Genomic landscape of lung cancer in the young.

Background: Lung cancer in the young is a rare entity of great interest due to the high frequency of targetable mutations. In this study, we explored the genomic landscape of non-small cell lung cancer (NSCLC) in young patients and compared it with genetic alterations in older patients. Methods: Comparative study of the genomic profile of NSCLC young (≤40 years old) vs older patients (>40 years old) from Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima, Peru. Archival paraffin-embedded tumor samples were profiled with FoundationOne CDx assay to identify short variants alterations (insertions and deletions), copy number variations (CNV), tumor mutational burden and microsatellite instability in 324 driver genes and rearrangements in 28 commonly rearranged genes. A targetable alteration was defined as any alteration in a driver oncogene for which an FDA approved therapy existed at the time of study enrollment. Results: Overall, 62 tumors were profiled, 32 from young and 30 from older patients. All clinicopathological features (smoking status, clinical stage, and histology) were similar between groups, except for gender (65.6% of females in the younger group vs 40% in the older group, P=0.043). At least one actionable mutation was present in 84.4% and 83.3% in younger and older patients, respectively. Alteration rates in the main genes were: BRAF, 3.1%(n=1) vs 0%; EGFR, 46.9% (n=15) vs 43.3% (n=13); ERBB2, 12.5% (n=4) vs 16.7% (n=5); KRAS, 15.6% (n=5) vs 16.7% (n=5); ALK, 6.3% (n=2) vs 3.3% (n=1); RET, 0.0% vs 3.3% (n=1); ROS1, 3.1% (n=1) vs 3.3% (n=1); NTRK1, 0.0% vs 3.3% (n=1) and MET, 3.1% (n=1) vs 13.3% (n=4). Mean TMB was 4.04 Mut/Mb (SD ± 3.98) for young vs 8.06 Mut/Mb (SD ± 9.84) for older patients (P=0.016). There were not significant differences in CNV, frequency of gene rearrangements, or microsatellites instability. Conclusion: NSCLC in the young in our cohort was characterized by a high frequency of actionable genetic aberrations and a low TMB, which was also true for our older patients. The enrichment of actionable mutations in young patients described in other reports might be attributed to differences in the etiology and clinicopathological characteristics between younger and older patients and therefore not be applicable to all populations.

Ivermectin susceptibility, sporontocidal effect, and inhibition of time to re-feed in the Amazonian malaria vector Anopheles darlingi.

BACKGROUND: Outdoor malaria transmission hinders malaria elimination efforts in the Amazon region and novel vector control tools are needed. Ivermectin mass drug administration (MDA) to humans kills wild Anopheles, targets outdoor-feeding vectors, and can suppress malaria parasite transmission. Laboratory investigations were performed to determine ivermectin susceptibility, sporontocidal effect and inhibition of time to re-feed for the primary Amazonian malaria vector, Anopheles darlingi. METHODS: To assess ivermectin susceptibility, various concentrations of ivermectin were mixed in human blood and fed to An. darlingi. Mosquito survival was monitored daily for 7 days and a non-linear mixed effects model with Probit analysis was used to calculate lethal concentrations of ivermectin that killed 50% (LC50), 25% (LC25) and 5% (LC5) of mosquitoes. To examine ivermectin sporonticidal effect, Plasmodium vivax blood samples were collected from malaria patients and offered to mosquitoes without or with ivermectin at the LC50, LC25 or LC5. To assess ivermectin inhibition of mosquito time to re-feed, concentrations of ivermectin predicted to occur after a single oral dose of 200 µg/kg ivermectin were fed to An. darlingi. Every day for 12 days thereafter, individual mosquitoes were given the opportunity to re-feed on a volunteer. Any mosquitoes that re-blood fed or died were removed from the study. RESULTS: Ivermectin significantly reduced An. darlingi survivorship: 7-day-LC50 = 43.2 ng/ml [37.5, 48.6], -LC25 = 27.8 ng/ml [20.4, 32.9] and -LC5 = 14.8 ng/ml [7.9, 20.2]. Ivermectin compound was sporontocidal to P. vivax in An. darlingi at the LC50 and LC25 concentrations reducing prevalence by 22.6 and 17.1%, respectively, but not at the LC5. Oocyst intensity was not altered at any concentration. Ivermectin significantly delayed time to re-feed at the 4-h (48.7 ng/ml) and 12-h (26.9 ng/ml) concentrations but not 36-h (10.6 ng/ml) or 60-h (6.3 ng/ml). CONCLUSIONS: Ivermectin is lethal to An. darlingi, modestly inhibits sporogony of P. vivax, and delays time to re-feed at concentrations found in humans up to 12 h post drug ingestion. The LC50 value suggests that a higher than standard dose (400-µg/kg) is necessary to target An. darlingi. These results suggest that ivermectin MDA has potential in the Amazon region to aid malaria elimination efforts.

Plagiarism, Cheating and Research Integrity: Case Studies from a Masters Program in Peru.

Plagiarism is a serious, yet widespread type of research misconduct, and is often neglected in developing countries. Despite its far-reaching implications, plagiarism is poorly acknowledged and discussed in the academic setting, and insufficient evidence exists in Latin America and developing countries to inform the development of preventive strategies. In this context, we present a longitudinal case study of seven instances of plagiarism and cheating arising in four consecutive classes (2011-2014) of an Epidemiology Masters program in Lima, Peru, and describes the implementation and outcomes of a multifaceted, "zero-tolerance" policy aimed at introducing research integrity. Two cases involved cheating in graded assignments, and five cases correspond to plagiarism in the thesis protocol. Cases revealed poor awareness of high tolerance to plagiarism, poor academic performance, and widespread writing deficiencies, compensated with patchwriting and copy-pasting. Depending on the events' severity, penalties included course failure (6/7) and separation from the program (3/7). Students at fault did not engage in further plagiarism. Between 2011 and 2013, the Masters program sequentially introduced a preventive policy consisting of: (i) intensified research integrity and scientific writing education, (ii) a stepwise, cumulative writing process; (iii) honor codes; (iv) active search for plagiarism in all academic products; and (v) a "zero-tolerance" policy in response to documented cases. No cases were detected in 2014. In conclusion, plagiarism seems to be widespread in resource-limited settings and a greater response with educational and zero-tolerance components is needed to prevent it.

Dermatomyositis: a clinicopathological study of 40 patients.

The histopathology of cutaneous lesions of dermatomyositis (DM) may be indistinguishable from acute cutaneous lesions of systemic lupus erythematosus (SLE). Misreported or incomplete clinical information may result in a clinicopathologic discrepancy and a delay in making a correct diagnosis of DM. The aim of this study was to systematically characterize the histopathologic findings of cutaneous lesions of DM and to determine if skin biopsy specimens of DM and SLE could be distinguished by light microscopic examination. Biopsies from 40 patients diagnosed with DM at the Wake Forest University School of Medicine from 1994 to 1999 were reviewed. The histological features by light microscopy were graded in a systematic fashion. We then assessed whether the cutaneous pathological changes of DM could be distinguished from those of SLE. Ten biopsy specimens each of DM and SLE (matched for anatomical site and lesion morphology) were randomized. Histological grading was performed in a blinded fashion, as was a histopathologic diagnosis (DM versus SLE). The most consistent histological findings of DM included increased dermal mucin, vacuolar alteration of the basal cell layer, and mild-to-moderate mononuclear cell inflammatory infiltrates. Our results show that the histological grading of SLE skin biopsies was nearly identical to that of DM. The correct histopathologic diagnosis of DM or SLE was made in 11 of the 20 skin biopsies without clinical information. Despite the limitations of our small sample size, these findings suggest that acute cutaneous lesions of SLE cannot be distinguished from DM. Clinicopathologic correlation is important for making a diagnosis of DM or SLE.

Mobilization of the iron centre in IscA for the iron-sulphur cluster assembly in IscU.

The biogenesis of iron-sulphur clusters requires the co-ordinated delivery of both iron and sulphur. It is now clear that sulphur in iron-sulphur clusters is derived from L-cysteine by cysteine desulphurases. However, the iron donor for the iron-sulphur cluster assembly still remains elusive. Our previous studies indicated that Escherichia coli IscA, a member of the iron-sulphur cluster assembly machinery, is an iron-binding protein that can provide iron for the iron-sulphur cluster assembly in a proposed scaffold IscU. To determine how the iron centre in IscA is transferred for the iron-sulphur cluster assembly in IscU, we explore the mobility of the iron centre in IscA. The UV-visible and EPR measurements show that L-cysteine, but not IscU, is able to mobilize the iron centre in IscA and make the iron available for the iron-sulphur cluster assembly in IscU. Other related biological thiols such as N-acetyl-L-cysteine or reduced glutathione have no effect on the iron centre of IscA, suggesting that L-cysteine is unique in mobilizing the iron centre of IscA. Nevertheless, L-cysteine alone is not sufficient to transfer the iron from IscA to IscU. Both L-cysteine and cysteine desulphurase (IscS) are required for the IscA-mediated assembly of iron-sulphur clusters in IscU. The results suggest that L-cysteine may have two distinct functions in the biogenesis of iron-sulphur clusters: to mobilize the iron centre in IscA and to provide sulphur via cysteine desulphurase (IscS) for the iron-sulphur cluster assembly in IscU.

Characteristics of office-based physician visits for cutaneous fungal infections. an analysis of 1990 to 1994 National Ambulatory Medical Care Survey Data.

To our knowledge, visits in the ambulatory setting due to cutaneous fungal infections have not been recently characterized. To provide descriptive epidemiology on ambulatory cutaneous fungal infection visits, we analyzed office-based physician visits for cutaneous fungal infections recorded in the National Ambulatory Medical Care Survey (NAMCS) from 1990 to 1994. The International Classification of Diseases (ICD-9) was used to define the cutaneous fungal infections. Sampling weights were applied to achieve the nationally representative estimates. From 1990 to 1994, an estimated 21.6 million physician office visits at an estimated cost of $216 million/y (office visit plus medication costs) were made for cutaneous fungal infection diagnoses. The total cost of office visits (without medication costs) was approximately $116 million/y. The total cost of the top 5 medications was approximately $68 million/y. According to an analysis of visits per physician specialist, dermatologists had the largest proportion of visits for cutaneous fungal infections. The cost associated with the diagnosis and management of cutaneous fungal infections is significant. Of all the physician specialists, dermatologists treated the most cutaneous fungal infections.