, 50 and 100 mg/kg) on the expression of two TGF-beta isoforms, the types I and II TGF-beta receptors and two putative TGF-beta responses, induction of integrins alpha(v) and beta3 mRNA, 2 h after oral administration and 26 h after vessel injury. Tranilast attenuated in a dose-dependent and reversible manner the injury-induced increases in mRNA levels encoding TGF-beta1, TGF-beta3, two type I TGF-beta receptors ALK-5 and ALK-2, and the type II receptor TbetaRII. At the highest dose mRNA levels encoding TGF-beta1 and TbetaRII were attenuated to levels approaching or below those observed in uninjured vessels. Messenger RNAs encoding TGF-beta3, ALK-5 and ALK-2 were all attenuated by between 70 and 74% (all P < 0.05). Tranilast also attenuated in a reversible manner the elevations in mRNA levels for integrins alpha(v) and beta3 observed after vessel injury, by 90 and 72%, respectively. We also investigated, in cultured smooth muscle cells derived from injured carotid arteries, the extent to which tranilast (300 mg/l) attenuated any increases in expression of type I and type II receptors stimulated by PDGF-BB and TGF-beta1, growth factors implicated in smooth muscle cell migration and proliferation in injured vessels. Increases in mRNA levels of the type I receptors ALK-5 and ALK-2 induced by PDGF-BB and TGF-beta1 were almost completely prevented by tranilast. Tranilast also prevented the PDGF-BB induced increases in TbetaRII but only partially inhibited the TGF-beta1 induced upregulation of TbetaRII. We conclude that tranilast can inhibit transcriptional mechanisms associated with the upregulation of TGF-beta and its receptor types in balloon catheter injured vessels. It is possible that these mechanisms contribute to its ability to reduce the frequency of restenosis after angioplasty.

Angioplasty, Balloon↗
PubMedDate not supplied

Initial results of automated lamellar keratoplasty for correction of myopia: one year follow-up.

PURPOSE: To report our initial results with automated lamellar keratoplasty (ALK) to correct myopia and to evaluate the short-term efficacy, safety, and predictability of this procedure. METHODS: A prospective series of 128 eyes of 81 consecutive patients who had ALK were reviewed for a mean follow-up of 13.6 months (range 12 to 19 months). Preoperative data, intraoperative parameters, and postoperative visual acuity, refraction, keratometric readings, and complications at 1 day, 1 week, 1, 3, and 6 months, 1 year, and last follow-up visit were used for analysis. The procedure was performed for myopia in 120 eyes (-4.50 to -13.25 diopters [D]) and for residual myopia following radial keratotomy (RK) in eight eyes (-1.75 D to -3.75 D). A hinged-flap technique was used in 17 cases (13%) once this method was introduced. RESULTS: Preoperative mean uncorrected visual acuity was 0.04 +/- 0.05 (20/500). Postoperatively (12 to 19 months), overall uncorrected visual acuity was 20/40 or better in 86.4% of eyes with a mean uncorrected acuity of 0.68 +/- 0.22 (20/30) 76.2% of eyes were within 1.00 D of emmetropia and 93.6%, within 2.00 D. After the initial ALK procedure, 77% of eyes had RK or astigmatic keratotomy (AK). Among the 29 eyes with ALK alone, 86% had 20/40 or better uncorrected visual acuity, with mean uncorrected acuity and mean corrected acuity of 0.69 +/- 0.21 (20/30) and 0.95 +/- 0.10 (20/21), respectively; 72% of eyes were within 1.00 D of emmetropia and 90%, within 2.00 D. In 4%, astigmatism increased more than 1.00 D from the preoperative value and 4% of eyes (5/128) had persistent irregular astigmatism. Four percent of eyes (5/128) had overcorrection, with a final spherical equivalent greater than +1.00 D. Epithelial growth in the interface requiring surgical removal occurred in 2% of cases. One eye with residual myopia from a previous RK lost the cap after ALK. A homologous donor graft was performed, which resulted in 20/30 uncorrected visual acuity. Best corrected visual acuity of two lines or more was lost in 6.3% of eyes (8/128). This was caused by irregular astigmatism in 63% of cases. CONCLUSIONS: The results of our initial experience indicate that ALK is a reasonably safe, effective, and predictable procedure for correction of high myopia and myopia following previous RK. With additional enhancement with RK/AK, good visual and refractive outcome can be expected.

Adult↗
PubMed2005

Thermodynamics, kinetics, and mechanism of (silox)3M(olefin) to (silox)3M(alkylidene) rearrangements (silox = tBu3SiO; M = Nb, Ta).

Olefin complexes (silox)(3)M(ole) (silox = (t)Bu(3)SiO; M = Nb (1-ole), Ta (2-ole); ole = C(2)H(4), C(2)H(3)Me, C(2)H(3)Et, C(2)H(3)C(6)H(4)-p-X (X = OMe, H, CF(3)), C(2)H(3)(t)Bu, (c)C(5)H(8), (c)C(6)H(10), (c)C(7)H(10) (norbornene)) rearrange to alkylidene isomers (silox)(3)M(alk) (M = Nb (1=alk), Ta (2=alk); alk = CHMe, CHEt, CH(n)Pr, CHCH(2)C(6)H(4)-p-X (X = OMe, H, CF(3) (Ta only)), CHCH(2)(t)Bu, (c)C(5)H(8), (c)C(6)H(10), (c)C(7)H(10) (norbornylidene)). Kinetics and labeling experiments suggest that the rearrangement proceeds via a delta-abstraction on a silox CH bond by the beta-olefin carbon to give (silox)(2)RM(kappa(2)-O,C-OSi(t)Bu(2)CMe(2)CH(2)) (M = Nb (4-R), Ta (6-R); R = Me, Et, (n)Pr, (n)Bu, CH(2)CH(2)C(6)H(4)-p-X (X = OMe, H, CF(3) (Ta only)), CH(2)CH(2)(t)Bu, (c)C(5)H(9), (c)C(6)H(11), (c)C(7)H(11) (norbornyl)). A subsequent alpha-abstraction by the cylometalated "arm" of the intermediate on an alpha-CH bond of R generates the alkylidene 1=alk or 2=alk. Equilibrations of 1-ole with ole' to give 1-ole' and ole, and relevant calculations on 1-ole and 2-ole, permit interpretation of all relative ground and transition state energies for the complexes of either metal.

Journal Article↗
PubMed1982

Cyclophosphamide plasma and cerebrospinal fluid kinetics with and without dimethyl sulfoxide.

Ten patients with brain tumors and indwelling ventricular reservoirs were pretreated with 5% to 10% dimethyl sulfoxide (DMSO) (intravenous, oral, or both) and were then treated with 1.0 to 1.25 gm/m2 cyclophosphamide (CYC). All patients were also on anticonvulsants and dexamethasone. CYC and alkylating activity (alk act) in plasma and concomitant ventricular cerebrospinal fluid (CSF) were measured by gas chromatography and p-nitrobenzyl pyridine assay. CYC entered the CSF without difficulty and was lost from CSF more slowly than from plasma. Alk act did not enter CSF as well as did CYC. DMSO did not alter any measured aspect of CYC or alk act disposition. Specifically, it did not alter the CYC plasma half-life (t1/2), CSF t1/2, peak CSF: peak plasma CYC concentration ratio, or the urinary excretion of CYC. DMSO did not alter the plasma t1/2 or urinary excretion of alk act or the peak CSF:peak plasma concentration ratio of alk act. Our data show reduced plasma t1/2 of CYC and increased plasma and urinary alk act. This may reflect tht effect of long-term therapy with anticonvulsants or steroids.

Adult↗
PubMed2001

Percentage of activated cytotoxic T-lymphocytes in anaplastic large cell lymphoma and Hodgkin's disease: an independent biological prognostic marker.

Recently, we demonstrated that the presence of high percentages of activated cytotoxic T-lymphocytes (CTLs) in biopsy specimens of both Hodgkin's disease (HD) and ALK negative anaplastic large cell lymphoma (ALCL) is associated with a poor prognosis. To test whether this biological prognostic factor is more important in predicting clinical outcome than histological diagnosis or clinical factors, we compared the prognostic value of these parameters in an expanded group of classical HD and ALK negative ALCL. Tumor biopsies of classical HD (n = 83) and ALK negative systemic nodal ALCL (n = 43) were investigated for the presence of activated CTLs by immunohistochemistry, using a monoclonal antibody directed against granzyme B. Percentages of activated CTLs were quantified using Q-PRODIT, and their prognostic value was compared to that of histological diagnosis and clinical parameters, including age and stage. Both in classical HD and ALK negative ALCL, a high percentage of activated CTLs (ie > or = 15%) identified a group of patients with poor overall and progression-free survival time, even when adjusted for stage. In multivariate analysis, percentage of activated CTLs remained a strong independent prognostic marker, and was more sensitive than histological diagnosis or clinical factors in predicting overall survival time. We conclude that a high percentage of activated CTLs in the reactive infiltrate of ALK negative ALCL and classical HD is a strong indicator for an unfavorable clinical outcome, regardless of histological diagnosis or clinical parameters. As such, this biological parameter may be an especially helpful tool to determine therapeutic strategies in cases in which the differentiation between ALK negative ALCL and HD remains difficult.

Adolescent↗
PubMed2002

Activation of anaplastic lymphoma kinase is responsible for hyperphosphorylation of ShcC in neuroblastoma cell lines.

Shc family of docking proteins, ShcA, ShcB and ShcC, play roles in cellular signal transduction by binding to phosphotyrosine residues of various activated receptor tyrosine kinases. Both ShcB and ShcC proteins are selectively expressed in the neural system of adult mouse tissues. In most of neuroblastoma cells, obvious tyrosine phosphorylation of ShcC was observed, whereas expression of ShcB was considerably low. Phosphoproteins associated with hyperphosphorylated ShcC were purified from neuroblastoma cell lines, and identified by mass-spectrometry. Anaplastic lymphoma kinase (ALK), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the PTB domain of ShcC in three neuroblastoma cells. In vitro kinase assay revealed that ShcC is a potent substrate of the activated ALK kinase. The ALK gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the ALK kinase, which results in hyperphosphorylation of ShcC. Constitutive activation of ALK appeared to interfere with signals from other receptor tyrosine kinases. ALK-ShcC signal activation, possibly caused by co-amplification with the N-myc gene, might give additional effects on malignant tumor progression of neuroblastoma.

Adult↗