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LY3295668 chemical characterization

shRNA suppressor screening data for H446 and MDA-MB-468 cells (tabs 1, 2) and RNA expression level associations with LY3295668 Abs IC50 values from 493 cancer cell lines (tab 3).

Supplementary figures

Abs IC50 values (µM) for 36 small molecule inhibitors across a panel of cancer cell lines.

Abs IC50 values (µM) for LY3295668 across a panel of 580 cell lines.

We analyzed the genetic variation among isolates of Pneumocystis jiroveci from Portuguese immunocompromised patients with PCP at the internal transcribed spacer (ITS) regions of the nuclear rRNA operon and at the dihydropteroate synthase (DHPS) gene. Pulmonary secretions from 42 patients with PCP corresponding to 43 episodes were studied. Demographic, immunological, and clinical data were obtained from all patients. By combining the two regions ITS1 and ITS2, we found 17 different ITS types of P. jiroveci, two of them were new types (Pb and Pe). The four most prevalent ITS types were Eg (23.3%), Eb and Ne (11.6% each), and Bi (9.3%). A single type was detected in 95.3% of the samples and 4.7% had mixed infections with three different ITS types. DHPS mutants were present in 17 (46%), and the wildtype was present in 20 (54%) of 37 isolates. No association was found between ITS and DHPS types and between DHPS types and therapy or response to anti-PCP treatment. Type Ne presented an association with negative response to anti-PCP treatment (P

The means by which humans acquire Pneumocystis carinii is not well understood. Whether it can be acquired from specific environmental sources or transmitted from person to person has not been determined. This study was designed to detect nucleic acids of P. carinii in air samples from various locations, including P. carinii-infected patients' homes and hospital rooms, non-P. carinii-infected patients' hospital rooms, empty hospital rooms, offices at Indiana University, and other homes in different locations. DNA was extracted from cellulose-ester filters through which air samples had been filtered, and the P. carinii DNA was amplified by PCR with primers specific for the internal transcribed spacer regions of rRNA. P. carinii DNA was found in 17 of 30 air samples (57%) from the rooms of P. carinii-infected patients. It was also found in 6 of the 21 other hospital rooms sampled (29%) but was not found in any of the offices, storage areas, or control homes. Environmental sampling suggests that the airborne presence of P. carinii genetic material and infectious organisms is plausible. The organism was also detected in locations where P. carinii patients were not immediately proximate, such as the hospital rooms of non-P. carinii-infected patients.

Analysis of sequence variations among isolates of Pneumocystis carinii f. sp. macacae from 14 Indian rhesus monkeys ( Macaca mulatta ) at the internal transcribed spacer (ITS) regions of the nuclear rRNA gene was undertaken. Like those from P. carinii f. sp. hominis , the ITS sequences from various P. carinii f. sp. macacae isolates were not identical. Two major types of sequences were found. One type of sequence was shared by 13 isolates. These 13 sequences were homologous but not identical. Variations were found at 13 of the 180 positions in the ITS1 region and 28 of the 221 positions in the ITS2 region. These sequence variations were not random but exhibited definite patterns when the sequences were aligned. According to this sequence variation, ITS1 sequences were classified into three types and ITS2 sequences were classified into five types. The remaining specimen had ITS1 and ITS2 sequences substantially different from the others. Although some specimens had the same ITS1 or ITS2 sequence, all 14 samples exhibited a unique whole ITS sequence (ITS1 plus ITS2). The 5.8S rRNA gene sequences were also analyzed, and only two types of sequences that differ by only one base were found. Unlike P. carinii f. sp. hominis infections in humans, none of the monkey lung specimens examined in this study were found to be infected by more than one type of P. carinii f. sp. macacae . These results offer insights into the genetic differences between P. carinii organisms which infect distinct species.

Pneumocystis carinii f. sp. hominis isolates from 207 clinical specimens from nine countries were typed based on nucleotide sequence variations in the internal transcribed spacer regions I and II (ITS1 and ITS2, respectively) of rRNA genes. The number of ITS1 nucleotides has been revised from the previously reported 157 bp to 161 bp. Likewise, the number of ITS2 nucleotides has been changed from 177 to 192 bp. The number of ITS1 sequence types has increased from 2 to 15, and that of ITS2 has increased from 3 to 14. The 15 ITS1 sequence types are designated types A through O, and the 14 ITS2 types are named types a through n. A total of 59 types of P. carinii f. sp. hominis were found in this study.

Recent developments in understanding the molecular mechanisms of cancer, coupled with large genomic datasets that detail the heterogeneity of the disease, have together led to a wealth of new cancer targets and therapeutic options. However, the restricted efficacy of these new agents and the emergence of resistance suggest that broader and more durable responses may be achieved through combination of these new drugs. To identify drug-drug combinations that may be effective in particular tumor types, we have developed an unbiased "synthetic lethal" screening approach to survey combination space across a diverse panel of tumor cell lines. We used this approach to test a panel of targeted drugs in all-versus-all fashion across 63 cell lines. Synergistic interactions were observed with the combination of an Aurora-A inhibitor, MK-5108, with navitoclax, an inhibitor of Bcl-2 family survival proteins. This combination, which was synergistic in a subset of the tumor cells, was further examined to identify the molecular determinants of synergy. Several features emerged from this analysis including the observation that Bcl-xL expression levels predict resistance to the single agent Aurora-A inhibitor and to synergy of combined MK-5108 and navitoclax. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A104. Citation Format: Xueqian Gong, Shaoling Jin, Farhana Merzoug, Xiang S. Ye, MaryJo Lallena, Jian Du, Yue Webster, Xiwen Ma, Christoph Reinhard, Phillip Iversen, Sean G. Buchanan. A screening method for the identification of potentially effective drug-drug combinations reveals a synergistic interaction between Aurora-A inhibitor MK-5108 and Bcl-xL inhibitor navitoclax. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A104.