Autophagy suppression in DNA damaged cells occurs through a newly identified p53-proteasome-LC3 axis.

Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Here, we report a mechanism by which autophagy is suppressed in cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Autophagy suppression is directly linked to cellular responses to DNA damage, and specifically the stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and an ex vivo organoid model. Our data indicate that suppression of autophagy, through a newly identified p53-proteasome-LC3 axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could potentially be important for realigning proteostasis in cells undergoing DNA damage repair.

GALAD score and a proposal for GALADUS model for detecting hepatocellular carcinoma in Vietnamese patients with chronic liver disease.

OBJECTIVE: The GALAD score, a serum biomarker-based model, predicts the likelihood of hepatocellular carcinoma (HCC) in patients with chronic liver disease. We evaluated the performance of the GALAD score compared to that of liver ultrasound in detecting HCC. PATIENTS AND METHODS: This study recruited a group of 136 patients with HCC and a control group of 436 patients with cirrhosis or chronic hepatitis B or hepatitis C. The performance of the GALAD score and ultrasound in detecting HCC in these patients was analyzed using the area under the receiver operating characteristic curve (AUC). The sensitivity and specificity of the optimal GALAD score were compared to those of ultrasound. RESULTS: The AUC of the GALAD score for detecting HCC was 0.940 [95% confidence interval (CI) 0.92-0.96], higher than that of ultrasound [0.939 (0.91-0.96), p < 0.001]. At a threshold of 1.24, the GALAD score had a sensitivity of 91.2% and a specificity of 81.9% for detecting HCC. The AUC of the GALAD score for early HCC detection was 0.75 (95% CI 0.71-0.80, p < 0.001; threshold 1.13, sensitivity 87.5%, specificity 67.8%, p < 0.001). The combination of GALAD and ultrasound (GALADUS score) showed further improvement, achieving an AUC of 0.97 (95% CI 0.96-0.99; cut-off point 1.37, sensitivity 95.6%, specificity 89.2%, p < 0.001). CONCLUSIONS: In our study, the GALADUS score showed improved performance compared to the GALAD score. Therefore, we suggest that the performance of the GALAD score should be reconsidered and that it should be evaluated in combination with ultrasound for HCC detection.

Urothelial progenitor cells: regional differences in the rat bladder.

OBJECTIVES: Because the trigone is a unique region in the caudal bladder with a higher risk of neoplasia, we hypothesized that this area would have a high proportion of progenitor cells. As yet there is no marker nor methodology to specifically isolate urothelial stem cells, and thus demonstrate multi-potential differentiation and self-renewal. Here, our goal was to evaluate the distribution of progenitor cells that carry two general major attributes of stem cells: clonogenicity and proliferative capacity. MATERIALS AND METHODS: The bladders of Fisher rats were divided into caudal and cephalic segments and primary cultures were established from the harvested urothelial cells. RESULTS: We found that colony-forming efficiency was almost 2-fold higher for cells from the caudal bladder compared to the cephalic bladder. Doubling time was significantly faster for cells harvested from the caudal bladder at initial plating. This suggested that the caudal bladder harbours a higher density of urothelial progenitor cells. With passage to p4, the differences between the upper and lower bladder were lost, suggesting selection of proliferative cells with serial passage. Based on Ki-67 staining, there was no geographical difference in cell proliferation under normal homeostatic in vivo conditions. CONCLUSIONS: These results demonstrate geographical sequestration of urothelial progenitor cells to the area of the bladder that encompasses the bladder neck and trigone, which may be a factor in pathological disparities between the trigone and remaining bladder.

HCN-encoded pacemaker channels: from physiology and biophysics to bioengineering.

The depolarizing membrane ionic current I(h) (also known as I(f), "f" for funny), encoded by the hyperpolarization-activated cyclic-nucleotide-modulated (HCN1-4) channel gene family, was first discovered in the heart over 25 years ago. Later, I(h) was also found in neurons, retina, and taste buds. HCN channels structurally resemble voltage-gated K(+) (Kv) channels but the molecular features underlying their opposite gating behaviors (activation by hyperpolarization rather than depolarization) and non-selective permeation profiles (> or =25 times less selective for K(+) than Kv channels) remain largely unknown. Although I(h) has been functionally linked to biological processes from the autonomous beating of the heart to pain transmission, the underlying mechanistic actions remain largely inferential and, indeed, somewhat controversial due to the slow kinetics and negative operating voltage range relative to those of the bioelectrical events involved (e.g., cardiac pacing). This article reviews the current state of our knowledge in the structure-function properties of HCN channels in the context of their physiological functions and potential HCN-based therapies via bioengineering.

239+240Pu, 90Sr and 137Cs inventories in surface soils of Vietnam.

Fallout 239+240Pu, 238Pu, 90Sr and 137Cs inventories in surface soils were measured for 20 locations in northern Vietnam yielding the mean values (+/- standard error) of 26.5+/-3.8 Bq m(-2) for 239+240Pu, 1048+/-143 Bq m(-2) for 137Cs and 212+/-28 Bq m(-2) for 90Sr. The concentrations of 137Cs and plutonium isotopes strongly correlate with each other resulting in a stable 239+240Pu/137Cs inventory ratio of 0.025+/-0.002. Among soil parameters, organic matter and fulvic acids strongly correlate with caesium and plutonium isotopes, especially in the 0-10 cm layer. 137Cs and 239+240Pu are distributed rather similarly over the 0-10 cm and 10-20 cm layers. At locations with high contents of sand (82-93%) along the South China Sea coast, the downward percolation by rainwater results in a higher accumulation of 239+240Pu and 137Cs in the 10-20 cm layer. The mean 137Cs/ 90Sr inventory ratio is 9.3+/-2.2, and the correlation is weak between these isotopes.

Recurrent secondary hyperparathyroidism after autotransplantation into the sternocleidomastoid muscle: report of a case with fine needle aspiration findings.

BACKGROUND: Recurrent hyperparathyroidism may occur following parathyroid autotransplantation due to autogenous function of the muscle-engrafted tissue. Parathyroid lesions are uncommonly diagnosed on cytology. CASE: A 31-year-old female with chronic renal failure presented with an elevated parathyroid hormone level and a neck mass in the left sternocleidomastoid muscle, the site of a previous parathyroid autograft. Fine needle aspiration of the mass revealed high cellularity, with perivascularly arranged, three-dimensional, branching clusters; individual cells; and naked nuclei exhibiting anisonucleosis. A diagnosis of parathyroid graft hyperplasia was made by fine needle aspiration and subsequently by histopathologic examination. CONCLUSION: Fine needle aspiration is an effective tool for confirming the presence of parathyroid autograft hyperplasia, thus allowing the correct surgical approach.

Fine-needle aspiration: technique and smear preparation.

Fine-needle aspiration is a rapid, accurate and inexpensive method to obtain a tissue specimen for diagnosis of suspicious lesions. The number of fine-needle aspirations performed can be expected to increase in this era of cost-conscious medicine. However, an accurate diagnosis is highly dependent on the quality of the smears, adequate clinical information and the experience of the pathologist. The clinician must be able to perform this procedure skillfully and provide good smears. Fine-needle aspiration skills can be learned by using the techniques described in this article and by continued training and experience. The most important factors are immobilization of the mass, the use of very small fine needles, sampling both with and without aspiration, use of multiple passes with the needle, reaspiration of any residual mass after fluid drainage if a cyst is encountered, aspiration of the margins of large masses, the two-slide smearing technique and rapid fixation of smears. Finally, extensive clinical information must be supplied to the pathologist interpreting the smears.

A pharmacoeconomic evaluation of the use of dexrazoxane in preventing anthracycline-induced cardiotoxicity in patients with stage IIIB or IV metastatic breast cancer.

A Markov model was developed to determine the cost of treating patients with stage IIIB or IV metastatic breast cancer with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) and dexrazoxane (administered after six courses of FAC) versus FAC alone. The primary end point in our economic study was cost per cardiac event avoided. Cost per life-year saved was also calculated, even though the survival advantage needs to be confirmed in follow-up studies. The model incorporated the direct medical costs of treating patients with chemotherapy, as well as the costs associated with treatment of any cardiac events that occurred. Data were collected for this analysis from several sources, including completed clinical trials on FAC plus dexrazoxane versus FAC plus placebo (obtained from two patient groups randomized at different time points), a panel of three oncologists, and a panel of three cardiologists. Analyses showed that therapy with dexrazoxane costs $5661.77 per cardiac event prevented. Sensitivity analyses on model variables were performed and showed that the basic results of the model did not change when parameters were varied. The clinical efficacy and cost-effectiveness of dexrazoxane as shown by the results of the current study encourage further investigation of the uses of dexrazoxane in other populations and against other comparators.

Dexrazoxane cardioprotection for patients receiving FAC chemotherapy: a pharmacoeconomic evaluation.

Anthracyclines are among the most effective and commonly-prescribed antitumor agents but have dose-limiting cumulative cardiotoxicity. We performed a pharmacoeconomic evaluation of the ability of dexrazoxane to prevent cardiac-related adverse events in patients with Stage IIIB or IV metastatic breast cancer who were treated with a median of 10 cycles of intravenous FAC (5-fluorouracil, doxorubicin and cyclophosphamide) at doses of 500/50/500 mg/m2 respectively. Dexrazoxane was given at 500 mg/m2 commencing at the seventh cycle of treatment. We determined the cost of each cardiac event prevented and the cost of each additional life-year saved by dexrazoxane use. The cost per cardiac event prevented was CDN $5745 and the cost per additional life-year saved was CDN $2856. With the increasing use of anthracyclines in Stages I and II breast cancer, these favorable clinical and economic results may broaden the range of therapeutic possibilities for anthracyclines in adjuvant and metastatic therapy of breast cancer.

The Papanicolaou smear: its value and limitations.

Although the Papanicolaou (Pap) smear is one of the most effective screening tests ever invented for a common cancer, it remains an imperfect test. The technical shortcomings of the Pap smear have been compounded by the general public's unrealistically high expectations of the test's accuracy, underestimations of the importance of regular smears, and the actions within the medico-legal system. To remedy some of the technical shortcomings, the Bethesda System, which better reflects our current knowledge about cervical neoplasia, has been proposed to replace the old Papanicolaou classification system. Although standardized cytologic criteria may reduce interobserver variability, the false-negative rate of Pap smears is at least 5%, even in the best laboratories. No amount of training or experience with human observers can reduce the error rate to zero. Automated Pap screening holds the promise of higher sensitivity, but no instruments to date have been approved as a sole means of primary screening. The family physician can play a unique role in overcoming the limitations of the Pap smear by educating patients about the value and limitations of the test, instituting patient-specific treatment or follow-up of abnormal smears based on clinical and cytologic findings, and encouraging patients to get regular smears at intervals based on risk.

A parametric study of the thoracic injury potential of basic taekwondo kicks.

A parametric investigation of the thoracic injury potential of basic taekwondo kicks was conducted through the use of computer simulations. Linkage-based models were employed to simulate the kinetics of the kicking leg and were used to drive a human thorax model. The results of the analysis according to the thoracic compression criterion indicated a minimal probability of severe injury (AIS4+) for swing kicks, nearly 0 percent and thrust kicks, less than three percent. The thoracic viscous criteria, on the other hand, predicted a severe injury probability of up to 100 percent for swing kicks and up to 80 percent for thrust kicks. Additional analysis showed that the injury potential was a strong function of the kick velocity and a weak function of the applied constant force. The injury potential was also found to be a weak function of the size and weight of the kicking leg, with variations in the peak compression and viscous response being typically below 5 percent for a 20 percent change in either the mass or the length.

Thoracic injury potential of basic competition taekwondo kicks.

A major concern in competition taekwondo is the injury potential posed by many of the powerful kicks used. An investigation of the kinetics of four kicks frequently used in competition was performed with high speed video. Velocities were measured, and energy was calculated. Typical values for basic swing kicks were 15 ms-1 and 200 J. Basic thrust kicks possessed 45% less velocity but 28% more energy than swing kicks. Linkage models were developed to simulate the motion and kinetics of the kicking leg. Injury potential was evaluated through thoracic compression and viscous criterion models. These models predict a significant probability of serious injury with all kicks, with thoracic deflections from 3 to 5 cm and peak viscous tolerance values from 0.9-1.4 ms-1, when no protective body equipment is used.