Influence of doping with selected organic molecules on the magnetic and electronic properties of bare, surface terminated and defect patterned Ti2C MXene monolayers.

In this study, based on density functional theory, we examine the interaction between the bare, F-, OH-terminated as well as defect patterned Ti2C and selected neurotransmitter (NT) and amino acids (AA) such as dopamine, glutamate, glycine and serine. We found that these molecules are dissociated at a specific location in bare Ti2C monolayers and concomitantly they form Ti-H bonds. The adsorbed molecules give rise to significant charge transfer between the adsorbates and underlying substrates and generally the electronic energy states are affected, band gaps are tuned and magnetic moments are attained significantly. In particular, the bare antiferromagnetic-Ti2C monolayer undergoes an antiferromagnetic-ferromagnetic transition upon adsorption of the amino acids and nucleobase molecules due to bond dissociation of molecules. Moreover, the electronic and magnetic properties of bare Ti2C are crucially changed in the presence of a vacancy. While pristine Ti2C is an AFM semiconductor, mono- and di-vacancy structures become ferromagnetic semiconductors. When adsorbed by molecules, the defect patterned Ti2C is spin-polarized and hence the surface results in a metallic state. We also reveal that the Ti2C structure is transformed to the non-magnetic (NM) ground state in the presence of both F- and OH-surface termination groups. When adsorbed to these organic molecules on a terminated Ti2C surface, the binding of molecules to this surface is generally weak and arises from van der Waals interactions. We determine that the binding energy of dopamine, which is absorbed on bare Ti2C in equilibrium in a solvent, was found to be 2.31 eV and the magnetic moment per supercell was reduced to 2.91µB.

How conformational transition depends on hydrophobicity of elastin-like polypeptides.

The three-dimensional structures of elastin-like polypeptides Val1-Pro2-Gly3-Xaa4-Gly5 were investigated by using the multicanonical Monte Carlo (MC) simulation procedure. By substituting different amino acids in the fourth position of the sequence, the thermodynamical variables are calculated in vacuo and in solvent to determine the hydrophobicity dependence of the conformational transition temperatures of the peptides. Resultant hydrophobicity scale is in good agreement with many hydrophobicity scales.

Differential chemotherapeutic susceptibility of human T-lymphocytes and B-lymphocytes in culture.

After previous work from this laboratory revealed that asparaginase was 800-2,000 times more inhibitory against human T-lymphocytes in culture than against B-lymphocytes, a similar further study of 13 chemotherapeutic and immunosuppressive agents was done. Cytosine arabinoside and 5-fluorouracil also had differential inhibitory activities on human T- and B-cells in culture. On the basis of the dose producing 50% inhibition of viable cell growth on day 5, cytosine arabinoside had 45-80 times more inhibitory activity against T-cells than against B-cells. In contrast to asparaginase and cytosine arabinoside, 5-fluorouracil had 10-20 times more inhibitory activity against B-cells. The rest of the chemotherapeutic and immunosupressive agents tested had minor or no differential activity. These findings indicated that T-cell response to asparaginase and cytosine arabinoside and B-cell response to 5-fluorouracil may be exploitable for the differential immunosuppressive effects presumed to be active in vivo. In addition, such differential responses may predict differential tumor cell behavior against these chemotherapeutic agents by T- and B-cell neoplasms in vivo.

L-asparagine requirements of human T-lymphocytes and B-lymphocytes in culture.

The characterization of two human T-lymphocyte lines revealed that they required exogenous L-asparagine for cell growth, whereas all four B-cell lines studied were L-asparagine independent. T-cells were 800-2,000 times more sensitive to Escherichia coli L-asparaginase than were B-cells. The cytotoxic effects of a high concentration of L-asparaginase on B-cells were not related to the hydrolysis of L-asparagine but were due to heat-labile and heat-resistant substances in the enzyme. The findings were consistent with reports that L-asparaginase is effective in suppressing cellular immunity and inducing remission in patients with acute lymphocytic leukemia, mainly a non-B-cell disease. Thus these cell lines provide in vitro models for the study of a nutritional approach to chemotherapy or immunotherapy.

Protein kinase C activity and multidrug resistance in MOLT-3 human lymphoblastic leukemia cells resistant to trimetrexate.

It has been suggested that protein kinase C (PKC) plays a role in multidrug resistance (MDR). In this study we assayed PKC activity in MOLT-3 human acute lymphoblastic leukemia cells and found an approximately 50% decrease in activity in MDR sublines made resistant to the lipophilic antifolate trimetrexate, when compared with trimetrexate-sensitive parent cells. The PKC activity of a methotrexate-resistant subline without MDR (MOLT-3/MTX10,000) was identical to that of parent cells. Although a downward trend was noted in PKC activity in the membrane fraction of cells with increasing trimetrexate resistance, there was no absolute correlation between the degree of MDR and the relative decrease in PKC activity. Using the same method, we also confirmed an over 6-fold increase in PKC activity in the MDR human breast cancer subline MCF-7/DOXR when compared with the sensitive parent cell line, MCF-7/WT. Because of this divergent relationship between relative PKC activity and MDR, we tested the effect of PKC inhibition and activation on drug resistance. The PKC inhibitor staurosporine, at both subtoxic and toxic concentrations as well as at concentrations shown to be inhibitory to PKC, failed to increase drug resistance of parent and resistant MOLT-3 cells and decrease drug resistance of MCF-7/WT and MCF-7/DOXR cells. Short-term exposure to 3-phorbol-12-myristate-13-acetate, which activated PKC 7.0-fold and 4.7-fold, respectively, in the membrane of MOLT-3 and resistant cells, resulted in small (1.3- to 1.8-fold), approximately equivalent, increases (rather than decreases) in resistance to doxorubicin, whereas for vincristine no consistent trend was observed. Identical results were also obtained with phorbol-12,13-dibutyrate. These results indicate that PKC activity can be decreased and increased in MDR cells. Both staurosporine inhibition and phorbol ester activation failed to produce changes in drug resistance that would be considered consistent with the resulting degree of PKC activity. Short-term phorbol ester exposure can change the sensitivity of the cells to doxorubicin without changing the relative drug resistance. PKC activity in these cells may then be unrelated to MDR.

Multidrug resistance in a human leukemic cell line selected for resistance to trimetrexate.

Trimetrexate (TMQ) is a lipophilic antifolate shown to have antitumor activity in humans. TMQ-resistant sublines of the MOLT-3 human acute lymphoblastic leukemia cell line were developed and were designated as MOLT-3/TMQ200, MOLT-3/TMQ800, and MOLT-3/TMQ2500 based on degrees of resistance to TMQ. The TMQ resistance was accompanied by 5- to 7-fold increases in dihydrofolate reductase activity and markedly reduced cellular TMQ accumulation. Methotrexate accumulation was not impaired in TMQ-resistant cells. TMQ retention (efflux) was unchanged in these TMQ-resistant cells. Verapamil enhanced the TMQ accumulation in the resistant cells to the level seen in the parent cells but had no effects on the TMQ retention. These sublines were cross-resistant not only to methotrexate but also to vincristine, doxorubicin, daunorubicin, and mitoxantrone. There was no cross-resistance to bleomycin or cisplatin. Resistance to vincristine, doxorubicin, daunorubicin, and mitoxantrone was reversed by verapamil. TMQ resistance was only minimally reversed by verapamil and methotrexate resistance not affected at all. Both cellular accumulation and retention of vincristine and daunorubicin in the TMQ-resistant cells were markedly decreased. Verapamil enhanced both accumulation and retention of the drug. Plasma membrane fractions of the TMQ-resistant cells analyzed by urea-sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by staining with Coomassie Blue revealed the presence of a distinct band with a molecular weight of 170,000. Immunoblot analysis with 125I-labeled monoclonal antibody raised against P-glycoprotein of multidrug-resistant Chinese hamster ovary cells (C219) cross-reacted with the Mr 170,000 protein of the TMQ-resistant cells. These results show that the TMQ-resistant cells displayed not only decreased TMQ uptake and increased dihydrofolate reductase but also characteristics associated with a classical multidrug-resistant phenotype. Multidrug resistance includes lipophilic antifolate.

Differences in chemotherapeutic susceptibility of human T-, B-, and non-T-/non-B-lymphocytes in culture.

Eleven human lymphoid cell lines, two T-cell lines, six B-cell lines and three non-T-/non-B-cell lines were evaluated for their asparagine dependence and for their chemotherapeutic susceptibility to asparaginase, cytosine arabinoside (ara-C), and 5-fluorouracil (FU). Two T-cell lines were asparagine dependent, whereas all B-cell and non-T-/non-B-cell lines were asparagine independent. These differences in nutritional requirements were consistent with as much as 5,000-fold differences in asparaginase sensitivity. B cells were found to be as much as 200-fold less sensitive to ara-C than T cells, irrespective of the benign or malignant nature of the cells or the presence or absence of EB virus infection. One non-T-/non-B-cell line with cell markers similar to the B-cell group behaved like a B-cell line. Two other non-T-/non-B-cells showed unique ara-C dose-response curves. FU sensitivity study revealed heterogeneity among B-cell groups. Non-T-/non-B-cell lines were uniformly FU insensitive. These differences in chemotherapeutic susceptibility were discussed in terms of usefulness as an in vitro model.

Recent developments in modeling heat transfer in blood perfused tissues.

Successful hyperthermia treatment of tumors requires understanding the attendant thermal processes in both diseased and healthy tissue. Accordingly, it is essential for developers and users of hyperthermia equipment to predict, measure and interpret correctly the tissue thermal and vascular response to heating. Modeling of heat transfer in living tissues is a means towards this end. Due to the complex morphology of living tissues, such modeling is a difficult task and some simplifying assumptions are needed. Some investigators have recently argued that Pennes' interpretation of the vascular contribution to heat transfer in perfused tissues fails to account for the actual thermal equilibration process between the flowing blood and the surrounding tissue and proposed new models, presumably based on a more realistic anatomy of the perfused tissue. The present review compares and contrasts several of the new bio-heat transfer models, emphasizing the problematics of their experimental validation, in the absence of measuring equipment capable of reliable evaluation of tissue properties and their variations that occur in the spatial scale of blood vessels with diameters less than about .2 mm. For the most part, the new models still lack sound experimental grounding, and in view of their inherent complexity, the best practical approach for modeling bio-heat transfer during hyperthermia may still be the Pennes model, providing its use is based on some insights gained from the studies described here. In such cases, these models should yield a more realistic description of tissue locations and/or thermal conditions for which the Pennes' model might not apply.

Forcible administration of antipsychotic medication.

KIE: A summary is provided of recent court decisions in Massachusetts and New Jersey which dealt with the right of mental patients to refuse psychoactive drugs. The courts expressly stated a qualified constitutional right to refuse medication but left unclear what standards and procedures a state must follow if it seeks to override a refusal.^ieng

Forcible administration of antipsychotic medication. State laws.

KIE: With growing numbers of involuntarily committed patients refusing antipsychotic drugs, state and federal courts have been called on to determine and balance the rights of patients and the duties of the state. Arkin, an attorney with the Office of the General Counsel of the American Medical Association, discusses the complex legal controversies involved, focusing particularly on several related cases as they wound their way through the Massachusetts Supreme Judicial Court, federal district and appellate courts, and the U.S. Supreme Court.^ieng

Effects of cell density on drug-induced cell kill kinetics in vitro (inoculum effect).

The effects of cell density on drug-induced cell kill kinetics were studied by means of clonogenic assay using 3 human leukaemia-lymphoma cell lines. Mitoxantrone, daunorubicin, doxorubicin, vincristine and bleomycin were progressively less efficacious when cell density increased (positive inoculum effects), whereas the effects of cis-platin and carboplatin were not influenced by cell density. Inoculum effects were related to the kind of chemotherapeutic agents tested, irrespective of the type of cell lines used. Preincubation of mitoxantrone or doxorubicin in the presence of cells in high density resulted in decreases in the cytocidal activity, whereas the effects of bleomycin, vincristine and cis-platin were unaffected. These results show that cell density affects the biological effect of certain chemotherapeutic agents. Inactivation of drugs by high densities of cells partially explains this phenomenon.

A sensitivity analysis of the Thermal Pulse Decay method for measurement of local tissue conductivity and blood perfusion.

The Thermal Pulse Decay (TPD) method for the determination of local tissue thermal conductivity and blood perfusion rate is based on a comparison of measured with theoretically calculated temperatures. A sensitivity analysis of the theoretical model is performed. This analysis supports the establishment of an experimental protocol which reduces the measurement errors: An "optimal" measurement time interval for typical perfusion rates (up to 6 mL/mL/min) was found to be between 3 and 11 s after the heat pulse is turned off. Within this interval, the maximum error in determination of tissue conductivity and blood perfusion caused by experimental measurement errors is expected not to exceed 5 percent. The presently chosen pulse duration of 3 s is in agreement with the analysis as a good compromise between accuracy and excessive tissue heating.

Computer-based system for continuous on-line measurements of tissue blood perfusion.

We describe a new system for an almost continuous, on-line measurement of local blood perfusion in living tissue. The technique uses a thermal method based on measurements of the tissue temperature decay after a short pulse (approximately equal to 3 s) of local heating. The instrumentation system consists of six small thermistor microprobes, a probe interface unit and a DEC LSI-11/23 microcomputer. The system is equipped with six thermistor channels, and the number can be increased with further signal conditioning modules, thereby increasing the locations at which blood perfusion can be measured. The results agree favourably with values for tissue blood flow obtained simultaneously using either the microspheres method or an electromagnetic probe. The system has been in use for three years and there is good reason to believe that it can be reliably applied in many situations where a continuous multichannel monitor of local blood perfusion is necessary.

Theory on thermal probe arrays for the distinction between the convective and the perfusive modalities of heat transfer in living tissues.

Recent suggestions for an improved model of heat transfer in living tissues emphasize the existence of a convective mode due to flowing blood in addition to, or even instead of, the perfusive mode, as proposed in Pennes' "classic" bioheat equation. In view of these suggestions, it might be beneficial to develop a technique that will enable one to distinguish between these two modes of bioheat transfer. To this end, a concept that utilizes a multiprobe array of thermistors in conjunction with a revised bioheat transfer equation has been derived to distinguish between, and to quantify the perfusive and convective contribution of blood to heat transfer in living tissues. The array consists of two or more temperature sensors one of which also serves to locally insert a short pulse of heat into the tissue prior to the temperature measurements. A theoretical analysis shows that such a concept is feasible. The construction of the system involves the selection of several important design parameters, i.e., the distance between the probes, the heating power, and the pulse duration. The choice of these parameters is based on computer simulations of the actual experiment.

Adaptive thermal modeling: a concept for measurement of local blood perfusion in heated tissues.

A new Adaptive Thermal Modeling (ATM) method for the measurement of local tissue blood perfusion rate is introduced. The method is based on a two-phase numerical technique. The first phase includes a fast, finite difference scheme for solution of the transient temperature field. The second phase involves iterative corrections of the perfusion until the modeled temperatures coincide with those measured by the temperature sensors. The results obtained from computer generated "data", as well as from laboratory experiments demonstrate the potential capability of the ATM method to continuously measure local perfusion rates in heated tissues. Rigorous analysis of the technique is planned for the near future so that it can be applied to in vivo measurements of local tissue blood perfusions.

A technique for measuring the thermal conductivity and evaluating the "apparent conductivity" concept in biomaterials.

A simple technique for measuring thermal conductivity of biomaterials is described. The method is based on depositing a pulse of heat into the material of choice, and fitting the subsequent local temperature decay to that predicted by a theoretical model. This transient method is most suitable in situations where frequent measurements of the thermal conductivity are desired. The method was evaluated by calculating the thermal conductivity of several inert materials. The measured conductivities compared well with published values. The developed technique was also used to examine the applicability of the "apparent conductivity" index to combine both conductive and blood-convective thermal effects in living, blood perfused tissues. Using both simulated and experimental results, it was shown that the changes in the apparent conductivity are highly correlated with changes in blood flow. However, quantitative application of this index must be restricted to conditions that are similar to those which existed at the time the apparent conductivity was measured.

Theoretical analysis of the large blood vessel influence on the local tissue temperature decay after pulse heating.

The influence of a large blood vessel (larger than 500 microns in diameter) on the local tissue temperature decay following a point source heating pulse was determined numerically using a sink/source method. It was assumed that the vessel was large enough so that the temperature of blood flowing within it remained essentially constant and was unaffected by any local tissue temperature transients. After the insertion of a point source heating pulse, the vessel influence on the local tissue transient temperature field was estimated by representing the vessel as a set of negative fictitious instantaneous heat sources with strength just sufficient to maintain the vessel at a constant temperature. In the surrounding tissue, the Pennes' tissue heat transfer equation was used to describe the temperature field. Computations have been performed for a range of vessel sizes, probe-vessel spacings and local blood perfusion rates. It was found that the influence of a large vessel on the local tissue temperature decay is more sensitive to its size and location rather than to the local blood perfusion rate. For a heating pulse of 3s duration and 5mW of power, there is a critical probe-vessel center distance 7R (R, vessel radius) beyond which the larger vessel influence on tissue temperature at the probe can be neglected.

Microvascular architecture within the pig kidney cortex.

Corrosion casts of the plastic (Mercox Cl-2B) filled pig kidney cortex vasculature were sliced either parallel or perpendicular to the kidney surface. Scanning electron microscopy photographs were taken of the casts. Montages of the photographs were analyzed using a digitizing tablet and microcomputer-based software. For vessels having diameters larger than 0.05 mm, their sizes, numbers per unit area, and branching patterns were studied with respect to the kidney cortex depth. Vascular branching diameters and angles within the cortex compare favorably with those reported for other major vascular systems. The microvascular dimensions and densities were used to predict the average blood flow velocity within the kidney cortex. It is expected that the results will facilitate a better insight into the contribution of flowing blood to the heat transfer process in perfused tissues.

Thermal pulse decay method for simultaneous measurement of local thermal conductivity and blood perfusion: a theoretical analysis.

Presented here is a theoretical analysis of the recently developed thermal pulse decay (TPD) method for a simultaneous measurement of local tissue conductivity and blood perfusion rate. The paper describes the theoretical model upon which the TPD method is based and details its capabilities and limitations. The theoretical aspects that affected the development of the measurement protocol are also discussed. The performance of the method is demonstrated with an experimental example which compares the measurements of local kidney blood perfusion rates made using the TPD method with the total renal blood flow obtained coincidentally using a blood flowmeter, in an anesthetized dog.