Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer

<p>Abstract</p> <p>Background</p> <p>Erlotinib is a Human Epidermal Growth Factor Receptor Type 1/tyrosine kinase (EGFR) inhibitor which is used for non-small-cell lung cancer treatment. Despite that erlotinib is considered to have a favorable safety profile, adverse events such as interstitial lung disease (ILD) were reported in pivotal studies. The authors report the first histologically confirmed case of fatal ILD associated with erlotinib therapy.</p> <p>Case Presentation</p> <p>The medical record of a patient who developed fatal ILD after receiving erlotinib treatment was reviewed to identify the cause of death and other factors potentially contributive to this adverse outcome. A 55-year-old smoker with no evidence of pre-existing interstitial disease developed bilateral ILD and respiratory failure which could be explained only as a toxicity of erlotinib. He had a history of stage IV left upper lobe squamous-cell carcinoma for which he had received three successive regimens of chemotherapy (ifosfamide plus gemcitabine, docetaxel, mitomycin plus navelbine), followed five months later by erlotinib. At initiation of erlotinib treatment there were no radiological signs suggestive of ILD disease or apparent clinical signs of respiratory distress. While the patient completed two months with erlotinib therapy he developed bilateral interstitial infiltrates; despite discontinuation of erlotinib he was admitted with respiratory failure two weeks later. Diagnostic work up for other causes of pneumonitis including infectious diseases, congestive cardiac failure and pulmonary infraction was negative. Empiric treatment with oxygene, corticosteroids and later with cyclophosphamide was ineffective and the patient progressively deteriorated and died. The clinical and post-mortem examination findings are presented and the possible association relationship between erlotinib induced ILD and previous chemotherapy is discussed.</p> <p>Conclusion</p> <p>Physicians should be alert to the fact that erlotinib related ILD, although infrequent, is potential fatal. The association between selective EGFR-inhibitors and ILD should be further investigated.</p

A C-terminal cysteine residue is required for peptide-based inhibition of the NGF/TrkA interaction at nM concentrations:implications for peptide-based analgesics

Inhibition of the NGF/TrkA interaction presents an interesting alternative to the use of non-steroidal anti-inflammatories and/or opioids for the control of inflammatory, chronic and neuropathic pain. Most prominent of the current approaches to this therapy is the antibody Tanezumab, which is a late-stage development humanized monoclonal antibody that targets NGF. We sought to determine whether peptides might similarly inhibit the NGF/TrkA interaction and so serve as future therapeutic leads. Starting from two peptides that inhibit the NGF/TrkA interaction, we sought to eliminate a cysteine residue close to the C-terminal of both sequences, by an approach of mutagenic analysis and saturation mutagenesis of mutable residues. Elimination of cysteine from a therapeutic lead is desirable to circumvent manufacturing difficulties resulting from oxidation. Our analyses determined that the cysteine residue is not required for NGF binding, but is essential for inhibition of the NGF/TrkA interaction at pharmacologically relevant peptide concentrations. We conclude that a cysteine residue is required within potential peptide-based therapeutic leads and hypothesise that these peptides likely act as dimers, mirroring the dimeric structure of the TrkA receptor

The Salivary Secretome of the Tsetse Fly Glossina pallidipes (Diptera: Glossinidae) Infected by Salivary Gland Hypertrophy Virus

Tsetse fly (Diptera; Glossinidae) transmits two devastating diseases to farmers (human African Trypanosomiasis; HAT) and their livestock (Animal African Trypanosomiasis; AAT) in 37 sub-Saharan African countries. During the rainy seasons, vast areas of fertile, arable land remain uncultivated as farmers flee their homes due to the presence of tsetse. Available drugs against trypanosomiasis are ineffective and difficult to administer. Control of the tsetse vector by Sterile Insect Technique (SIT) has been effective. This method involves repeated release of sterilized males into wild tsetse populations, which compete with wild type males for females. Upon mating, there is no offspring, leading to reduction in tsetse populations and thus relief from trypanosomiasis. The SIT method requires large-scale tsetse rearing to produce sterile males. However, tsetse colony productivity is hampered by infections with the salivary gland hypertrophy virus, which is transmitted via saliva as flies take blood meals during membrane feeding and often leads to colony collapse. Here, we investigated the salivary gland secretome proteins of virus-infected tsetse to broaden our understanding of virus infection, transmission and pathology. By this approach, we obtain insight in tsetse-hytrosavirus interactions and identified potential candidate proteins as targets for developing biotechnological strategies to control viral infections in tsetse colonies

Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Adsorption Behavior of Perfluorinated Compounds on Thin-film Composite Membranes

Drinking and Wastewater Applications II sessionPerfluorinated compounds (PFCs), emerging contaminants, are globally distributed due to their persistent and bioaccumulative characteristics. The static adsorption behavior of PFCs on BW30, NF90, and NF270 membranes and the effect of the physico-chemical properties of the membranes and structure of Perfluorinated compounds (PFCs) on interactions between them have been thoroughly investigated. Two classes of PFCs were evaluated: perfluorosulfonic acid (PFOS) and perfluoroalkanoic acid with 5, 7, 9, and 11 carbon atoms. Adsorption of PFCs increased with increasing ionic strength, and decreasing pH due to decreased electrostatic repulsion between membrane surfaces and PFCs. The extent of PFOS adsorption on each membrane was higher than the extent of comparable perfluorononanoic acid (PFNA) adsorption. This is attributed to the easy migration of PFOS to the membrane surface from aqueous solution compared with PFNA. The adsorption of PFCs on thin-film composite membranes strongly depended on the material composing the active layer of the membranes. NF270 membranes (a piperazine based membrane) showed higher adsorption of PFOS and PFNA compounds compared with BW30 and NF90 membranes (polyamide based membranes). The BW30 polyamide membrane, which has a coating layer with aliphatic carbon and hydroxyl groups, had less interaction with PFOS and PFNA than the NF90 polyamide membrane. Increased chain length of PFCs increased adsorption. This research shows that the adsorption behavior of PFCs on commercial thin-film composite membranes depends on the electrostatic interaction of both membranes and PFCs as a function of the applied solution chemistry, the active layer material of the membranes, and the chain length/functional group of PFC

Gold nanorod-encapsulated biodegradable polymeric matrix for combined photothermal and chemo-cancer therapy

Chun-Chiao Chuang,1,* Chih-Chi Cheng,1,* Pei-Ying Chen,1 Chieh Lo,1 Yi-Ning Chen,1 Min-Hsiung Shih,2,3 Chien-Wen Chang1 1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan, Republic of China; 2Research Center of Applied Sciences (RCAS), Academia Sinica, Taipei, 11529, Taiwan, Republic of China; 3Department of Photonics, National Chiao Tung University (NCTU), Hsinchu, 30010, Taiwan, Republic of China *These authors contributed equally to this work Purpose: A biocompatible nanocomplex system co-encapsulated with gold nanorods (AuNRs) and doxorubicin (DOX) was investigated for its potentials on the combined photothermal- and chemotherapy.Materials and methods: Hydrophobic AuNRs were synthesized by the hexadecyltrimethylammonium bromide (CTAB)-mediated seed growth method, and then, they received two-step surface modifications of polyethylene glycol (PEG) and dodecane. The AuNR/DOX/poly(lactic-co-glycolic acid) (PLGA) nanocomplexes were prepared by emulsifying DOX, AuNR, and PLGA into aqueous polyvinyl alcohol solution by sonication. Human serum albumin (HSA) was used to coat the nanocomplexes to afford HSA/AuNR/DOX&ndash;PLGA (HADP). Size and surface potential of the HADP nanocomplexes were determined by using a Zetasizer. Cytotoxicity and cellular uptake of the HADP were analyzed by using MTT assay and flow cytometry, respectively. In&nbsp;vitro anticancer effects of the HADP were studied on various cancer cell lines. To assess the therapeutic efficacy, CT26 tumor-bearing mice were intravenously administered with HADP nanocomplexes and laser treatments, followed by monitoring of the tumor growth and body weight.Results: Size and surface potential of the HADP nanocomplexes were 245.8 nm and -8.6 mV, respectively. Strong photothermal effects were verified on the AuNR-loaded PLGA nanoparticles (NPs) in&nbsp;vitro. Rapid and repeated drug release from the HADP nanocomplexes was successfully achieved by near-infrared (NIR) irradiations. HSA significantly promoted cellular uptake of the HADP nanocomplexes to murine colon cancer cells as demonstrated by cell imaging and flow cytometric studies. By combining photothermal and chemotherapy, the HADP nanocomplexes exhibited strong synergistic anticancer effects in&nbsp;vitro and in&nbsp;vivo.Conclusion: An NIR-triggered drug release system by encapsulating hydrophobic AuNR and DOX inside the PLGA NPs has been successfully prepared in this study. The HADP NPs show promising combined photothermal- and chemotherapeutic effects without inducing undesired side effects on a murine colon cancer animal model. Keywords: gold nanomaterials, photothermal therapy, triggered drug release, albumin, biodegradable nanoparticles&nbsp