Giving the Terminally ILL Their Due (Process): A Case for Expanded Access to Experimental Drugs through the Political Process

The stated purpose of the Food and Drug Administration ( FDA or Agency ) is to promote and protect the public health. In furtherance of this end, the FDA has created a regulatory framework to ensure that drugs marketed to the general public are both safe and effective. However, critics insist that the FDA\u27s paternalistic drug approval process does little to achieve its goal. At the onset of the AIDS epidemic in the 1980s, criticism of the FDA intensified, as the FDA\u27s lengthy and expensive drug approval process hindered terminally ill AIDS patients\u27 access to potentially lifesaving treatment. Advocates for these patients clamored for increased and expedited access to experimental drugs. In response, the FDA liberalized its experimental drug policies. This response was not enough, however, to save Abigail Burroughs. Abigail, a twenty-one year-old honors student at the University of Virginia, died in 2001 after exhausting all FDA-approved treatments for her cancer. Prior to her death, Abigail unsuccessfully attempted to gain access through clinical trials to the experimental cancer drugs Iressa and Erbitux (since approved by the FDA). In Abigail Alliance v. Von Eschenbach, a lawsuit filed by the foundation named in Abigail\u27s honor, a three-judge panel of the Court of Appeals for the District of Columbia Circuit ruled in May 2006 that terminally ill patients have a due process right of access to such experimental drugs. However, the D.C. Circuit reheard the case en banc and reversed the decision 8-2 in August 2007. The Supreme Court denied the Abigail Alliance for Better Access to Developmental Drugs\u27s ( Abigail Alliance\u27s or Alliance\u27s ) petition for a writ of certiorari in January. Even if the Court had taken the case, however, it likely would have followed precedent and deferred to Congress and the FDA on the question of drug regulation.10 Despite the Court\u27s denial of Abigail Alliance\u27s petition-and despite the likely disposition had the Court granted cert-it is time to reform the FDA framework so that it no longer impedes the access of terminally ill patients to experimental drugs. This Note concludes that the greatest prospect for successful reform lies in the legislative process. Reform of the FDA framework through the courts or through the administrative process is likely to prove unavailing. To show why, this Note first reviews the history of FDA regulation, both generally and as applied to terminally ill patients. The Note then demonstrates that the courts cannot bring about successful reform. Proponents of greater access to experimental drugs have no statutory argument and only weak constitutional arguments. Thus, courts should exercise restraint and defer to the judgment of Congress and the FDA on the question of drug regulation-a question of science and medicine. Once the need for some government regulation of scientific and medical questions is acknowledged, Congress and executive agencies-the political branches, rather than the judicial branch-are best equipped to fine tune regulatory policy

High-density information storage in an absolutely defined aperiodic sequence of monodisperse copolyester

Synthesis of a polymer composed of a large discrete number of chemically distinct monomers in an absolutely defined aperiodic sequence remains a challenge in polymer chemistry. The synthesis has largely been limited to oligomers having a limited number of repeating units due to the difficulties associated with the step-by-step addition of individual monomers to achieve high molecular weights. Here we report the copolymers of ??-hydroxy acids, poly(phenyllactic-co-lactic acid) (PcL) built via the cross-convergent method from four dyads of monomers as constituent units. Our proposed method allows scalable synthesis of sequence-defined PcL in a minimal number of coupling steps from reagents in stoichiometric amounts. Digital information can be stored in an aperiodic sequence of PcL, which can be fully retrieved as binary code by mass spectrometry sequencing. The information storage density (bit/Da) of PcL is 50% higher than DNA, and the storage capacity of PcL can also be increased by adjusting the molecular weight (~38???kDa)

Methods for the integration of combined PET/MR into radiotherapy planning

Despite recent advances in radiotherapy (RT) there are still tumor types for which a high fraction of recurrences is observed following treatment. Limiting factors in current treatment concepts seem to be inaccuracies in image-based tumor delineation and missing consideration of the biological heterogeneity of individual tumors. In this respect, the abundant anatomical and functional information provided by magnetic resonance imaging (MRI) and positron emission tomography (PET) may lead to major advances in RT treatment. Recently available combined PET/MR scanners allow for the acquisition of simultaneous, intrinsically registered PET/MR data, facilitating their combined analysis for the integration into RT. In this thesis, dedicated methods and algorithms for the analysis and integration of the multimodal PET/MR datasets into RT are developed. In the first part, a method for multimodal deformable registration is developed, to enable the spatial transformation of PET/MR data to the computed tomography used for treatment planning. The second part is concerned with the development of an automatic tumor segmentation algorithm, considering PET and MR information simultaneously. In the last part, a correlation analysis of various functional datasets is motivated and performed in order to support the definition of a biologically adapted dose prescription.Trotz jüngster Fortschritte in der Strahlentherapie (ST) gibt es noch immer Tumorarten mit einem hohen Prozentsatz an Rezidiven nach der Behandlung. Limitierende Faktoren in aktuellen Behandlungskonzepten scheinen vor allem Ungenauigkeiten in der bildbasierten Tumorabgrenzung sowie die fehlende Berücksichtigung der biologischen Heterogenität der einzelnen Tumoren zu sein. In dieser Hinsicht erscheint die Einbeziehung der vielfältigen anatomischen und funktionellen Bildgebungsmöglichkeiten der Magnetresonanztomographie (MRT), sowie der Positronenemissionstomographie (PET), in die ST vielversprechend. Seit kurzem verfügbare PET/MR-Scanner erlauben die Akquisition simultaner, intrinsisch registrierter PET/MR-Datensätze, wodurch deren kombinierte Analyse und Integration in die Therapieplanung erleichtert wird. Diese Arbeit befasst sich mit der Entwicklung von dedizierten Methoden und Algorithmen für die Analyse und Integration der multimodalen PET/MR-Datensätze in die ST. Im ersten Teilprojekt wurde eine Methode zur multimodalen deformierbaren Registrierung entwickelt, um die räumliche Transformation der PET/MR-Daten auf die zur Therapieplanung notwendige Computertomographie-Aufnahme zu ermöglichen. Im zweiten Teil wurde ein Algorithmus zur automatischen Tumorsegmentierung unter simultaner Berücksichtigung von PET- und MR-Information entwickelt. Abschließend wurde im dritten Teil eine Korrelationsanalyse der funktionellen PET- und MR-Datensätze motiviert und ausgeführt, um die Definition einer biologisch adaptierten Dosisverschreibung zu unterstützen

Stereoselective Polymerization of 3,6-Disubstituted N‑Vinylcarbazoles

Poly(N-vinylcarbazole) (PNVC-H) is a valuable nonconjugated photoconductive polymer, but the free radical polymerization conditions typically used for its synthesis do not control polymer stereochemistry and are not tolerant to many substituted N-vinylcarbazoles. Here, we report the stereoselective cationic polymerization of a series of 3,6-disubtituted N-vinylcarbazole derivatives using a chiral scandium-bis(oxazoline) Lewis acid catalyst. The combination of asymmetric ion-pairing catalysis and inherent monomer stereoelectronics facilitated stereoselective polymerization at room temperature, which enabled the polymerization of less soluble 3,6-disubstituted-N-vinylcarbazole derivatives. Isotactic halogen-substituted PNVCs demonstrated self-assembly in solution through halogen-halogen bonding, which was not observed in their atactic counterparts. Initial spectral characterization displayed a wide range of excitation-emission profiles for substituted PNVCs, which demonstrate the promise of these materials as a new class of nonconjugated photoconductive polymers for optoelectronic applications. Overall, these results showcase a diverse class of isotactic poly(N-vinylcarbazoles), highlight the benefits of identifying alternative stereocontrol mechanisms for polymerization, and expand the suite of accessible nonconjugated hole-transport materials

Polymer sequencing by molecular machines: A framework for predicting the resolving power of a sliding contact force spectroscopy sequencing method

We evaluate an AFM-based single molecule force spectroscopy method for mapping sequences in otherwise difficult to sequence heteropolymers, including glycosylated proteins and glycans. The sliding contact force spectroscopy (SCFS) method exploits a sliding contact made between a nanopore threaded over a polymer axle and an AFM probe. We find that for sliding α- and β- cyclodextrin nanopores over a wide range of hydrophilic monomers, the free energy of sliding is proportional to the sum of two dimensionless, easily calculable parameters representing the relative partitioning of the monomer inside the nanopore or in the aqueous phase, and the friction arising from sliding the nanopore over the monomer. Using this relationship we calculate sliding energies for nucleic acids, amino acids, glycan and synthetic monomers and predict on the basis of these calculations that SCFS will detect N- and O-glycosylation of proteins and patterns of sidechains in glycans. For these applications, SCFS offers an alternative to sequence mapping by mass spectrometry or newly-emerging nanopore technologies that may be easily implemented using a standard AFM

Machine-Learning-Guided Discovery of 19F MRI Agents Enabled by Automated Copolymer Synthesis

Modern polymer science suffers from the curse of multidimensionality. The large chemical space imposed by including combinations of monomers into a statistical copolymer overwhelms polymer synthesis and characterization technology and limits the ability to systematically study structure-property relationships. To tackle this challenge in the context of 19F magnetic resonance imaging (MRI) agents, we pursued a computer-guided materials discovery approach that combines synergistic innovations in automated flow synthesis and machine learning (ML) method development. A software-controlled, continuous polymer synthesis platform was developed to enable iterative experimental-computational cycles that resulted in the synthesis of 397 unique copolymer compositions within a six-variable compositional space. The nonintuitive design criteria identified by ML, which were accomplished by exploring <0.9% of the overall compositional space, lead to the identification of >10 copolymer compositions that outperformed state-of-the-art materials

Mechanical recycling of polylactide, upgrading trends and combination of valorization techniques

The upcoming introduction of polylactides in the fractions of polymer waste encourages technologists to ascertain its valorization at the best quality conditions. Mechanical recycling of PLA represents one of the most cost-effective methodologies, but the recycled materials are usually directed to downgraded applications, due to the inherent thermomechanical degradation affecting its mechanical, thermal and rheological performance. In this review, the current state of mechanical recycling of PLA is reported, with special emphasis on a multi-scale comparison among different studies. Additionally, the applications of physical and chemical upgrading strategies, as well as the chances to blend and/ or composite recycled PLA are considered. Moreover, the different valorization techniques that can be combined to optimize the value of PLA goods along its life cycle are discussed. Finally, a list of different opportunities to nurture the background of the mechanical recycling of PLA is proposed, in order to contribute to the correct waste management of PLA wastes