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Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.

Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.

This Pamphlet provides assistance to the military operations analyst and guidance for the combat developments study officer in the selection and use of appropriate measures of effectiveness to evaluate and compare land combat systems and subsystems. The scope of the pamphlet covers the development, formulation, and use of measures of effectiveness in the combat developments process. Included are the roles of measures of effectiveness in the analysis, test and experimentation, and documentation of Army doctrinal, organizational and materiel systems concepts. The critically important role of measures of effectiveness in the decision process for combat systems development is highlighted. Emphasis is on the methodology to develop measures of effectiveness -- a process which can best be described, at present, as an art trying to become a science. Additional emphasis is placed upon the impact that selective measures of effectiveness can have on modeling, military judgement, and the degrees of various sorts of risks which may be involved in conclusions. A compendium of examples of measures of effectiveness (MOE) is provided that illustrates the methodology.

Contents: Organization of the Instruction Manual; Program Dyna1; Program Dyan2; Program Dyna3; Program Dyna4; Program Dyna5; Program WASRX; Program PTRS1; Program PTRS2; Data File Dynaval; Data file Dyncom and Date File WASRFILE., See also Volume 1, AD-A037 052.

Table of Contents: Optimization Techniques Considered; Linear Programming as the Optimization Technique; Adapting the Static IFRS Model to LP; The Military Construction Cost; The Pilot Training Rate (PTR) Maximizer; and Computer Usage and Program Instructions., See also Volume 1, AD-A037 055.

The purpose of the Phase III study was to refine the Static IFRS model and to expand the IFRS concept by developing three additional planning tools for use by Navy decision-makers as follows: Dynamic planning tool; Optimization model; and Fleet Readiness Training Squadron planning tool. The Dynamic planning tool simulates the undergraduate pilot training program on a weekly basis whereas the Static IFRS assumes an even annual flow of students. The Optimization model has two segments-a PTR Maximizer that calculates the maximum annual pilot training rate (PTR) possible for a given facilities inventory and a MCON Minimizer that calculates the minimum facility cost phase-to-base assignment for a desired PTR. The Fleet Readiness Training (FRT) model provides planning information for the readiness training squadrons and is designed similarly to the Static IFRS model. The Phase III documentation consists of the following four reports: The Integrated Facilities Requirements Study (IFRS) Phase III, ORI TR 645; Development of the Automated Dynamic Model for the Integrated Facilities Requirements Study (IFRS) Phase III, ORI TR 646; Development of the Optimization Model for the Integrated Facilities Requirements Study (IFRS) Phase III, ORI TR 647; and Development of the Fleet Air Readiness Training Model for the Integrated Facilities Requirements Study (IFRS) Phase III, ORI TR 648., See also Volume 1, AD-A037 050.

The objective of this study is to develop a first generation, or prototype, optimization model that provides the decision-maker with information concerning where each undergraduate pilot training phase should be located in order to: Maximize the pilot training rate (PTR) for a given facility's inventory (i.e., facility stock); and Minimize the military construction cost (MCON) for a desired PTR. The development of the Optimization model is within the general scope of the Integrated Facilities Requirements Study (IFRS) and is one of the series of management tools developed under the IFRS study., See also Volume 2, AD-A037 056.

Contents: The Dynamic Air Readiness Training Model; Data Initialization; Dynamic Simulation; The Aviation Statistical Report Module; Student Input Module; Shock Module; Error Messages; and The Dynamic IFRS Data Files., See also Volume 3, AD-A037 054.

This report documents the Fleet Readiness Training (FRT) Planning model developed as part of the third phase of the Integrated Facilities Requirements Study (IFRS). In Phase I, two analytic submodels were developed. The first, a Logistics Support Requirements Generator, estimates personnel, aircraft, and fuel requirements for each phase of undergraduate pilot training at the Naval Air Training Command (NATRACOM). The second, a Pacing Facilities Requirements submodel, calculates facility requirements for each phase of training. The purpose of the Phase II study was to develop a preliminary total systems IFRS management planning tool (including the two submodels developed in Phase I, as well as Base Loading, Facilities Excess/Deficiency, and Total Cost submodels), and automate the model so that it provides quick, accurate, and relevant information for use in the decision-making process. This Static IFRS model has been in continuous operation since March 1970. The purpose of the Phase III study was to refine the Static IFRS model and to expand the IFRS concept by developing three additional planning tools for use by Navy decision-makers as follows: Dynamic planning tool; Optimization model; and Fleet Readiness Training Squadron planning tool. The Dynamic planning tool simulates the undergraduate pilot training program on a weekly basis whereas the Static IFRS assumes an even annual flow of students., See also Volume 3, AD-A037 058.

This report documents the Dynamic Planning model developed as part of the third phase of the Integrated Facilities Requirements Study (IFRS). The purpose of the Phase III study was to refine the Static IFRS model and to expand the IFRS concept by developing three additional planning tools for use by Navy decision-makers as follows: Dynamic planning tool; Optimization model; and Fleet Readiness Training Squadron planning tool., See also Volume 2, AD-A037 053.

This report documents the Fleet Readiness Training (FRT) Planning model developed as part of the third phase of the Integrated Facilities Requirements Study (IFRS)., See also Volume 4, AD-A037 059.

This volume describes the overall system characteristics and flow for all computer programs included in the automated Fleet Readiness Training (FRT) model. The purpose of the programmer's manual is to provide the verbal description, flow charts, variable dictionary, program and subroutine dictionary, and program listing for each of the computer programs that constitute the automated model of the FRT. This programmer's manual provides Navy personnel with the information required to understand the logic of the programming and to make changes to the programs as necessary., See also Volume 1, AD-A037 057.

This report summarizes the third phase of the Integrated Facilities Requirements Study (IFRS). It has been prepared for the Systems Analysis Division of the Office of the Assistant Commander for Facilities Planning (Code 20), Naval Facilities Engineering Command (NAVFAC), Department of the Navy, as part of Contract N00025-67-C-0031 (NBy-78672) awarded to Operations Research, Inc., in June 1970., See also Volume 2, AD-A037 051.

Using N-formyl protection and N, N'-dicyclohexylcarbodimide coupling, a simple, direct procedure is described for the incorporation of a variety of amino acids with reactive side chains into peptides. Included amongose synthesized were three series of peptides or peptide esters containing (1) up to five tyrosine residues, (2) up to four tryptophan residues, and (3) up to four methionine residues. The procedure consisted of coupling the N-formylamino acid to the amino acid ester by means of N,N'-dicyclohexylcarbodiimide. The resulting N-formyl peptide ester was deformylated with alcoholic hydrogen chloride and the product was neutralized to give the dipeptide ester. Successive repetitions of this procedure using the peptide ester and more N-formylamino acid progressively lengthened the peptide chain. Saponification of the peptide ester at any intermediate stage produced the corresponding free peptide. By means of crystalline enzymes the L-configuration was demonstrated for most, but not all, residues. For the most part, the susceptibilities of the peptides conformed with the known specificities of the enzymes. Variation of Rf with chain length was studied for each series of peptides in several different solvent systems. (Author), Presented in part at National Meeting of American Chemical Society (133rd), San Francisco, Calif., April 16, 1958.

The analysis of the results of the preliminary experimental program has been pursued with emphasis on the visible radiation from vacuum gaps. The results are consistent with both thermal and transition radiation phenomena. The 320 kv system has been assembled and the components necessary for the pilot experiment checked out, viz. the vacuum chamber, the bakeout system, the high voltage generator and control unit, the feedthrough bushing and the electrodes support and adjustment mechanism. Fabrication has been initiated on the other components such as the magnetic field coils, power supply for same and the energy storage system. Much useful information and technology was gained from the solving of the problems encountered. The design of the pilot two-level partial factorial experiment was slightly modified to lessen the confustion of bakeout with other interactions. As many as possible of the prebreakdown phenomena will be monitored continuously in order to describe completely the vacuum gap and the electrode surfaces during this experiment. (Author)

Efforts were continued on a feasibility and de sign study for electrostatic generators. Progress was made in the study of high voltage insulation in vacuum. The superiority of titanium alloy Ti-7Al-4Mo as an electrode material over other high strength materials, which was deter mined with small electrodes, was confirmed for large area electrodes. Forty-five kv/mm was insulated over 1000 cm sq/ft areas with the titanium alloy and 35 kv/mm with stainless steel coated with an epoxy. Much time was lost due to malfunctions of the high speed shaft seal on the 1 - 3 kw generator. Although a reasonable pres sure level can be maintained with the shaft spinning, oil vapor, which is an acknowledged enemy of vacuum insulation, accumulated in the system to the detriment of the electric field properties of the generator. Data has been obtained on the operation of vacuum-insulated generators. Using a smaller machine, the first power run has been made using dielectric-coated stator blades and a rotor system completely at shaft potential.

Advancing the Physical Culture Propaganda; The Editor Curtailing His Business Activities; Nothing the Matter With the World; Where Destructive Criticism is Warranted; Exercise as a Cure For Worry; The Outdoor Life; Health- And Strength-Building Simplified; The Passing of the Helpless Woman; Out-of-doors With the Health-Seeker; Need Motherhood Prove An Ordeal?; Treating Catarrh and Measles; Our Debt to the Date-palm; Out of the Beaten Path; Athletic Sports On Shipboard; The Breaking-in of Percy; Anent the Salisbury Regimen; Eggs and Their Food Value; Making Our School System Sensible; Simplicity and Common Sense In Diet; Living the Radiant Life; Shall the Cow be the Mother of Our Children?; The Mental Aspect of Health-building; From New England to California on Foot; A New System of Self-defense; Progress Paragraphs; Outdoor Life and Athletics; General Question Department; Virtues of Our Methods Proven; Comment, Counsel and Criticism, Volume This archival material has been provided for educational purposes. Ball State University Libraries recognizes that some historic items may include offensive content. Our statement regarding objectionable content is available at: https://dmr.bsu.edu/digital/about