Phase II study of weekly paclitaxel for docetaxel-resistant metastatic breast cancer in Japan

The purpose of the study was to evaluate the efficacy of weekly paclitaxel (PTX) against metastatic breast cancer (MBC) that was resistant to docetaxel (DTX) given every 3 weeks. A multicenter phase II study was performed. Women with MBC resistant to DTX were eligible for enrollment. DTX resistance was defined as no tumor response to DTX and stable disease, partial response, or complete response to DTX preceding disease progression. PTX 80 mg/m(2) was administered over 1 hour once a week for 3 weeks per 4-week cycle. Among 47 enrolled patients, 46 patients were assessable for response and toxicity. The overall objective response rate (complete responses [CRs] and partial responses [PRs]) was 17.4% and overall clinical benefit rate (CRs, PRs, and stable disease >or=24 weeks) was 26.1%. The median time to progression was 11 weeks. There were a few severe hematologic toxicities related to the therapy, with grade 4 neutropenia (4.3%) and thrombocytopenia (2.2%). Grade 3 anaphylaxis and grade 3 neuropathy were observed in one patient (2.2%) each. The median delivered dose intensity was 77.6 mg/m(2)/week, 97.1% of the planned dose intensity. Weekly PTX has activity in patients with MBC resistant to DTX every 3 weeks.     

Angiotensin converting enzyme inhibition for cardiac hypertrophy in patients with end‐stage renal disease: What is the evidence?

Dialysis patients show a high prevalence of cardiovascular complications among which left ventricular hypertrophy is one of the most frequent and is independently predictive of mortality. A recent study indicates that partial regression of left ventricular hypertrophy improves mortality and reduces cardiovascular events in end-stage renal disease (ESRD) patients, suggesting the importance of targeting therapeutic strategies to reduce cardiac hypertrophy and improve the outcome in these patients. The pathogenesis of left ventricular hypertrophy in ESRD patients is multifactorial and includes hypertension, activation of the renin-angiotensin system, increased sympathetic activity, chronic volume overload, chronic anaemia and hyperparathyroidism. In this paper, we review the available experimental and clinical evidence showing the important contribution of the renin-angiotensin system as well as its interaction with the sympathetic nervous system in the pathogenesis of left ventricular hypertrophy in ESRD patients. Furthermore, we summarize the results of currently available clinical studies that examined the effects of angiotensin-converting enzyme inhibition or angiotensin receptor antagonism on left ventricular hypertrophy in ESRD patients, and review evidences that support the use of angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists in the ESRD population.     

Novel mechanisms of tubulointerstitial injury in IgA nephropathy: a new therapeutic paradigm in the prevention of progressive renal failure

IgA nephropathy (IgAN) runs a highly variable clinical course with frequent involvement of tubulointerstitial damage. Notably, renal progression correlates more closely with the severity of tubulointerstitial lesions than with the degree of glomerular lesions In IgAN. Mesangial IgA deposition induces local release of cytokines, complement, and angiotensin II leading to glomerular inflammation. It remains unclear how mesangial IgA deposition leads to tubulointerstitial injury in IgAN. Moreover, IgA deposits are rarely detected in renal interstitium in IgAN. We hypothesize that mediators released from mesangial cells triggered by IgA deposition leads to activation of proximal tubular epithelial cells. Our preliminary findings implicate a glomerulotubular cross talk with mediators released from the mesangium contributing to the pathogenesis of tubulointerstitial damage in IgAN. We have also found the expression of angiotensin II subtype-1 receptor or angiotensin II subtype-2 receptor in proximal tubular epithelial cells differs from that of mesangial cells. One potential therapeutic approach is to counterbalance the growth-stimulatory effects of angiotensin II through subtype-1 receptor in tubular epithelial cells by subtype-2 receptor-mediated apoptosis and growth inhibition. These novel findings may provide clinicians new therapeutic approach for selective blockade of the RAS in IgAN.     

Post-translational modifications of self antigens: implications for autoimmunity

Alterations in amino acid sequence can generate neo-epitopes from self proteins, causing autoaggressive immune attack. There is a range of possible post-translational modifications (PTMs) of mammalian proteins that can allow immune recognition of neo-self epitopes. These effects can vary from overt increase in affinity of MHC or T-cell receptor binding, to more subtle effects on the activity of proteolytic enzymes involved in antigen processing. Furthermore, intriguing insights into how the complex interactions between inflammation, enzyme activity and protein modification can direct self recognition are beginning to be unearthed.     

Functional outcomes of intramuscular botulinum toxin type A in the upper limbs of children with cerebral palsy: a phase II trial

OBJECTIVE: To describe the functional and family-centered assessment protocol and outcomes of a phase II trial evaluating upper-limb function after botulinum toxin injections in children with cerebral palsy (CP). DESIGN: Intervention study, case series, phase II trial, follow-up at 2 weeks and 3 and 6 months. SETTING: Specialist outpatient physical disabilities clinic within a public pediatric teaching hospital. PARTICIPANTS: Convenience sample of 16 children with CP (age range, 2-12y). INTERVENTIONS: Botulinum toxin type A (Botox) injections after electrical stimulation localization of appropriate muscle. MAIN OUTCOME MEASURES: The Canadian Occupational Performance Measure (COPM), Goal Attainment Scale (GAS), Melbourne Assessment of Unilateral Upper Limb Function, Child Health Questionnaire (CHQ), parent questionnaire, Modified Ashworth Scale (MAS), Tardieu scale, and active (AROM) and passive (PROM) range of motion. RESULTS: On the COPM, there was significant improvement at 3 months and 6 months. On the GAS, the T-scores were 42 and 47 at 3 and 6 months, respectively. On the Melbourne Assessment and CHQ, there was no significant change. The parent questionnaire indicated acceptability of injections and positive outcomes. On the MAS, there was a significant reduction in tone at 2 weeks, with a return to baseline by 6 months. On the Tardieu scale, there was a significant increase in angle of first catch at 2 weeks, but only the elbow maintained a significant difference at 3 and 6 months. No significant change was found for AROM or PROM. CONCLUSIONS: Sustained functional outcomes occurred after botulinum toxin injections despite increasing muscle tone after an initial reduction in tone. Randomized controlled trials are required.     

Attenuation of the alcohol preference of C57BL/6 mice during chronic renal failure

The C57BL/6 inbred mouse strain is known for its strong, genetically determined preference for alcohol over water. In this study we examined the voluntary alcohol consumption (VAC) of C57BL/6 mice during chronic renal failure (CRF). Two weeks after the surgical induction of renal failure, CRF mice, together with normal and sham-operated control mice, were submitted to a standard 24-day VAC protocol. The mice were offered water for the first 6 days (period of acclimatization), alcohol (10% ethanol solution) for the next 4 days (period of forced alcohol exposure), and a choice between water and alcohol for the last 14 days (VAC period). The results (mean +/- SEM) obtained from the last 8 days of the VAC period were significantly different (P <.05) between CRF mice and the 2 control groups. As expected, CRF mice had a higher total fluid intake than did normal and sham-operated controls (9.5 +/- 0.2 vs 5.4 +/- 0.2 and 5.4 +/- 0.2 g/d). Surprisingly, despite their increased total fluid consumption, CRF mice nearly abolished their absolute alcohol intake compared with that of both control groups (3.2 +/- 0.5 vs 13.1 +/- 0.8 and 14.2 +/- 1.1 g alcohol/kg body wt/d). The resulting alcohol preference ratio (g alcohol/g total fluid) was markedly decreased in the CRF mice compared with that in both control groups (0.09 +/- 0.01 vs 0.62 +/- 0.03 and 0.64 +/- 0.05). We conclude that the innate alcohol preference of C57BL/6 mice is nearly abolished during CRF. Additional studies to clarify the mechanism of this striking change in drinking pattern are required, with special emphasis on the possible role of angiotensin II, which is involved in thirst regulation and known to reduce the alcohol consumption of normal alcohol-preferring rats.     

Prediction of mortality in an Indian intensive care unit

Objective To compare hospital outcome prediction using an artificial neural network model, built on an Indian data set, with the APACHE II (Acute Physiology and Chronic Health Evaluation II) logistic regression model.Design Analysis of a database containing prospectively collected data.Setting Medical-neurological ICU of a university hospital in Mumbai, India.Subjects Two thousand sixty-two consecutive admissions between 1996 and1998.Interventions None.Measurements and results The 22 variables used to obtain day-1 APACHE II score and risk of death were recorded. Data from 1,962 patients were used to train the neural network using a back-propagation algorithm. Data from the remaining 1,000 patients were used for testing this model and comparing it with APACHE II. There were 337 deaths in these 1,000 patients; APACHE II predicted 246 deaths while the neural network predicted 336 deaths. Calibration, assessed by the Hosmer-Lemeshow statistic, was better with the neural network (=22.4) than with APACHE II (=123.5) and so was discrimination (area under receiver operating characteristic curve =0.87 versus 0.77, p=0.002). Analysis of information gain due to each of the 22 variables revealed that the neural network could predict outcome using only 15 variables. A new model using these 15 variables predicted 335 deaths, had calibration (=27.7) and discrimination (area under receiver operating characteristic curve =0.88) which was comparable to the 22-variable model (p=0.87) and superior to the APACHE II equation (p<0.001).Conclusion Artificial neural networks, trained on Indian patient data, used fewer variables and yet outperformed the APACHE II system in predicting hospital outcome.Electronic Supplementary Material Supplementary material is available in the online version of this article at Part of this work was presented at the Sixth Annual Critical Care Congress of the Indian Society for Critical Care Medicine, Bangalore, India     

Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins

We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in this mechanism. The ability of transport proteins to recognise NU/ICRF 505 as a substrate was evaluated in model systems either transfected with breast cancer-resistance protein 1 (Bcrp1), multidrug-resistance protein 2 (Mrp2) or Mrp3, or overexpressing MRP1 or P-170 glycoprotein. Results from chemosensitivity assays suggested that NU/ICRF 505 was not a substrate for any of the above proteins. In drug accumulation studies in human colon cancer cell lines NU/ICRF 505 was taken up avidly and retained in cells lacking UGTs (HCT116), whereas, following equally rapid uptake, it was cleared rapidly from cells displaying UGT activity (HT29) as glucuronide metabolites. HT29 cells were shown to express MRP1 and 3, but not P-170 glycoprotein, MRP2 or breast cancer-resistance protein. The major glucuronide of NU/ICRF 505 inhibited ATP-dependent transport of estradiol 17-beta-glucuronide in Sf9 insect cell membrane vesicles containing MRP1 or MRP3, while co-incubation of HT29 cells with the MRP antagonist, MK571, significantly restored intracellular concentrations of NU/ICRF 505. These data lead us to conclude that the presence of a glucuronide transporter is essential for glucuronidation to represent a major de novo resistance mechanism and that UGTs will contribute more as a primary resistance mechanism when the parent drug (e.g. NU/ICRF 505) is not itself recognised by transport proteins.     

Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling

Transforming growth factor (TGFbeta) is a 25-kDa dimeric polypeptide that plays a key role in a variety of physiological processes and disease states. Blocking TGFbeta signaling represents a potentially powerful and conceptually novel approach to the treatment of disorders in which the signaling pathway is constitutively activated, such as cancer, chronic inflammation with fibrosis and select immune disorders. In this paper, we describe the biological properties of a novel series of quinazoline-derived inhibitors of the type I transforming growth factor receptor kinase (TbetaKIs) that bind to the ATP-binding site and keep the kinase in its inactive conformation. These compounds effectively inhibited TGFbeta-induced Smad2 phosphorylation in cultured cells in vitro with an IC(50) between 20 and 300 nM. Moreover, TbetaKIs were able to broadly block TGFbeta-induced reporter gene activation. Finally, TbetaKIs inhibited TGFbeta-mediated growth inhibition of normal murine mammary epithelial cells (NMuMG) and mink lung epithelial cells (Mv1Lu), and TGFbeta-induced epithelial-mesenchymal transdifferentiation (EMT) of NMuMG cells. Thus, these chemical TbetaKIs have the potential to be further developed as anti-cancer and -fibrosis agents. In addition, they represent valuable new tools for dissecting the biochemical mechanisms of TGFbeta signal transduction and understanding the role of TGFbeta signaling pathways in different physiological and disease processes.