Kidney Exchange to Overcome Financial Barriers to Kidney Transplantation.

Organ shortage is the major limitation to kidney transplantation in the developed world. Conversely, millions of patients in the developing world with end-stage renal disease die because they cannot afford renal replacement therapy-even when willing living kidney donors exist. This juxtaposition between countries with funds but no available kidneys and those with available kidneys but no funds prompts us to propose an exchange program using each nation's unique assets. Our proposal leverages the cost savings achieved through earlier transplantation over dialysis to fund the cost of kidney exchange between developed-world patient-donor pairs with immunological barriers and developing-world patient-donor pairs with financial barriers. By making developed-world health care available to impoverished patients in the developing world, we replace unethical transplant tourism with global kidney exchange-a modality equally benefitting rich and poor. We report the 1-year experience of an initial Filipino pair, whose recipient was transplanted in the United states with an American donor's kidney at no cost to him. The Filipino donor donated to an American in the United States through a kidney exchange chain. Follow-up care and medications in the Philippines were supported by funds from the United States. We show that the logistical obstacles in this approach, although considerable, are surmountable.

Immediate reconstruction with implants in women with invasive breast cancer does not affect oncological safety in a matched cohort study.

Physicians are still concerned about the oncological safety regarding immediate breast reconstruction (IBR) in breast cancer patients. This study aimed to evaluate possible differences between local, regional, and distant recurrences between women having implant-based reconstruction versus women operated with mastectomy alone. Secondary aims were to evaluate time to oncological treatment as well as disease-free and breast-cancer-specific survival. In a retrospective cohort designed study, 300 reconstructed patients with invasive breast cancer were matched with 300 patients from the population-based Regional Breast Cancer Register of the Stockholm-Gotland health-care region operated with mastectomy alone. They were matched for age, tumor size, nodal stage, and year of operation. Also included were patients treated with neoadjuvant chemotherapy and postoperative radiotherapy. The median follow-up for both the groups was 11.5 years (range 2-20). There were no significant differences in the local recurrence rate, 8.2% in the IBR group and 9.0% in the control group or in the regional recurrence rate, 8.2% versus 9.7%. Distant metastases occurred more frequently in the control group (27.1%) when compared to the IBR group (20.3%). There were no significant differences in time to treatment or in complications rate. Breast cancer mortality was 17% for the IBR group and 23% in the control group during follow-up. This long-term follow-up survey with a well-matched control group demonstrates that IBR with implants is safe to offer patients with invasive breast cancer without any negative effect on the oncological safety.

Unusual nucleoside triphosphate donors for nucleoside kinases: 3'-deoxyadenosine-2'-triphosphate and 2'-deoxyadenosine-3'-triphosphate.

Two non-conventional analogues of ATP, 3'-deoxyadenosine-2'-triphosphate (3'-d-2'-ATP) and 2'-deoxyadenosine-3'-triphosphate (2'-d-3'-ATP), the syntheses of which are described, were examined as potential phosphate donors for the nucleoside kinases: 2'-deoxycytidine kinase (dCK), cytosolic thymidine kinase (TK1) and mitochondrial thymidine kinase (TK2). The reactions were monitored by means of a mixture of [gamma-32P]ATP and cold analogue, and/or with the use of 3H-labelled acceptors and cold donor. With dCK, using equimolar mixtures of ATP with each analogue, and dC as acceptor, phosphate transfer from 3'-d-2'-ATP and 2'-d-3'-ATP amounted to 34% and 14%, respectively. With each analogue used alone (each at concentration of 100 microM), phosphate transfer from 3'-d-2'-ATP was 55% that from ATP, and from 2'-d-3'-ATP 16%. With human TK2, and equimolar mixtures of [gamma-32P]ATP with each of the analogues, and 1 microM dT as acceptor, there was no detectable transfer from either analogue. But, when each analogue was used alone, phosphate transfer attained 11% and 5%, respectively, that for ATP alone. With the low affinity form of human TK1, and dT as acceptor, only low phosphate transfer occurred with either analogue used alone. Both compounds exhibited Michaelis-Menten kinetics (with significantly lower Vmax than ATP), while ATP exhibited cooperative kinetics with all three kinases.

Evolutionary weighting of image features for diagnosing of CNS tumors.

This paper concerns an application of evolutionary feature weighting for diagnosis support in neuropathology. The original data in the classification task are the microscopic images of ten classes of central nervous system (CNS) neuroepithelial tumors. These images are segmented and described by the features characterizing regions resulting from the segmentation process. The final features are in part irrelevant. Thus, we employ an evolutionary algorithm to reduce the number of irrelevant attributes, using the predictive accuracy of a classifier ('wrapper' approach) as an individual's fitness measure. The novelty of our approach consists in the application of evolutionary algorithm for feature weighting, not only for feature selection. The weights obtained give quantitative information about the relative importance of the features. The results of computational experiments show a significant improvement of predictive accuracy of the evolutionarily found feature sets with respect to the original feature set.

Substrate/inhibitor specificities of human deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2).

Substrate/inhibitor specificities of nucleoside analogues with modified sugar moieties toward highly purified deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2) from human leukemic spleen have been examined. Substrate activities of cytosine nucleosides vs dCK were as follows: 2'-fluoro-dC > 2'-O-methyl-C > araC > 2'-fluoro-2'-deoxy-araC > 3'-O-methyl-dC = 3'-fluoro-2',3'-ddC > cytosine beta-L-riboside > 2',3'-ddC > C = 1-(4-hydroxy-1,2,-butadienyl)-cytosine (cytalene) = 2'-azido-dC. Modified purine nucleosides were only feeble substrates: ara-A > 2'-fluoro-2',3'-dideoxy-araA = 2'-O-methyl-A. With TK1 and TK2, similar sugar-modified analogues of dU and dT were feeble substrates. Surprisingly alpha-dT was a relatively good substrate, as well some beta-L-ribonucleo-sides. Several 5'-substituted analogues of dC were good non-substrate inhibitors of dCK and, to a lesser extent, of TK2. The overall data are relevant to the role of these enzymes in "activation" (by phosporylation) of nucleoside analogues with antiviral and antitumor activities.

Intelligent decision support in pathomorphology.

This paper presents a novel approach to computer-supported diagnosing based on microscopic images of histological sections. A method of extraction of textural feature is presented, which is in a sense complementary to the texture-based segmentation. The textural feature is obtained by tracing the process of image segmentation. For classification, a n2-classifier oriented to multi-class problems has been used. The paper presents also an empirical verification of the proposed approach on 700 microscopic images representing 14 classes of CNS neuroepithelial tumours, in which case an encouraging accuracy of classification on the testing set (70.6%) has been obtained.

Nucleoside triphosphate donors for nucleoside kinases: donor properties of UTP with human deoxycytidine kinase.

The reported higher efficiency of UTP, relative to ATP, as phosphate donor for deoxycytidine kinase (dCK), has been extended and found to apply to both dCyd and dAdo as acceptors. UTP as phosphate donor was shown to follow strictly Michaelis kinetics, with Km = 1 microM, in striking contrast to ATP, which exhibits marked negative cooperativity (Hill coef. = 0.7) with a several-fold higher Kmapp = 15 microM. Phosphate transfer was followed directly with use of mixtures of [gamma-32P]ATP and cold UTP as donors, or with 3H-labeled acceptors and cold donors. With equimolar concentrations of ATP and UTP (50 microM or 1 mM each), and dCyd or dAdo as acceptor, only minimal phosphate transfer occurred from ATP (3-10%). With a 6:1 ratio of ATP:UTP, hence exceeding the intracellular ratio, phosphate transfer from ATP increased, but still did not exceed 25-40% with either dCyd or dAdo as acceptor. Moreover, relative ATP transfer is dependent on the dCyd concentration. We conclude that the major intracellular phosphate donor for dCK is not ATP, but UTP. Preliminary data for human thymidine kinases (TK1 and TK2) exhibit quite different behaviour. The foregoing, together with literature data, are highly relevant to in vitro studies on the properties of the nucleoside kinases, and to the design of chemotherapeutically active nucleoside analogues.

Substrate/inhibitor properties of human deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2) towards the sugar moiety of nucleosides, including O'-alkyl analogues.

Nucleoside analogues with modified sugar moieties have been examined for their substrate/inhibitor specificities towards highly purified deoxycytidine kinase (dCK) and thymidine kinases (tetrameric high-affinity form of TK1, and TK2) from human leukemic spleen. In particular, the analogues included the mono- and di-O'-methyl derivatives of dC, dU and dA, syntheses of which are described. In general, purine nucleosides with modified sugar rings were feebler substrates than the corresponding cytosine analogues. Sugar-modified analogues of dU were also relatively poor substrates of TK1 and TK2, but were reasonably good inhibitors, with generally lower Ki values vs TK2 than TK1. An excellent discriminator between TK1 and TK2 was 3'-hexanoylamino-2',3'-dideoxythymidine, with a Ki of approximately 600 microM for TK1 and approximately 0.1 microM for TK2. 3'-OMe-dC was a superior inhibitor of dCK to its 5'-O-methyl congener, consistent with possible participation of the oxygen of the (3')-OH or (3')-OMe as proton acceptor in hydrogen bonding with the enzyme. Surprisingly alpha-dT was a good substrate of both TK1 and TK2, with Ki values of 120 and 30 microM for TK1 and TK2, respectively; and a 3'-branched alpha-L-deoxycytidine analogue proved to be as good a substrate as its alpha-D-counterpart. Several 5'-substituted analogues of dC were good non-substrate inhibitors of dCK and, to a lesser extent, of TK2. Finally, some ribonucleosides are substrates of the foregoing enzymes; in particular C is a good substrate of dCK, and 2'-OMe-C is an even better substrate than dC.