Due to the development of multidrug resistance in Streptococcus pneumoniae, research has begun to define new drug targets for pneumonia therapy. Different research groups have identified a lipoprotein, PsaA that is important for pneumonia virulence. PsaA is a manganese transporter that is required for bacterial virulence and growth. We have employed computer modeling to virtually screen a small-molecule database for inhibition of PsaA function by targeting the metal binding pocket, performing receptor-based virtual screening and molecular docking and scoring to identify potential inhibitors of PsaA function. We have developed an assay for screening compounds, including the use of a PsaA mutant, testing of multiple compounds, and identification of compounds that inhibit Streptococcus pneumoniae growth at concentrations less than 20 μM. We experimentally tested the effect on Mn uptake and their PsaA dependence for 42 compounds, but these experiments suggested that these compounds were affecting bacterial growth by a different mechanism.

The complex pathobiologic mechanisms of emphysema are not fully understood, leaving this deadly disease without effective pharmacotherapy for a cure. This project hypothesized that the sulfated dehydropolymer of caffeic acid (CDSO3) exhibits Fe2+ chelation-based hypoxia inducible factor-1a (HIF-1a) up-regulatory protective activities against in vitro emphysematous cell death and for in vivo reversal of emphysema induced with SU5416, a vascular endothelial growth factor blocker. Using in vitro chromogenic competitive inhibition assays, CDSO3 was shown to chelate Fe2+ (IC50 of 23 µM), but not Fe3+ ions. The trypan blue exclusion and lactate dehydrogenase assays were then employed to examine the cytoprotective activities of CDSO3 against inflammatory, oxidative, elastolytic, and apoptotic cell death using alveolar macrophages, epithelial and endothelial cells. CDSO3 at 10 µM produced significant protective activities against these emphysematous cell deaths by 50-154 %. These protective effects were opposed by the addition of the HIF-1a inhibitors, CAY10585 and echinomycin, and excess Fe2+, but not Fe3+, ions. Emphysema was then induced in rats following a subcutaneous injection of SU5416 at 20 mg/kg, after which CDSO3 at 60 µg/kg was administered to the lungs 3 times/week for two weeks. Treadmill exercise endurance (EE) was measured to assess the functional impairment, while lung tissues were removed for morphological assessments of alveolar airspace enlargement (MLI) and destruction (DI), as well as to measure protein levels using Western blot. SU5416 significantly impaired EE, MLI, and DI by 81 %, 47 %, and 5-fold, compared to the healthy animals, and these were significantly reversed by CDSO3 by 66, 74, and 87 %. CDSO3 treatment did not change the lung cytoplasmic expression of histone deacetylase 2 (HDAC2), HIF-1a, or a pro-apoptotic marker, BAX. However, induction with SU5416 significantly reduced VEGF expression by 52 % and increased cleaved caspase-3 expression by 1.5-fold, compared to the healthy animals, while CDSO3 normalized the expressions of both proteins in these emphysematous animals. However, when CDSO3 was pre-mixed with excess Fe2+, the reversal activities of CDSO3 were diminished. In conclusion, this study has demonstrated the Fe2+ chelation-based HIF-1a up-regulatory dependent in vitro and in vivo lung repairing efficacies for CDSO3 in emphysema.

Overexposure to UV (ultraviolet) radiation has been linked to a number of deleterious effects on human health, particularly epidermal malignancies, which consist of both melanoma and non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma. In the 1950’s, an epidermal compound known as Urocanic Acid (UCA) was discovered whose trans isoform was shown to display photoprotective effects against UV radiation. Not long after, the cis-UCA isomer was found to act as a mediator of immune suppression, causing UCA to be removed from all cosmetic products on the commercial market, most notably sunscreen. Numerous studies conducted after this finding further corroborated cis-UCA’s immunosuppressive properties, showing evidence for the ability of cis-UCA to inhibit contact hypersensitivity responses, delayed-type hypersensitivity responses, and allograft rejection. Early evidence for a mechanism of action behind cis-UCA’s immunosuppressive properties were widespread, including modulation of antigen-presenting cells, interaction with histamine receptors, and regulation of cytokine expression. The immunosuppressive nature of cis-UCA quickly became associated with an ability to facilitate cancerous progression, particularly regarding epidermal malignancies. Interesting theories were raised about the evolutionary basis for cis-UCA’s immunosuppressive nature, including speculation that cis-UCA was meant to induce immunosuppression following ultraviolet exposure in order to prevent autoimmune responses against sunburned epidermal cells. After the turn of the 20th century, new research continued to facilitate modern day understanding of the role of UCA. Evidence showed that UCA was ultimately derived from filaggrin within the stratum corneum, interacted with key immune effectors including T-lymphocytes and Langerhans cells, and potentially contributed to acidification of the stratum corneum. Despite the negative reputation cis-UCA has received in regards to facilitating skin cancer evasion of the immune system, research has shown that its immunosuppressive effects may allow it to serve as potent anti-inflammatory therapeutic. In regards to skin cancer, targeting of UCA as a therapeutic varies widely. Some have suggested using UCA as a measure of sunscreen efficacy, as an indirect target that when inhibited can reduce tumor growth, and as a biomarker for skin cancer risk. Others have begun developing UCA-based mimics that retain the benefits of UCA, while avoiding any deleterious effects. The role of UCA in non-melanoma and melanoma malignancies is not well understood, making targeting of UCA as a therapeutic challenging. The aim of this paper is to comprehensively review the scientific literature regarding the pre-21st century history of UCA, followed by an in-depth analysis of post-21st century research. The objective is to determine the overall potential of UCA to serve as a therapeutic target for UV-associated health conditions, most notably dermatologic malignancies.

Bakgrund: Lungcancer är den femte vanligaste cancerformen i Sverige, i vilken cirka 3650 personer dör varje år. Den ökar bland kvinnor och minskar bland män och den uppkommer vanligast i 70-årsåldern. Lungcancer orsaker mer än en miljon dödsfall varje år över hela världen där rökning utgör den största riskfaktorn. Lungcancer delas följaktligen in i två huvudgrupper baserad på cellform: småcellig och icke-småcellig lungcancer. Icke-småcellig lungcancer förkortas till NSCLC (non-small cell lung cancer) och utgör cirka 80% av all lungcancerfall. Syfte: Med detta arbete vill jag undersökaSkillnaden i progressionfri överlevnad för patinter som behandlades med reversibla jämfört med icke-reversibla EGFR-kinasinhibitorer under cancerbehandling. Metod: Arbetet har baserats på fem vetenskapliga artiklar som hämtades från databasen PubMed. I artiklarna undersöktes effektivitet och säkerhet hos reversibla och icke reversibla EGFR-tyrosinkinashämmare som har administrerats patienter drabbade av lungcancer med EGFR-mutationer. Resultat: Följaktligen visade det sig att icke- reversibel EGFR-tyrosinkinashämmaren osimertinib har en signifikant förbättring i progressionsfri överlevnad jämfört med reversibla EGFR-tyrosinkinashämmare gefitinib och erlotinib. Den progressionsfria medianöverlevnaden var längre vid användning av osimertinib än de reversibla hämmareerlotinib och gefitinib. Detta resulterade icirka 18 månader överlevnadvid användning av osimertinib och 10 månader vid användning av erlotinib och gefitinib. Slutsats:Jag visarhär att icke-reversibel EGFR-tyrosinkinashämmare osimertinibkan användas för patienter med icke-småcellig lungcancer NSCLC. Den har visat en signifikant förbättrad effekt som förstahandsbehandling jämfört med reversibla första generationens EGFR-hämmare gefitinib och erlotinib. Osimertinib är aktiv mot vanliga EGFR- mutationer, framför allt del-19 och L858R, och mot resistensmutationen T790M i exon 20 som bildas vid behandling med första generationens reversibla EGFR-kinasinhibitorer. / Background: Lung cancer is the fifth most common cancer type in Sweden, of which about 3650 people die every year. Its incidence increases among women and decreases among men and it is most common at the age of 70. Approximately there are more than one million deaths each year worldwide caused by lung cancer. Smoking is the most common risk factor. Lung cancer is divided into two main groups: small cell and non-small cell lung cancer. Non-small cell lung cancer is shortened to NSCLC accounts for about 80% of all lung cancers.  Purpose: The goal of this paper is to determine the difference in drug resistance for reversible compared to non-reversible EGFR kinase inhibitors during lung cancer treatment. Based on five scientific articles retrieved from the PubMed database, I investigated the efficacy and safety of reversible and non-reversible EGFR tyrosine kinase inhibitors in patients who have lung cancer with EGFR mutations.  Result: The results showed that the non-reversible EGFR tyrosine kinase inhibitor osimertinib doens't give a significant improvement in progression-free survival compared to reversible the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. For osimertinib the median progression-free survival was longer when compared to the reversible inhibitors erlotinib and gefitinib: approximately 18 months in comparison to 10 months, respectively. Conclusion: The non-reversible EGFR tyrosine kinase inhibitors osimertinib may be preferably used in patients with non-small cell lung cancer NSCLC. It has shown an improved significant efficacy in the first-hand compared to reversible first-generation EGFR tyrosine kinase inhibitors (gefitinib, erlotinib). It is active against common EGFR mutations, especially del 19 and L858R, and against resistance mutation T790M in exon 20 generated during first generation treatment reversible EGFR kinase inhibitors erlotinib and gefitinib.

BACKGROUND: Adjudication is a standardized, objective, and often blinded mechanism designed to assess clinical events with increased accuracy. It is performed by a centralized committee of independent reviewers, who are specialized, expert physicians who have no involvement with either the treatment of study subjects or the trial sponsor. Adjudication can decrease variability and bias in study results and increase the likelihood of correct identification, assessment, and categorization of clinical events such as potential malignancies diagnosed through histopathology. Histopathology is highly variable due to the subjective nature of the assessments. THESIS: If it is the case that there are clinically significant discrepancies between local and central diagnoses and that central adjudication yields more accurate diagnoses than a local pathologist, then it should be accepted that adjudication ought to be more widely used in clinical trials to assess histopathology-related safety outcomes and endpoints. METHODS AND STATISTICS: This is a retrospective cross-sectional study assessing interrater variability between local and central diagnoses of biopsy samples in a clinical trial setting using kappa scores and percent agreement. Certified Professional Coders (CPC) and central pathologists used the International Classification of Diseases for Oncology revision 3 (ICD-O 3) to codify the local and central assessments to permit comparison. Three statistical groups (group A: the full dataset, group B: pathology sub-specialty reading groups, and group C: non-melanoma skin cancers versus all other malignancies) were assessed for interrater variability in seven separate analyses: neoplasm versus non-neoplasm (analysis 1), benign versus malignant including non-neoplasms (analysis 2.1), benign versus malignant excluding non-neoplasms (analysis 2.2), discrepancies in morphology and/or behavior including non-neoplasms (analysis 3.1), discrepancies in morphology and/or behavior excluding non-neoplasms (analysis 3.2), all discrepancies leading to differences in treatment (analysis 4.1), and all discrepancies leading to difference in treatment with round 1 matches removed (analysis 4.2). RESULTS: 602 cases comprised the dataset. Based on kappa scores, there is near perfect agreement between the central and local lab diagnoses in analyses 1, 2.1, and 2.2 in group A (all cases in the dataset). The percent agreement for these analyses is above 90%. The group A (full dataset) kappa score and percent agreement decreased to 0.59 and 68.3%, respectively, in analysis 3.1 (discrepancies in morphology and/or behavior codes, including non-neoplasms). When non-neoplasms were removed (analysis 3.2), the kappa score and percent agreement were 0.52 and 57.0%, respectively. In group C, NMSC had substantial kappa agreement in analyses 1, 2.1, and 2.2, whereas all other malignancies had near perfect kappa agreement. All percent agreements were above 88% and surpassed the minimally acceptable threshold for interrater percent agreement in healthcare (80%). Group B divided the data set into 10 sub-specialty reading groups. Kappa scores ranged from 0.66 (GYN) to 1.00 (lung) in analysis 1; the analysis 1 kappa score for lymphoma was 0.55, but this was not statistically significant. In analysis 2.1, lung and sarcoma had the highest kappa scores (1.00) and dermatology and GYN had the lowest (0.71). As in analysis 1, the kappa score for lymphoma was 0.55 but was not statistically significant. When non-neoplasms were removed from analysis 2.2, 6 of the 10 sub-groups had kappa scores of 1.00, but all 6 had sample sizes less than 10. Percent agreement ranged from 80 to 100 percent. When all cases were considered regardless of number of rounds of review (analysis 4.1), about 90% of diagnoses would have similar courses of treatment. All sub-groups except sarcoma reached the minimally acceptable agreement rate in healthcare (80%). In the remaining 33% of cases that did not have matching diagnoses in round 1 (analysis 4.2), 34% may have different courses of treatment depending on whether the local or central diagnoses was used. Mid-study updates to the charter and CPC/reviewer manuals and processing of specimens did not have a significant impact on results. CONCLUSION: Although there is little discrepancy between local and central pathologists on whether malignancies exist among samples, there is discord regarding specific diagnoses and their associated treatments. Adjudication can assist in decreasing this discordance in order to develop the most specific and accurate safety profile for a compound.

Book Summary: The Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care contains the most authoritative information on nonprescription drug pharmacotherapy, nutritional supplements, medical foods, nondrug and preventive measures, and complementary therapies. The 18th edition shows students and practitioners how to assess and triage a patient's medical complaints. And it provides FDA-approved dosing information for nonprescription medications along with evidence-based research on the efficacy and safety of over-the-counter, herbal, and homeopathic medications.

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Learning Objectives: Describe the rationale for the belief that opioids have no maximum dose Describe the data supporting the rationale that high doses of opioids increase toxicity Describe the data supporting the rationale that high doses of opioids do not improve outcomes Identify potential safety concerns with patients taking high doses of opioids

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