CDKN1C/p57kip2 Is a Candidate Tumor Suppressor Gene in Human Breast Cancer

BACKGROUND. CDKN1C (also known as p57KIP2) is a cyclin-dependent kinase inhibitor previously implicated in several types of human cancer. Its family members (CDKN1A/p21CIP1 and B/p27KIP1) have been implicated in breast cancer, but information about CDKN1C's role is limited. We hypothesized that decreased CDKN1C may be involved in human breast carcinogenesis in vivo. METHODS. We determined rates of allele imbalance or loss of heterozygosity (AI/LOH) in CDKN1C, using an intronic polymorphism, and in the surrounding 11p15.5 region in 82 breast cancers. We examined the CDKN1C mRNA level in 10 cancers using quantitative real-time PCR (qPCR), and the CDKN1C protein level in 20 cancers using immunohistochemistry (IHC). All samples were obtained using laser microdissection. Data were analyzed using standard statistical tests. RESULTS. AI/LOH at 11p15.5 occurred in 28/73 (38%) informative cancers, but CDKN1C itself underwent AI/LOH in only 3/16 (19%) cancers (p = ns). In contrast, CDKN1C mRNA levels were reduced in 9/10 (90%) cancers (p < 0.0001), ranging from 2–60% of paired normal epithelium. Similarly, CDKN1C protein staining was seen in 19/20 (95%) cases' normal epithelium but in only 7/14 (50%) cases' CIS (p < 0.004) and 5/18 (28%) cases' IC (p < 0.00003). The reduction appears primarily due to loss of CDKN1C expression from myoepithelial layer cells, which stained intensely in 17/20 (85%) normal lobules, but in 0/14 (0%) CIS (p < 0.00001). In contrast, luminal cells displayed less intense, focal staining fairly consistently across histologies. Decreased CDKN1C was not clearly associated with tumor grade, histology, ER, PR or HER2 status. CONCLUSION. CDKN1C is expressed in normal epithelium of most breast cancer cases, mainly in the myothepithelial layer. This expression decreases, at both the mRNA and protein level, in the large majority of breast cancers, and does not appear to be mediated by AI/LOH at the gene. Thus, CDKN1C may be a breast cancer tumor suppressor.Department of Defense Breast Cancer Research Program (DAMD 17-99-1-9573); National Institutes of Health PHS (CA081078); LaPann Fun

Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Cote d\u27Ivoire

BackgroundA single co-administered dose of ivermectin (IVM) plus diethylcarbamazine (DEC) plus albendazole (ALB), or triple-drug therapy, was recently found to be more effective for clearing microfilariae (Mf) than standard DEC plus ALB currently used for mass drug administration programs for lymphatic filariasis (LF) outside of sub-Saharan Africa. Triple-drug therapy has not been previously tested in LF-uninfected individuals from Africa. This study evaluated the pharmacokinetics (PK), safety, and efficacy of triple-drug therapy in people with and without Wuchereria bancrofti infection in West Africa.MethodsIn this open-label cohort study, treatment-naïve microfilaremic (>50 mf/mL, n = 32) and uninfected (circulating filarial antigen negative, n = 24) adults residing in Agboville district, Côte d’Ivoire, were treated with a single dose of IVM plus DEC plus ALB, and evaluated for adverse events (AEs) until 7 days post treatment. Drug levels were assessed by liquid chromatography and mass spectrometry. Persons responsible for assessing AEs were blinded to participants’ infection status.FindingsThere was no difference in AUC0-inf or Cmax between LF-infected and uninfected participants (P>0.05 for all comparisons). All subjects experienced mild AEs; 28% and 25% of infected and uninfected participants experienced grade 2 AEs, respectively. There were no severe or serious adverse events. Only fever (16 of 32 versus 4 of 24, PConclusionsModerate to heavy W. bancrofti infection did not affect PK parameters for IVM, DEC or ALB following a single co-administered dose of these drugs compared to uninfected individuals. The drugs were well tolerated. This study confirmed the efficacy of the triple-drug therapy for clearing W. bancrofti Mf and has added important information to support the use of this regimen in LF elimination programs in areas of Africa without co-endemic onchocerciasis or loiasis.Trial registrationClinicalTrials.gov NCT02845713.</div

Update on the current status of onchocerciasis in Cote d’Ivoire following 40 years of intervention: Progress and challenges

Background Onchocerciasis control in Côte d’Ivoire started with aerial insecticide spraying in 1974 and continued with community directed treatment with ivermectin (CDTi) from 1992 to the present. Onchocerciasis and lymphatic filariasis (LF) are co-endemic in 46 of the 81 health districts in the country. Fourteen and 12 districts are endemic for only LF or onchocerciasis, respectively. This paper aims to review the impact of past interventions on onchocerciasis in Côte d’Ivoire between 1975 and 2013, and review plans for disease elimination. Methods We reviewed microfilaria (MF, skin snip) prevalence and community microfilarial load (CMFL) data from published reports from 53 health districts during two major epidemiological assessment periods. Data from 1975 through 1991 provided information on the impact of vector control, and data from 1992 through 2016 provided information on the impact of CDTi. Results Weekly aerial insecticide spraying in 8 endemic districts between 1975 and 1991 reduced the overall MF prevalence by 68.1% from 43.5% to 13.9%. The CMFL also decreased in 7 out of 8 surveyed communities by 95.2% from 9.24 MF/snip to 0.44 MF/snip. Ivermectin distribution started in 1992. The coverage targets for control (65% of the total population) was reached in most endemic districts, and some areas achieved 80% coverage. Two sets of surveys were conducted to assess the impact of CDTi. Results from the first repeat surveys showed a significant decrease in overall MF prevalence (by 75.7%, from 41.6% to 10.1%). The second follow-up evaluation showed further improvement in most endemic districts and also documented major reductions in CMFL compared to baseline. Conclusions Extensive data collected over many years document the very significant impact of interventions conducted by the National Onchocerciasis and other Eyes Diseases Control Programme during challenging times with periods of civil unrest. The Health Ministry has now integrated efforts to control neglected tropical diseases and adopted the goal of onchocerciasis elimination

Assessing the presence of Wuchereria bancrofti in vector and human populations from urban communities in Conakry, Guinea

The Global Programme to Eliminate Lymphatic Filariasis was launched in 2000 with the goal of interrupting transmission of lymphatic filariasis (LF) through multiple rounds of mass drug administration (MDA). In Guinea, there is evidence of ongoing LF transmission, but little is known about the most densely populated parts of the country, including the capital Conakry. In order to guide the LF control and elimination efforts, serological and entomological surveys were carried out to determine whether or not LF transmission occurs in Conakry.; The prevalence of circulating filarial antigen (CFA) of Wuchereria bancrofti was assessed by an immuno-chromatography test (ICT) in people recruited from all five districts of Conakry. Mosquitoes were collected over a 1-year period, in 195 households in 15 communities. A proportion of mosquitoes were analysed for W. bancrofti, using dissection, loop-mediated isothermal amplification (LAMP) assay and conventional polymerase chain reaction (PCR).; CFA test revealed no infection in the 611 individuals examined. A total of 14,334 mosquitoes were collected; 14,135 Culex (98.6 %), 161 Anopheles (1.1 %) and a few other species. Out of 1,312 Culex spp. (9.3 %) and 51 An. gambiae (31.7 %) dissected, none was infected with any stage of the W. bancrofti parasite. However, the LAMP assay revealed that 1.8 % of An. gambiae and 0.31 % of Culex spp. were positive, while PCR determined respective prevalences of 0 % and 0.19 %.; This study revealed the presence of W. bancrofti DNA in mosquitoes, despite the apparent absence of infection in the human population. Although MDA interventions are not recommended where the prevalence of ICT is below 1 %, the entomological results are suggestive of the circulation of the parasite in the population of Conakry. Therefore, rigorous surveillance is still warranted so that LF transmission in Conakry would be identified rapidly and adequate responses being implemented

Evidence of a Large-Scale Functional Organization of Mammalian Chromosomes

Evidence from inbred strains of mice indicates that a quarter or more of the mammalian genome consists of chromosome regions containing clusters of functionally related genes. The intense selection pressures during inbreeding favor the coinheritance of optimal sets of alleles among these genetically linked, functionally related genes, resulting in extensive domains of linkage disequilibrium (LD) among a set of 60 genetically diverse inbred strains. Recombination that disrupts the preferred combinations of alleles reduces the ability of offspring to survive further inbreeding. LD is also seen between markers on separate chromosomes, forming networks with scale-free architecture. Combining LD data with pathway and genome annotation databases, we have been able to identify the biological functions underlying several domains and networks. Given the strong conservation of gene order among mammals, the domains and networks we find in mice probably characterize all mammals, including humans

The Alström Syndrome Protein, ALMS1, Interacts with α-Actinin and Components of the Endosome Recycling Pathway

Alström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS

Integrating computationally assembled mouse transcript sequences with the Mouse Genome Informatics (MGI) database

Databases of experimentally generated and computationally derived transcript sequences are valuable resources for genome analysis and annotation. The utility of such databases is enhanced when the sequences they contain are integrated with such biological information as genomic location, gene function, gene expression and phenotypic variation. We present the analysis and results of a semi-automated process of connecting transcript assemblies with highly curated biological information for mouse genes that is available through the Mouse Genome Informatics (MGI) database

Correlation between the spatial distribution of circumstellar disks and massive stars in the young open cluster NGC 6611. II: Cluster members selected with Spitzer/IRAC

Context: the observations of the proplyds in the Orion Nebula Cluster, showing clear evidence of ongoing photoevaporation, have provided a clear proof about the role of the externally induced photoevaporation in the evolution of circumstellar disks. NGC 6611 is an open cluster suitable to study disk photoevaporation, thanks to its large population of massive members and of stars with disk. In a previous work, we obtained evidence of the influence of the strong UV field generated by the massive cluster members on the evolution of disks around low-mass Pre-Main Sequence members. That work was based on a multi-band BVIJHK and X-ray catalog purposely compiled to select the cluster members with and without disk. Aims: in this paper we complete the list of candidate cluster members, using data at longer wavelengths obtained with Spitzer/IRAC, and we revisit the issue of the effects of UV radiation on the evolution of disks in NGC 6611. Methods: we select the candidate members with disks of NGC 6611, in a field of view of 33'x34' centered on the cluster, using IRAC color-color diagrams and suitable reddening-free color indices. Besides, using the X-ray data to select Class III cluster members, we estimate the disks frequency vs. the intensity of the incident radiation emitted by massive members. Results: we identify 458 candidate members with circumstellar disks, among which 146 had not been revealed in our previous work. Comparing of the various color indices we used to select the cluster members with disk, we claim that they detect the excesses due to the emission of the same physical region of the disk: the inner rim at the dust sublimation radius. Our new results confirm that UV radiation from massive stars affects the evolution of nearby circumstellar disks.Comment: Accepted for publication at Astronomy & Astrophysic

The Hubble constant from galaxy lenses: impacts of triaxiality and model degeneracies

The Hubble constant can be constrained using the time delays between multiple images of gravitationally lensed sources. In some notable cases, typical lensing analyses assuming isothermal galaxy density profiles produce low values for the Hubble constant, inconsistent with the result of the HST Key Project (72 +- 8 km/s/Mpc). Possible systematics in the values of the Hubble constant derived from galaxy lensing systems can result from a number of factors, e.g. neglect of environmental effects, assumption of isothermality, or contamination by line-of-sight structures. One additional potentially important factor is the triaxial structure of the lensing galaxy halo; most lens models account for halo shape simply by perturbing the projected spherical lensing potential, an approximation that is often necessary but that is inadequate at the levels of triaxiality predicted in the CDM paradigm. To quantify the potential error introduced by this assumption in estimates of the Hubble parameter, we strongly lens a distant galaxy through a sample of triaxial softened isothermal halos and use an MCMC method to constrain the lensing halo profile and the Hubble parameter from the resulting multiple image systems. We explore the major degeneracies between the Hubble parameter and several parameters of the lensing model, finding that without a way to accurately break these degeneracies accurate estimates of the Hubble parameter are not possible. Crucially, we find that triaxiality does not significantly bias estimates of the Hubble constant, and offer an analytic explanation for this behaviour in the case of isothermal profiles. Neglected triaxial halo shape cannot contribute to the low Hubble constant values derived in a number of galaxy lens systems.Comment: Minor revisions to match version published in MNRAS. 13 pages, 11 figure