Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase

Tryptophan (Trp) catabolizing enzymes play an important and complex role in the development of cancer. Significant evidence implicates them in a range of inflammatory and immunosuppressive activities. Whereas inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) have been reported and analyzed in the clinic, fewer inhibitors have been described for tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase-2 (IDO2) which also have been implicated more recently in cancer, inflammation and immune control. Consequently the development of dual or pan inhibitors of these Trp catabolizing enzymes may represent a therapeutically important area of research. This is the first report to describe the development of dual and pan inhibitors of IDO1, TDO and IDO2

The Lantern Vol. 68, No. 1, Fall 2000

• In Attempting to Imitate J. Agard (III) • Headstones • Calligraphy Grace • Fifty Years • Morning • The Millstone • Quick Stop-Off • Jesus Wept (SuperBuick Bodybag) • Just a God • Amy • Silver Doubloons • Ogbanje • Left Behind • Asymmetrical Smile • Sundays • Pie in the Sky • No Surprises • Bill Gooden\u27s Son • Downcast Eyes Meet Tablecloth • Wetlands • Desperate Actions • Receiving End • A Pack of Matches • Coffeehttps://digitalcommons.ursinus.edu/lantern/1157/thumbnail.jp

The Lantern Vol. 68, No. 1, Fall 2000

• In Attempting to Imitate J. Agard (III) • Headstones • Calligraphy Grace • Fifty Years • Morning • The Millstone • Quick Stop-Off • Jesus Wept (SuperBuick Bodybag) • Just a God • Amy • Silver Doubloons • Ogbanje • Left Behind • Asymmetrical Smile • Sundays • Pie in the Sky • No Surprises • Bill Gooden\u27s Son • Downcast Eyes Meet Tablecloth • Wetlands • Desperate Actions • Receiving End • A Pack of Matches • Coffeehttps://digitalcommons.ursinus.edu/lantern/1157/thumbnail.jp

The Lantern Vol. 67, No. 2, Spring 2000

• Dearest Yarn-Spinner • My Poem, This Tongue In Your Eye • 15th & Rodman • Vision • Linguistics • Casting Cartesian Shadows • On the Defensive • Sea Sick but Still Docked • Urban Dreams • Wolf of the Steppes • Josephine • Happy Birthday to Me • I Have Never Been to Africa • Pa-pou • Onion[s] • Intimacy • Three Trick Pony • Blazer • In My Tea • Emmaless • Dreamcatcher • Repetition • With the Turn of the Reel • Fault Lines • The Shrink Is In • The dancE • Exam • Another Post-Apocalyptic Christmas • The Circumstances of My Prolonged Depressionhttps://digitalcommons.ursinus.edu/lantern/1156/thumbnail.jp

A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

<p>Abstract</p> <p>Background</p> <p>Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.</p> <p>Methods</p> <p>In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.</p> <p>Results</p> <p>Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.</p> <p>Conclusions</p> <p>Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.</p

Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions with high morbidity and mortality. Supportive care management of SJS/TEN is highly variable. A systematic review of the literature was performed by dermatologists, ophthalmologists, intensivists, and gynecologists with expertise in SJS/TEN to generate statements for supportive care guideline development. Members of the Society of Dermatology Hospitalists with expertise in SJS/TEN were invited to participate in a modified, online Delphi-consensus. Participants were administered 9-point Likert scale questionnaires regarding 135 statements. The RAND/UCLA Appropriateness Method was used to evaluate and select proposed statements for guideline inclusion; statements with median ratings of 6.5 to 9 and a disagreement index of ≤1 were included in the guideline. For the final round, the guidelines were appraised by all of the participants. Included are an evidence-based discussion and recommendations for hospital setting and care team, wound care, ocular care, oral care, urogenital care, pain management, infection surveillance, fluid and electrolyte management, nutrition and stress ulcer prophylaxis, airway management, and anticoagulation in adult patients with SJS/TEN

Immobilized peptides/amino acids on solid supports for metal remediation

Recently, a significant amount of work has focused on metal binding by natural systems for various applications. This review will focus on the utility of amino acids, short peptides, and proteins that have been immobilized onto solid supports for use in metal binding, These systems include single amino acids, poly-amino acids, and peptides immobilized onto supports such as silica, polymer resins, and membranes. Also included are the studies involving the use of immobilized amino acids in ion-exchange chromatographyPeer reviewe