Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma.

Cancer-related fatigue (CRF) is one of the most common complications in patients with multiple cancer types and severely affects patients' quality of life. However, there have only been single symptom-relieving adjuvant therapies but no effective pharmaceutical treatment for the CRF syndrome. Dichloroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase kinase, has been tested as a potential therapy to slow tumor growth, based largely on its effects in vitro to halt cell division. We found that although DCA did not affect rates of tumor growth or the efficacy of standard cancer treatment (immunotherapy and chemotherapy) in two murine cancer models, DCA preserved physical function in mice with late-stage tumors by reducing circulating lactate concentrations. In vivo liquid chromatography-mass spectrometry/mass spectrometry studies suggest that DCA treatment may preserve membrane potential, postpone proteolysis, and relieve oxidative stress in muscles of tumor-bearing mice. In all, this study provides evidence for DCA as a novel pharmaceutical treatment to maintain physical function and motivation in murine models of CRF.NEW & NOTEWORTHY We identify a new metabolic target for cancer-related fatigue, dichloroacetate (DCA). They demonstrate that in mice, DCA preserves physical function and protects against the detrimental effects of cancer treatment by reducing cancer-induced increases in circulating lactate. As DCA is already FDA approved for another indication, these results could be rapidly translated to clinical trials for this condition for which no pharmaceutical therapies exist beyond symptom management.

The effect of cricoid and paralaryngeal force on upper oesophageal occlusion during induction of anaesthesia: a randomised, crossover study.

The aim of this study was to evaluate the effectiveness of cricoid and paralaryngeal force for oesophageal entrance occlusion during induction of anaesthesia. Seventy-four patients were included in this randomised, crossover study. The relative position of the glottis and outer anteroposterior diameter of the upper oesophageal entrance were assessed at baseline, after the application of 30 N cricoid and paralaryngeal force, and after induction of anaesthesia. The occlusion rate of the oesophageal entrance with cricoid and paralaryngeal force was assessed during direct laryngoscopy. The relative position of the upper oesophageal entrance to the glottis changed in 45 out of 74 patients after induction of anaesthesia and during direct laryngoscopy compared with the awake state. The application of cricoid and paralaryngeal force decreased the mean (SD) diameter of the upper oesophageal entrance to a similar degree in awake (8.5 (2.1) mm to 6.4 (1.7) mm and 6.5 (1.6) mm, respectively; p < 0.001) and anaesthetised (8.7 (2.2) mm to 6.5 (1.7) mm and (6.7 (1.9) mm, respectively; p < 0.001) states. During direct laryngoscopy, the occlusion rate of the oesophageal entrance was greater with cricoid compared with paralaryngeal force (46/74 vs. 26/74, respectively; p = 0.002). The relative position of the upper oesophageal entrance to the glottis may change after induction of anaesthesia and during direct laryngoscopy. Cricoid and paralaryngeal force both decrease the diameter of the upper oesophageal entrance in awake and anaesthetised states. Occlusion of the oesophageal entrance is achieved more frequently with cricoid force compared with paralaryngeal force during direct laryngoscopy.

Landscape of Elderly Suicide in South Korea: Its Trend According to Age, Gender, and Educational Attainment.

South Korea has one of the highest suicide rates in the world, and the most alarming suicide rate is among its elders. This study aims to understand the social, historical, and cultural context of the Korean older adults and examine suicide trends based on that understanding. The results show that the suicide risk increases with age, the male suicide rate outweighs that of females, and the suicide rate decreases with educational attainment. In addition, several suggestions for reducing elderly suicide rate are addressed, including differentiating the existing social services for elders by age and expanding suicide prevention programs beyond schools to communities so that all people in need can access them.

Clinicopathologic characteristics of double primary endometrial and colorectal cancers in a single institution.

AIM: To investigate the clinicopathologic and genetic correlations between double primary endometrial and colorectal cancer related to Lynch syndrome and to analyze germline mutations in mismatch repair genes in endometrial cancer patients in Korea. METHODS: Thirteen patients diagnosed with pathologically endometrial and colorectal cancer between January 2005 and November 2016 in a single institution were enrolled in the study. The medical records were retrospectively analyzed. The genetic mutational information of endometrial cancer in Korea was retrieved from the literature review. RESULTS: Endometrial cancer was diagnosed first in eight (62%) patients, and one patient was diagnosed with colorectal cancer first. Endometrioid adenocarcinoma was reported in 10 of 13 (77%) endometrial cancer patients. Endometrial cancer was found at the low uterine segment in three patients. Three of four patients had high microsatellite instability. The loss of mismatch repair proteins was confirmed in 7 of 11 cases using immunohistochemistry. Four patients fulfilled clinical criteria based on a family history of cancer. Overall, the incidence of suspected Lynch syndrome was 77% (10/13). Four of them underwent genetic testing and three were found to have a pathogenic germline mutation. A possible founder mutation, c.1757_1758insC in MLH1, was observed in 21 germline mutation information from literature review. CONCLUSION: The present study describes the clinicopathologic data of double primary endometrial and colorectal cancer patients and supports that these patients should undergo closed approach for Lynch syndrome. Moreover, a possible founder mutation in Korean endometrial cancer patients was identified.

Dynamic and Combinatorial Landscape of Histone Modifications during the Intraerythrocytic Developmental Cycle of the Malaria Parasite.

A major obstacle in understanding the complex biology of the malaria parasite remains to discover how gene transcription is controlled during its life cycle. Accumulating evidence indicates that the parasite's epigenetic state plays a fundamental role in gene expression and virulence. Using a comprehensive and quantitative mass spectrometry approach, we determined the global and dynamic abundance of histones and their covalent post-transcriptional modifications throughout the intraerythrocytic developmental cycle of Plasmodium falciparum. We detected a total of 232 distinct modifications, of which 160 had never been detected in Plasmodium and 88 had never been identified in any other species. We further validated over 10% of the detected modifications and their expression patterns by multiple reaction monitoring assays. In addition, we uncovered an unusual chromatin organization with parasite-specific histone modifications and combinatorial dynamics that may be directly related to transcriptional activity, DNA replication, and cell cycle progression. Overall, our data suggest that the malaria parasite has a unique histone modification signature that correlates with parasite virulence.

Three concurrent variations of the aberrant right subclavian artery, the non-recurrent laryngeal nerve and the right thoracic duct.

We herein report a case showing three anatomical variations including the aberrant right subclavian artery (ARSA), the non-recurrent laryngeal nerve (NRLN) and the right thoracic duct in a 59-year-old male cadaver. The right subclavian artery (RSA) arose from the descending aorta next to the left subclavian artery and coursed in between the oesophagus and the thoracic vertebrae. The recurrent laryngeal nerve did not coil around the RSA but directly entered the larynx. Lastly the thoracic duct terminated into the right brachiocephalic vein. This study makes an embryological assumption that the abnormal development of the RSA had happened first and subsequently caused NRLN and the thoracic duct drainage variation. As to our knowledge, only two reports have been made previously concerning such concurrent variations. Therefore, this case report alerts anatomists and clinicians to the possibility of simultaneous occurrence of ARSA, NRLN and the right thoracic duct.

Identification of a novel HLA-B*15 variant, B*15:367, using sequence-based typing in a Korean woman.

New allele, B*15:367, differs from B*15:11:01 by a single nucleotide exchange at codon 222 (GAG→AAG).

An apicoplast localized ubiquitylation system is required for the import of nuclear-encoded plastid proteins.

Apicomplexan parasites are responsible for numerous important human diseases including toxoplasmosis, cryptosporidiosis, and most importantly malaria. There is a constant need for new antimalarials, and one of most keenly pursued drug targets is an ancient algal endosymbiont, the apicoplast. The apicoplast is essential for parasite survival, and several aspects of its metabolism and maintenance have been validated as targets of anti-parasitic drug treatment. Most apicoplast proteins are nuclear encoded and have to be imported into the organelle. Recently, a protein translocon typically required for endoplasmic reticulum associated protein degradation (ERAD) has been proposed to act in apicoplast protein import. Here, we show ubiquitylation to be a conserved and essential component of this process. We identify apicoplast localized ubiquitin activating, conjugating and ligating enzymes in Toxoplasma gondii and Plasmodium falciparum and observe biochemical activity by in vitro reconstitution. Using conditional gene ablation and complementation analysis we link this activity to apicoplast protein import and parasite survival. Our studies suggest ubiquitylation to be a mechanistic requirement of apicoplast protein import independent to the proteasomal degradation pathway.

Identification of novel PIKFYVE gene mutations associated with Fleck corneal dystrophy.

PURPOSE: To report the identification of a novel frameshift mutation and copy number variation (CNV) in PIKFYVE in two probands with fleck corneal dystrophy (FCD). METHODS: Slit-lamp examination was performed to identify characteristic features of FCD. After genomic DNA was collected, PCR amplification and automated sequencing of all 41 exons of PIKFYVE was performed. Using genomic DNA, quantitative PCR (qPCR) was performed to detect CNVs within PIKFYVE. RESULTS: In the first FCD proband, numerous panstromal punctate opacities were observed in each of the proband's corneas, consistent with the diagnosis of FCD. Screening of PIKFYVE demonstrated a novel heterozygous frameshift mutation in exon 19, c.3151dupA, which is predicted to encode for a truncated PIKFYVE protein, p.(Asp1052Argfs*18). This variant was identified in an affected sister but not in the proband's unaffected mother or brother or 200 control chromosomes. The second FCD proband presented with bilateral, discrete, punctate, grayish-white stromal opacities. Exonic screening of PIKFYVE revealed no causative variant. However, CNV analysis demonstrated the hemizygous deletion of exons 15 and 16. CONCLUSIONS: We report a novel heterozygous frameshift mutation (c.3151dupA) and a CNV in PIKFYVE, representing the first CNV and the fifth frameshift mutation associated with FCD.

Identification of presumed pathogenic KRT3 and KRT12 gene mutations associated with Meesmann corneal dystrophy.

PURPOSE: To report potentially pathogenic mutations in the keratin 3 (KRT3) and keratin 12 (KRT12) genes in two individuals with clinically diagnosed Meesmann corneal dystrophy (MECD). METHODS: Slit-lamp examination was performed on the probands and available family members to identify characteristic features of MECD. After informed consent was obtained, saliva samples were obtained as a source of genomic DNA, and screening of KRT3 and KRT12 was performed. Potentially pathogenic variants were screened for in 200 control chromosomes. PolyPhen-2, SIFT, and PANTHER were used to predict the functional impact of identified variants. Short tandem repeat genotyping was performed to confirm paternity. RESULTS: Slit-lamp examination of the first proband demonstrated bilateral, diffusely distributed, clear epithelial microcysts, consistent with MECD. Screening of KRT3 revealed a heterozygous missense variant in exon 1, c.250C>T (p.(Arg84Trp)), which has a minor allele frequency of 0.0076 and was not identified in 200 control chromosomes. In silico analysis with PolyPhen-2 and PANTHER predicted the variant to be damaging to protein function; however, SIFT analysis predicted tolerance of the variant. The second proband demonstrated bilateral, diffusely distributed epithelial opacities that appeared gray-white on direct illumination and translucent on retroillumination. Neither parent demonstrated corneal opacities. Screening of KRT12 revealed a novel heterozygous insertion/deletion variant in exon 6, c.1288_1293delinsAGCCCT (p.(Arg430_Arg431delinsSerPro)). This variant was not present in either of the proband's parents or in 200 control chromosomes and was predicted to be damaging by PolyPhen-2, PANTHER, and SIFT. Haplotype analysis confirmed paternity of the second proband, indicating that the variant arose de novo. CONCLUSIONS: We present a novel KRT12 mutation, representing the first de novo mutation and the first indel in KRT12 associated with MECD. In addition, we report a variant of uncertain significance in KRT3 in an individual with MECD. Although the potential pathogenicity of this variant is unknown, it is the first variant affecting the head domain of K3 to be reported in an individual with MECD and suggests that disease-causing variants associated with MECD may not be restricted to primary sequence alterations of either the helix-initiation or helix-termination motifs of K3 and K12.

The IVAIRE project--a randomized controlled study of the impact of ventilation on indoor air quality and the respiratory symptoms of asthmatic children in single family homes.

UNLABELLED: A randomized controlled trial was carried out to measure the impact of an intervention on ventilation, indoor air contaminants, and asthma symptoms of children. Eighty-three asthmatic children living in low-ventilated homes were followed over 2 years. Several environmental parameters were measured during the summer, fall, and winter. The children were randomized after Year 1 (43 Intervention; 40 Control). The intervention included the installation of either a Heat Recovery Ventilator (HRV) or Energy Recovery Ventilator (ERV). During the fall and winter seasons, there was a significant increase in the mean ventilation rate in the homes of the intervention group. A statistically significant reduction in mean formaldehyde, airborne mold spores, toluene, styrene, limonene, and α-pinene concentrations was observed in the intervention group. There was no significant group difference in change in the number of days with symptoms per 14 days. However, there was a significant decrease in the proportion of children who experienced any wheezing (≥1 episode) and those with ≥4 episodes in the 12-month period in the intervention group. This study indicates that improved ventilation reduces air contaminants and may prevent wheezing. Due to lack of power, a bigger study is needed. PRACTICAL IMPLICATIONS: Positive findings from this study include the fact that, upon recruitment, most of the single family homes with asthmatic children were already equipped with a mechanical ventilation system and had relatively good indoor air quality. However, the 8-h indoor guideline for formaldehyde (50 µg/m3) was frequently exceeded and the ventilation rates were low in most of the homes, even those with a ventilation system. Both ERVs and HRVs were equally effective at increasing air exchange rates above 0.30 ACH and at preventing formaldehyde concentrations from exceeding the 50 µg/m3 guideline during the fall and winter seasons. Furthermore, the ERVs were effective at preventing excessively low relative humidities in the homes. Based on observed difference of risk, intervention to increase ventilation in five sample homes and children would prevent 1 home to exceed the indoor air long-term formaldehyde guideline and prevent 1 asthmatic child experiencing at least one episode of wheezing over a year.

First Report of Clover yellow vein virus on White Clover (Trifolium repens) in South Korea.

White clover (Trifolium repens L.) is a herbaceous, perennial plant that has become one of the most widely distributed legumes in the world. It is extensively used in grass-legume pastures, but also has the potential to invade agricultural lands and natural ecosystems. White clover is a well-known natural host for Alfalfa mosaic virus (AMV), Clover yellow vein virus (ClYVV), Soybean dwarf virus (SbDV), Beet western virus (BWYV), Tomato spotted wilt virus (TSWV), Zucchini yellow mosaic virus (ZYMV), etc (1). In July 2013, during a survey to determine the presence of different viruses infecting weed plants in South Korea, three white clover leaf samples showing yellow mosaic symptoms were collected from Taean County, South Chungcheong Do Province, South Korea. In order to identify the infecting virus, total RNA from three leaf samples was extracted using the Tri-reagent (MRC Reagent, Inc., OH) as described by the manufacturer, and was applied to the large-scale oligonucleotide (LSON) chip (3), wherein probes specific to a ClYVV isolate produced a positive reaction. All three samples tested were positive for ClYVV. To confirm this result, ClYVV-specific primers were designed using the sequences of four ClYVV isolates from NCBI (GenBank Accession Nos. AF185959, AF203536, DQ333346, and NC003536). Total RNA was extracted from symptomatic white clover samples using Easy-Spin Total RNA Extraction Kit (iNtRon, Daejeon, Korea) and used as template for RT-PCR. The positive control RNA was used from ClYVV GM isolate (KF975894) and negative control RNA used symptomless white clover plants. The ClYVV coat protein (CP) gene was amplified by RT-PCR using the specific primer pairs ClYVV-CP-F / ClYVV-CP-R (5'-CAAGAGCAGCACGATGAG-3' and 5'-CTCGCTCTATAAAGATCAGAT-3'). DNA fragments of the expected size (1,042 bp) were obtained from the white clover Korea isolate (AB930132), and the PCR product was cloned into a T&A cloning vector (RBC Bioscience, Taipei, Taiwan) and sequenced directly in both directions. BLAST analyses of the nucleotide sequence CP gene fragments revealed the highest identity with 98% with other ClYVV isolates (AF203536). To determine the experimental host range of the ClYVV Korea isolate, we inoculated five species (Chenopodium amaranticolor, C. quinoa, Nicotiana clevelandii, N. benthamiana, and Trifolium repens) in three families using this isolate. All test plants were mechanically inoculated with 0.1 M phosphate buffered saline (Takara, Tokyo, Japan). Each test plant was inoculated nine times and grown in a greenhouse maintained at 27 to 33°C. Necrotic local lesions were produced on inoculated leaves of C. amaranticolor, C. quinoa, and N. clevelandii 4 to 6 days post-inoculation. After 10 to 14 days, C. amaranticolor and C. quinoa showed systemic chlorotic spot symptoms, and N. clevelandii, N. benthamiana, and T. repens showed chlorotic spot, mild mosaic, and mosaic in the upper leaves, respectively. Up to now, in South Korea, ClYVV has been detected in gladiolus (Gladiolus gandavensis) (3) and soybean (Glycine max) (4). ClYVV can be easily transmitted by insect, aphid, or mechanical inoculation and has a host range including tobacco, soybean, etc. The presence of ClYVV could become an important threat to crop production in South Korea. To our knowledge, this is the first report of a ClYVV infection of the white clover plant in South Korea. References: (1) B. L. Denny and P. L. Guy. Australas. Plant Pathol. 38:270, 2009. (2) M. Nam et al. Plant Pathol. J. 30:51, 2014. (3) I. S. Park et al. Korean J. Plant Pathol. 14:74, 1998. (4) J. C. Shin et al. Plant Dis. 98:1283, 2014.

The E3 ubiquitin ligase XIAP restricts Anaplasma phagocytophilum colonization of Ixodes scapularis ticks.

Ubiquitination is a posttranslational modification that regulates protein degradation and signaling in eukaryotes. Although it is acknowledged that pathogens exploit ubiquitination to infect mammalian cells, it remains unknown how microbes interact with the ubiquitination machinery in medically relevant arthropods. Here, we show that the ubiquitination machinery is present in the tick Ixodes scapularis and demonstrate that the E3 ubiquitin ligase named x-linked inhibitor of apoptosis protein (XIAP) restricts bacterial colonization of this arthropod vector. We provide evidence that xiap silencing significantly increases tick colonization by the bacterium Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis. We also demonstrate that (i) XIAP polyubiquitination is dependent on the really interesting new gene (RING) catalytic domain, (ii) XIAP polyubiquitination occurs via lysine (K)-63 but not K-48 residues, and (iii) XIAP-dependent K-63 polyubiquitination requires zinc for catalysis. Taken together, our data define a role for ubiquitination during bacterial colonization of disease vectors.

Predictive factors for tuberculosis in patients with a TB-PCR-negative bronchial aspirate.

PURPOSE: Pulmonary tuberculosis (PTB), with a tuberculosis (TB)-polymerase chain reaction (PCR)-negative bronchial aspirate (BA), but a positive culture result is often encountered in clinical practice. However, limited data are available concerning clinical judgment in patients with suspected PTB and a TB-PCR-negative BA pending culture results. The present study aimed to identify predictors for PTB in patients with a TB-PCR-negative BA. METHODS: A retrospective study was conducted on patients who had undergone a bronchoscopy because of suspected PTB. Clinical, laboratory, and computed tomography (CT) findings were investigated in PTB patients with TB-PCR-negative but positive culture BA results, and non-PTB patients with a radiographic lesion comparable to the former. RESULTS: Of 250 patients screened, 31 (12 %) were diagnosed with PTB by positive culture results only. Of these 31 patients, 30 (97 %) had a lesion within one-third of the hemithorax as determined by chest radiography. In the final analysis of 30 PTB and 65 non-PTB patients with comparable radiographic lesions, a positive QuantiFERON-TB Gold In-Tube (QFT) result was independently associated with an increased risk of a positive TB culture. CT findings of consolidation were a negative predictor for PTB. Patients with a negative QFT result and consolidation had a negative predictive value of 95 % for PTB, while patients with a positive QFT result and nodular CT abnormalities without consolidation had a positive predictive value of 86 % for PTB. CONCLUSION: The simple combination of CT findings of consolidation and QFT test results may help clinicians to refine decision-making in patients with a TB-PCR-negative BA.

Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis.

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine's contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine's contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.

Unraveling the ubiquitome of the human malaria parasite.

Malaria is one of the deadliest infectious diseases worldwide. The most severe form is caused by the eukaryotic protozoan parasite Plasmodium falciparum. Recent studies have highlighted the importance of post-translational regulations for the parasite's progression throughout its life cycle, protein ubiquitylation being certainly one of the most abundant. The specificity of its components and the wide range of biological processes in which it is involved make the ubiquitylation pathway a promising source of suitable targets for anti-malarial drug development. Here, we combined immunofluorescent microscopy, biochemical assays, in silico prediction, and mass spectrometry analysis using the multidimensional protein identification technology, or MudPIT, to describe the P. falciparum ubiquitome. We found that ubiquitin conjugates are detected at every morphological stage of the parasite erythrocytic cycle. Furthermore, we detected that more than half of the parasite's proteome represents possible targets for ubiquitylation, especially proteins found to be present at the most replicative stage of the asexual cycle, the trophozoite stage. A large proportion of ubiquitin conjugates were also detected at the schizont stage, consistent with a cell activity slowdown to prepare for merozoite differentiation and invasion. Finally, for the first time in the human malaria parasite, our results strongly indicate the presence of heterologous mixed conjugations, SUMO/UB. This discovery suggests that sumoylated proteins may be regulated by ubiquitylation in P. falciparum. Altogether, our results present the first stepping stone toward a better understanding of ubiquitylation and its role(s) in the biology of the human malaria parasite.

Large-scale EEG neural network changes in response to therapeutic TMS.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective therapy for patients with treatment-resistant depression. TMS likely induces functional connectivity changes in aberrant circuits implicated in depression. Electroencephalography (EEG) "microstates" are topographies hypothesized to represent large-scale resting networks. Canonical microstates have recently been proposed as markers for major depressive disorder (MDD), but it is not known if or how they change following TMS. METHODS: Resting EEG was obtained from 49 MDD patients at baseline and following six weeks of daily TMS. Polarity-insensitive modified k-means clustering was used to segment EEGs into constituent microstates. Microstates were localized via sLORETA. Repeated-measures mixed models tested for within-subject differences over time and t-tests compared microstate features between TMS responder and non-responder groups. RESULTS: Six microstates (MS-1 - MS-6) were identified from all available EEG data. Clinical response to TMS was associated with increases in features of MS-2, along with decreased metrics of MS-3. Nonresponders showed no significant changes in any microstate. Change in occurrence and coverage of both MS-2 (increased) and MS-3 (decreased) correlated with symptom change magnitude over the course of TMS treatment. CONCLUSIONS: We identified EEG microstates associated with clinical improvement following a course of TMS therapy. Results suggest selective modulation of resting networks observable by EEG, which is inexpensive and easily acquired in the clinic setting.

Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier status.

Rare deleterious mutations in BRCA1 and BRCA2 are associated with an elevated risk of breast and ovarian cancer. Whether or not common variants in these genes are independently associated with risk of breast cancer remains unclear. In this study, we included 632 Caucasian women with asynchronous contralateral breast cancer (CBC, cases) and 1,221 women with unilateral breast cancer (UBC, controls) from the WECARE (Women's Environment, Cancer and Radiation Epidemiology) Study. BRCA1 and BRCA2 deleterious mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing, yielding including 88 BRCA1 and 60 BRCA2 deleterious mutation carriers. We also genotyped samples on the Illumina Omni1-Quad platform. We assessed the association between CBC risk and common (minor allele frequency (MAF) > 0.05) single-nucleotide polymorphisms (SNPs) in BRCA1 (n SNPs = 22) and BRCA2 (n SNPs = 30) and haplotypes using conditional logistic regression accounting for BRCA1/BRCA2 mutation status. We found no significant associations between any single-SNPs or haplotypes of BRCA1 or BRCA2 and risk of CBC among all women. When we stratified by BRCA1 and BRCA2 mutation carrier status, we found suggestive evidence that risk estimates for selected SNPs in BRCA1 (rs8176318, rs1060915, and rs16940) and BRCA2 (rs11571686, rs206115, and rs206117) may differ in non-carriers and carriers of deleterious mutations in BRCA1 and BRCA2. One common haplotype on BRCA1 was inversely significantly associated with risk only among non-BRCA1 and BRCA2 carriers. The association between common variants in BRCA1 and BRCA2 and risk of CBC may differ depending on BRCA1 and BRCA2 mutation carrier status.

A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum.

BACKGROUND: In recent years, a major increase in the occurrence of drug resistant falciparum malaria has been reported. Choline analogs, such as the bisthiazolium T4, represent a novel class of compounds with strong potency against drug sensitive and resistant P. falciparum clones. Although T4 and its analogs are presumed to target the parasite's lipid metabolism, their exact mechanism of action remains unknown. Here we have employed transcriptome and proteome profiling analyses to characterize the global response of P. falciparum to T4 during the intraerythrocytic cycle of this parasite. RESULTS: No significant transcriptional changes were detected immediately after addition of T4 despite the drug's effect on the parasite metabolism. Using the Ontology-based Pattern Identification (OPI) algorithm with an increased T4 incubation time, we demonstrated cell cycle arrest and a general induction of genes involved in gametocytogenesis. Proteomic analysis revealed a significant decrease in the level of the choline/ethanolamine-phosphotransferase (PfCEPT), a key enzyme involved in the final step of synthesis of phosphatidylcholine (PC). This effect was further supported by metabolic studies, which showed a major alteration in the synthesis of PC from choline and ethanolamine by the compound. CONCLUSION: Our studies demonstrate that the bisthiazolium compound T4 inhibits the pathways of synthesis of phosphatidylcholine from choline and ethanolamine in P. falciparum, and provide evidence for post-transcriptional regulations of parasite metabolism in response to external stimuli.