Interaction between Darunavir and Etravirine Is Partly Mediated by CYP3A5 Polymorphism.

PLoS One. 2016;11(10):e0165631

Authors: Belkhir L, Elens L, Zech F, Panin N, Vincent A, Yombi JC, Vandercam B, Haufroid V

Abstract
OBJECTIVES: To assess the impact of the loss-of-function CYP3A5*3 allele (rs776746, 6986A>G SNP) on darunavir (DRV) plasma concentrations.
METHODS: 135 HIV-1 infected patients treated with DRV-based therapy were included in the study and plasma samples were obtained immediately before drug intake in order to determine DRV trough concentrations using an ultra performance liquid chromatography method (UPLC) with diode-array detection (DAD). Noteworthy is the fact that in 16 (11.9%) patients, etravirine (ETR) was combined with DRV. CYP3A5 genotypes were determined using real time PCR method (TaqMan® genotyping assay). The patients were then classified into CYP3A5 expressors (CYP3A5*1 allele carriers) and non-expressors (CYP3A5*3 homozygous). Subsequently, the association between DRV plasma trough concentration ([DRV]plasma) and CYP3A5 genotype-based expression status was analyzed.
RESULTS: 45% of the patients were classified as CYP3A5 expressors. In the whole cohort, mean [DRV]plasma was not different between CYP3A5 expressors and non-expressors (1894ng/ml [CI95%: 1566-2290] versus 1737ng/ml [CI95%: 1468-2057], p = 0.43). However, in the subgroup of the 16 patients receiving DRV combined with ETR, a significantly lower [DRV]plasma was observed for CYP3A5 expressors when compared to non-expressors (1385ng/ml [CI95%:886.3-2165] versus 3141ng/ml [CI95%:2042-4831], p = 0.007).
CONCLUSIONS: Interaction between DRV and ETR is partly mediated by CYP3A5 polymorphism with lower DRV plasma trough concentrations in CYP3A5 expressors suggesting a specific ETR-driven CYP3A5 activation only in CYP3A5 expressors. Consequently, these patients might be more at risk of infra-therapeutic [DRV]plasma. This potentially important observation is a good illustration of a genotype-based drug interaction, which could also have considerable consequences if translated to other CYP3A5-metabolized drugs. Further investigations are thus needed to confirm this association and to explore its clinical impact, mainly in the African population among whom CYP3A5 expressors are more frequent, before recommending systematic CYP3A5 pre-emptive genotyping for DRV-ETR co-administration.

PMID: 27788239 [PubMed - indexed for MEDLINE]

Destabilization of mitochondrial functions as a target against breast cancer progression: Role of TPP(+)-linked-polyhydroxybenzoates.

Toxicol Appl Pharmacol. 2016 Oct 15;309:2-14

Authors: Sandoval-Acuña C, Fuentes-Retamal S, Guzmán-Rivera D, Peredo-Silva L, Madrid-Rojas M, Rebolledo S, Castro-Castillo V, Pavani M, Catalán M, Maya JD, Jara JA, Parra E, Calaf GM, Speisky H, Ferreira J

Abstract
Mitochondrion is an accepted molecular target in cancer treatment since it exhibits a higher transmembrane potential in cancer cells, making it susceptible to be targeted by lipophilic-delocalized cations of triphenylphosphonium (TPP(+)). Thus, we evaluated five TPP(+)-linked decyl polyhydroxybenzoates as potential cytotoxic agents in several human breast cancer cell lines that differ in estrogen receptor and HER2/neu expression, and in metabolic profile. Results showed that all cell lines tested were sensitive to the cytotoxic action of these compounds. The mechanism underlying the cytotoxicity would be triggered by their weak uncoupling effect on the oxidative phosphorylation system, while having a wider and safer therapeutic range than other uncouplers and a significant lowering in transmembrane potential. Noteworthy, while the TPP(+)-derivatives alone led to almost negligible losses of ATP, when these were added in the presence of an AMP-activated protein kinase inhibitor, the levels of ATP fell greatly. Overall, data presented suggest that decyl polyhydroxybenzoates-TPP(+) and its derivatives warrant future investigation as potential anti-tumor agents.

PMID: 27554043 [PubMed - indexed for MEDLINE]

Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.

Nat Cell Biol. 2016 Aug;18(8):897-909

Authors: Walerych D, Lisek K, Sommaggio R, Piazza S, Ciani Y, Dalla E, Rajkowska K, Gaweda-Walerych K, Ingallina E, Tonelli C, Morelli MJ, Amato A, Eterno V, Zambelli A, Rosato A, Amati B, Wiśniewski JR, Del Sal G

Abstract
In cancer, the tumour suppressor gene TP53 undergoes frequent missense mutations that endow mutant p53 proteins with oncogenic properties. Until now, a universal mutant p53 gain-of-function program has not been defined. By means of multi-omics: proteome, DNA interactome (chromatin immunoprecipitation followed by sequencing) and transcriptome (RNA sequencing/microarray) analyses, we identified the proteasome machinery as a common target of p53 missense mutants. The mutant p53-proteasome axis globally affects protein homeostasis, inhibiting multiple tumour-suppressive pathways, including the anti-oncogenic KSRP-microRNA pathway. In cancer cells, p53 missense mutants cooperate with Nrf2 (NFE2L2) to activate proteasome gene transcription, resulting in resistance to the proteasome inhibitor carfilzomib. Combining the mutant p53-inactivating agent APR-246 (PRIMA-1MET) with the proteasome inhibitor carfilzomib is effective in overcoming chemoresistance in triple-negative breast cancer cells, creating a therapeutic opportunity for treatment of solid tumours and metastasis with mutant p53.

PMID: 27347849 [PubMed - indexed for MEDLINE]

Rho GTPases: RAC1 polymorphisms affected platinum-based chemotherapy toxicity in lung cancer patients.

Cancer Chemother Pharmacol. 2016 Aug;78(2):249-58

Authors: Zou T, Yin J, Zheng W, Xiao L, Tan L, Chen J, Wang Y, Li X, Qian C, Cui J, Zhang W, Zhou H, Liu Z

Abstract
PURPOSE: Lung cancer is the leading cause of cancer deaths in the world. The toxicity of platinum-based chemotherapy is a main reason limiting its clinical effects. RAC1, as a member of the Rho family of small guanosine triphosphatases (GTPases), was reported to be related to most cancers, such as breast cancer, gastric cancer, testicular germ cell cancer, and lung cancer. Its potential of becoming a drug target in cancer treatment has been investigated in recent years. The aim of this study was to investigate the association between genetic polymorphisms and platinum-based chemotherapy toxicity.
METHODS: We enrolled 317 lung cancer patients randomly. Nineteen polymorphisms of HSP genes and Rho family genes were genotyped by Sequenom MassARRAY. The logistic regression was performed by PLINK to compare the relevance of polymorphisms and toxicity outcome.
RESULTS: We found that the polymorphisms of RAC1 rs836554, rs4720672, and rs12536544 were significantly associated with platinum-based chemotherapy toxicity (p = 0.018, p = 0.044, and p = 0.021, respectively).
CONCLUSIONS: RAC1 rs836554, rs4720672, and rs12536544 polymorphisms may be novel and useful genetic markers to predict the toxicity induced by platinum-based chemotherapy in lung cancer patients.

PMID: 27299748 [PubMed - indexed for MEDLINE]

Translation of Human-Induced Pluripotent Stem Cells: From Clinical Trial in a Dish to Precision Medicine.

J Am Coll Cardiol. 2016 May 10;67(18):2161-76

Authors: Sayed N, Liu C, Wu JC

Abstract
The prospect of changing the plasticity of terminally differentiated cells toward pluripotency has completely altered the outlook for biomedical research. Human-induced pluripotent stem cells (iPSCs) provide a new source of therapeutic cells free from the ethical issues or immune barriers of human embryonic stem cells. iPSCs also confer considerable advantages over conventional methods of studying human diseases. Since its advent, iPSC technology has expanded with 3 major applications: disease modeling, regenerative therapy, and drug discovery. Here we discuss, in a comprehensive manner, the recent advances in iPSC technology in relation to basic, clinical, and population health.

PMID: 27151349 [PubMed - indexed for MEDLINE]

Is sweat chloride predictive of severity of cystic fibrosis lung disease assessed by chest computed tomography?

Pediatr Pulmonol. 2017 Jun 06;:

Authors: Caudri D, Zitter D, Bronsveld I, Tiddens H

Abstract
BACKGROUND: Cystic Fibrosis (CF) lung disease is characterized by a marked heterogeneity. Sweat chloride-level is a functional marker of the CF Transmembrane Regulator (CFTR) protein and could be an important predictor of later disease severity.
METHODS: In this retrospective analysis children from the Rotterdam CF clinic with available sweat chloride level at diagnosis and at least one routine spirometry-controlled volumetric chest CT scan in follow-up were included. CT scans were scored using the CF-CT scoring system (% of maximum). Associations between sweat chloride-levels and CF-CT scores were calculated using linear regression models, adjusting for age at sweat test and age at follow-up. Because structural lung damage develops over the course of many years, effect modification by the age at follow-up CT-scan was tested for by age-stratification.
RESULTS: In 59 children (30 male) sweat chloride was measured at diagnosis (median age 0.5 years, range 0-13) and later chest CT performed (median age 14 years, range 6-18). Sweat chloride was associated with significantly higher CT-CT total score, bronchiectasis score, and mucus plugging score. Stratification for age at follow-up in tertiles showed this association remained only in the oldest age group (range 15-18 years). In that subgroup associations were found with all but one of the CF-CT subscores, as well as with all tested lung functions parameters.
CONCLUSION: Sweat chloride-level is a significant predictor of CF lung disease severity as determined by chest CT and lung function. This association could only be demonstrated in children with follow-up to age 15 years and above.

PMID: 28586522 [PubMed - as supplied by publisher]

Impact of enzymatic digestion on bacterial community composition in CF airway samples.

PeerJ. 2017;5:e3362

Authors: Williamson KM, Wagner BD, Robertson CE, Johnson EJ, Zemanick ET, Harris JK

Abstract
BACKGROUND: Previous studies have demonstrated the importance of DNA extraction methods for molecular detection of Staphylococcus, an important bacterial group in cystic fibrosis (CF). We sought to evaluate the effect of enzymatic digestion (EnzD) prior to DNA extraction on bacterial communities identified in sputum and oropharyngeal swab (OP) samples from patients with CF.
METHODS: DNA from 81 samples (39 sputum and 42 OP) collected from 63 patients with CF was extracted in duplicate with and without EnzD. Bacterial communities were determined by rRNA gene sequencing, and measures of alpha and beta diversity were calculated. Principal Coordinate Analysis (PCoA) was used to assess differences at the community level and Wilcoxon Signed Rank tests were used to compare relative abundance (RA) of individual genera for paired samples with and without EnzD.
RESULTS: Shannon Diversity Index (alpha-diversity) decreased in sputum and OP samples with the use of EnzD. Larger shifts in community composition were observed for OP samples (beta-diversity, measured by Morisita-Horn), whereas less change in communities was observed for sputum samples. The use of EnzD with OP swabs resulted in significant increase in RA for the genera Gemella (p < 0.01), Streptococcus (p < 0.01), and Rothia (p < 0.01). Staphylococcus (p < 0.01) was the only genus with a significant increase in RA from sputum, whereas the following genera decreased in RA with EnzD: Veillonella (p < 0.01), Granulicatella (p < 0.01), Prevotella (p < 0.01), and Gemella (p = 0.02). In OP samples, higher RA of Gram-positive taxa was associated with larger changes in microbial community composition.
DISCUSSION: We show that the application of EnzD to CF airway samples, particularly OP swabs, results in differences in microbial communities detected by sequencing. Use of EnzD can result in large changes in bacterial community composition, and is particularly useful for detection of Staphylococcus in CF OP samples. The enhanced identification of Staphylococcus aureus is a strong indication to utilize EnzD in studies that use OP swabs to monitor CF airway communities.

PMID: 28584706 [PubMed - in process]

Immunonutrition in patients with cyctic fibrosis leads to drop of serum amyloid A and increase of oxidative stress.

J Clin Biochem Nutr. 2017 May;60(3):176-179

Authors: Hloch O, Charvat J, Fila L, Jan H

Abstract
The aim of the present study is to evaluate of the impact of immunonutrition on parameters of oxidative stress and inflammation in patients with cystic fibrosis and malnutrition. In the 30 patients with cystic fibrosis and long-term enteral nutrition support for malnutrition the effect of standard and immunonutrion sipping on oxidative stress and inflammatory activity parameters was compared. Malonyldialdehyde (MDA) as parameter of oxidative stress and serum amyloid A (SAA), interleukin 1 and 6, hsCRP, IgM, IgA, IgG as parameters of inflammatory activity were examined. Immunonutrition decreased SAA to 17.6 mg/L comparing to 25.6 mg/L when standard nutrition was given (p = 0.014). MDA was 0.66 µM on standard and 0.96 µM on immunonutrition support (p<0.01). The significant negative correlation was recorded between MDA and SAA, hs-CRP, interleukin 6, IgA and IgG. In conclusion, the application of immunonutrition in patients with cystic fibrosis and malnutrition is associated with drop of SAA but with the rise of MDA.

PMID: 28584399 [PubMed - in process]

The role of AxyZ transcriptional regulator in the overproduction of AxyXY-OprZ multidrug efflux system in Achromobacter spp. mutants selected by tobramycin.

Antimicrob Agents Chemother. 2017 Jun 05;:

Authors: Bador J, Neuwirth C, Grangier N, Muniz M, Germé L, Bonnet J, Pillay VG, Llanes C, de Curraize C, Amoureux L

Abstract
AxyXY-OprZ is an RND-type efflux system that confers innate aminoglycoside resistance to Achromobacter spp. We investigated here about a putative TetR family transcriptional regulator encoded by the axyZ gene located upstream of axyXY-oprZ In-frame axyZ gene deletion assay led to increased MICs of antibiotic substrates of the efflux system: aminoglycosides, cefepime, fluoroquinolones, tetracyclines and erythromycin, indicating that the product of axyZ negatively regulates expression of axyXY-oprZ Moreover we identified an amino-acid substitution at position 29 of AxyZ (V29G) in a clinical Achromobacter strain that occurred during the course of chronic respiratory tract colonization in a cystic fibrosis (CF) patient. This substitution, also detected in 3 other strains exposed in vitro to tobramycin, led to the increase in axyY transcription level (5 to 17-fold) together with the increase in antibiotic resistance level. This overproduction of AxyXY-OprZ is the first description of antibiotic resistance acquisition due to modification of a chromosomally encoded mechanism in Achromobacter and might have potential impact on the management of infected CF patients. Indeed tobramycin is widely used for aerosol therapy within this population and we have demonstrated that it easily selects mutants with increased minimal inhibitory concentrations of aminoglycosides but also fluoroquinolones, cefepime and tetracyclines.

PMID: 28584156 [PubMed - as supplied by publisher]

Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN.

Proc Natl Acad Sci U S A. 2017 Jun 05;:

Authors: Kumar N, Su CC, Chou TH, Radhakrishnan A, Delmar JA, Rajashankar KR, Yu EW

Abstract
Strains of the Burkholderia cepacia complex (Bcc) are Gram-negative opportunisitic bacteria that are capable of causing serious diseases, mainly in immunocompromised individuals. Bcc pathogens are intrinsically resistant to multiple antibiotics, including β-lactams, aminoglycosides, fluoroquinolones, and polymyxins. They are major pathogens in patients with cystic fibrosis (CF) and can cause severe necrotizing pneumonia, which is often fatal. Hopanoid biosynthesis is one of the major mechanisms involved in multiple antimicrobial resistance of Bcc pathogens. The hpnN gene of B. multivorans encodes an integral membrane protein of the HpnN family of transporters, which is responsible for shuttling hopanoids to the outer membrane. Here, we report crystal structures of B. multivorans HpnN, revealing a dimeric molecule with an overall butterfly shape. Each subunit of the transporter contains 12 transmembrane helices and two periplasmic loops that suggest a plausible pathway for substrate transport. Further analyses indicate that HpnN is capable of shuttling hopanoid virulence factors from the outer leaflet of the inner membrane to the periplasm. Taken together, our data suggest that the HpnN transporter is critical for multidrug resistance and cell wall remodeling in Burkholderia.

PMID: 28584102 [PubMed - as supplied by publisher]

Disease-modifying drug therapy in cystic fibrosis.

Paediatr Respir Rev. 2017 Mar 14;:

Authors: Harman K, Dobra R, Davies JC

Abstract
Whilst substantial progress has been made in the treatment of cystic fibrosis, the disease still carries a significant burden in terms of symptoms, requirement for treatment and early mortality. The last decade has witnessed a new era in the development of small molecule drugs targeting the CFTR protein, which for the first time may provide a truly disease-modifying approach to treatment. This article reviews progress and highlights some of the current and future challenges in CFTR modulator therapies.

PMID: 28583720 [PubMed - as supplied by publisher]

Safety of endoscopic sinus surgery in children with cystic fibrosis.

Int J Pediatr Otorhinolaryngol. 2017 Jul;98:25-28

Authors: Tumin D, Hayes D, Kirkby SE, Tobias JD, McKee C

Abstract
INTRODUCTION: Data on the safety of endoscopic sinus surgery (ESS) are limited in children with cystic fibrosis (CF). We used a multi-institutional surgical registry to examine ESS outcomes in children with CF.
METHODS: The 2014-2015 American College of Surgeons' National Surgical Quality Improvement Program-Pediatric database was queried for patients age <18 years undergoing elective ESS. Prolonged hospital stay (>1 day), 30-day readmission, and 30-day unplanned reoperation were compared according to presence of CF diagnosis.
RESULTS: The data included 213 children with CF (age 10 ± 5 years, 105/108 male/female) and 821 children without CF (age 10 ± 5 years, 504/317 male/female). CF patients were more likely than non-CF patients to require prolonged hospital stay (30% vs. 9%, p < 0.001), yet had similar rates of readmission (6% vs. 4%; p = 0.189) and reoperation (0 vs. 1%; p = 0.133). All readmissions but one among CF patients were unrelated to ESS. In the non-CF cohort, reasons for ESS-related readmissions included recurrence of sinusitis, postoperative pain, and bleeding.
CONCLUSIONS: We demonstrate the safety of ESS in the largest cohort of children with CF reviewed to date. Multi-institutional review of ESS safety may contribute to monitoring expansion of this intervention in children with CF.

PMID: 28583497 [PubMed - in process]

Personalised medicine in asthma: from curative to preventive medicine.

Eur Respir Rev. 2017 Jan;26(143):

Authors: Guilleminault L, Ouksel H, Belleguic C, Le Guen Y, Germaud P, Desfleurs E, Leroyer C, Magnan A

Abstract
The concept of asthma has changed substantially in recent years. Asthma is now recognised as a heterogeneous entity that is complex to treat. The subdivision of asthma, provided by "cluster" analyses, has revealed various groups of asthma patients who share phenotypic features. These phenotypes underlie the need for personalised asthma therapy because, in contrast to the previous approach, treatment must be tailored to the individual patient. Determination of the patient's asthma phenotype is therefore essential but sometimes challenging, particularly in elderly patients with a multitude of comorbidities and a complex exposure history. This review first describes the various asthma phenotypes, some of which were defined empirically and others through cluster analysis, and then discusses personalisation of the patient's diagnosis and therapy, addressing in particular biological therapies and patient education. This personalised approach to curative medicine should make way in the coming years for personalised preventive and predictive medicine, focused on subjects at risk who are not yet ill, with the aim of preventing asthma before it occurs. The concept of personalised preventive medicine may seem a long way off, but is it really?

PMID: 28049124 [PubMed - indexed for MEDLINE]

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy.

Invest Ophthalmol Vis Sci. 2017 Jun 01;58(7):2906-2914

Authors: Khan KN, El-Asrag ME, Ku CA, Holder GE, McKibbin M, Arno G, Poulter JA, Carss K, Bommireddy T, Bagheri S, Bakall B, Scholl HP, Raymond FL, Toomes C, Inglehearn CF, Pennesi ME, Moore AT, Michaelides M, Webster AR, Ali M, for NIHR BioResource-Rare Diseases and UK Inherited Retinal Disease Consortium

Abstract
Purpose: Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study.
Methods: Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein.
Results: Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses.
Conclusions: This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.

PMID: 28586915 [PubMed - in process]

A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy.

PLoS One. 2017;12(6):e0179170

Authors: Weiss GJ, Byron SA, Aldrich J, Sangal A, Barilla H, Kiefer JA, Carpten JD, Craig DW, Whitsett TG

Abstract
BACKGROUND: Small cell lung cancer (SCLC) that has progressed after first-line therapy is an aggressive disease with few effective therapeutic strategies. In this prospective study, we employed next-generation sequencing (NGS) to identify therapeutically actionable alterations to guide treatment for advanced SCLC patients.
METHODS: Twelve patients with SCLC were enrolled after failing platinum-based chemotherapy. Following informed consent, genome-wide exome and RNA-sequencing was performed in a CLIA-certified, CAP-accredited environment. Actionable targets were identified and therapeutic recommendations made from a pharmacopeia of FDA-approved drugs. Clinical response to genomically-guided treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
RESULTS: The study completed its accrual goal of 12 evaluable patients. The minimum tumor content for successful NGS was 20%, with a median turnaround time from sample collection to genomics-based treatment recommendation of 27 days. At least two clinically actionable targets were identified in each patient, and six patients (50%) received treatment identified by NGS. Two had partial responses by RECIST 1.1 on a clinical trial involving a PD-1 inhibitor + irinotecan (indicated by MLH1 alteration). The remaining patients had clinical deterioration before NGS recommended therapy could be initiated.
CONCLUSIONS: Comprehensive genomic profiling using NGS identified clinically-actionable alterations in SCLC patients who progressed on initial therapy. Recommended PD-1 therapy generated partial responses in two patients. Earlier access to NGS guided therapy, along with improved understanding of those SCLC patients likely to respond to immune-based therapies, should help to extend survival in these cases with poor outcomes.

PMID: 28586388 [PubMed - in process]

Whole Exome Sequencing in Eight Thai Patients With Leber Congenital Amaurosis Reveals Mutations in the CTNNA1 and CYP4V2 Genes.

Invest Ophthalmol Vis Sci. 2017 Apr 01;58(4):2413-2420

Authors: Jinda W, Taylor TD, Suzuki Y, Thongnoppakhun W, Limwongse C, Lertrit P, Trinavarat A, Atchaneeyasakul LO

Abstract
Purpose: Our goal was to describe the clinical and molecular genetic findings in Thai patients with Leber congenital amaurosis (LCA).
Methods: Whole exome sequencing (WES) was performed in eight unrelated patients. All genes responsible for inherited retinal diseases (IRDs) based on RetNet were selected for analysis. Potentially causative variants were filtered through a bioinformatics pipeline and validated using Sanger sequencing. Segregation analysis of the causative genes was performed in family members when available.
Results: Eleven deleterious variants, six nonsense and five missense, were identified in seven genes: four LCA-associated genes (CEP290, IQCB1, NMNAT1, and RPGRIP1), one gene responsible for syndromic LCA (ALMS1), and two IRDs-related genes (CTNNA1 and CYP4V2). Clinical reassessment supported the diagnosis of syndromic LCA in those patients harboring potentially pathogenic variants in the ALMS1. Interestingly, two causative genes, CTNNA1 and CYP4V2, previously reported to cause butterfly-shaped pigment dystrophy (BSPD) and Bietti's crystalline dystrophy (BCD), respectively, were detected in two other patients. These two patients developed rapid and severe visual loss in contrast to BSPD and BCD patients in previous studies. The results of this study demonstrate that causative variants identified in the CTNNA1 and CYP4V2 genes are also associated with LCA.
Conclusions: This is the first report describing the molecular genetics and clinical manifestations of Thai patients with LCA. The present study expands the spectrum of LCA-associated genes, which is a benefit for molecular diagnosis. The identification of mutations in the CTNNA1 and CYP4V2 genes requires further elucidation in larger cohorts with LCA.

PMID: 28453600 [PubMed - indexed for MEDLINE]

Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein.

World J Gastroenterol. 2016 Dec 28;22(48):10680-10686

Authors: Ghiringhelli F, Richard C, Chevrier S, Végran F, Boidot R

Abstract
Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase (PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients (Check2 for the first patient and RAD51C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.

PMID: 28082821 [PubMed - indexed for MEDLINE]

Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System.

Drug Saf. 2017 Jun 05;:

Authors: Cutroneo PM, Giardina C, Ientile V, Potenza S, Sottosanti L, Ferrajolo C, Trombetta CJ, Trifirò G

Abstract
INTRODUCTION: Anti-vascular endothelial growth factor (anti-VEGF) drugs are widely used for the treatment of several cancers and retinal diseases. The systemic use of anti-VEGF drugs has been associated with an increased risk of serious adverse reactions. Whether this risk is also related to intravitreal administration of anti-VEGF drugs is unclear.
OBJECTIVE: The aim of this study was to provide an overview of the safety of anti-VEGF drugs in oncology and ophthalmology settings using the Italian Spontaneous Reporting System (SRS).
METHODS: We selected all suspected adverse drug reaction (ADR) reports attributed to anti-VEGF drugs and conducted descriptive frequency analyses stratified by indication of use. As a measure of disproportionality, we calculated the proportional reporting ratio with 95% confidence intervals at the level of standardized Medical Dictionary for Regulatory Activities (MedDRA(®)) queries (SMQs).
RESULTS: Of a total of 2472 anti-VEGF drug-related reports, 2173 (87.9%) and 299 (12.1%) were attributed to systemic and intravitreal use of these drugs, respectively. The frequency of serious ADRs reported was higher for intravitreal administration of anti-VEGF drugs than for systemic use in patients with cancer (58.9 vs. 34.1%) (p < 0.001) and were disproportionally associated with ischemic heart disease and thromboembolic and cerebrovascular events. Most serious ADRs related to anti-VEGF drugs in patients with cancer are known and clinically relevant (e.g., gastrointestinal and vascular disorders).
CONCLUSIONS: This study documented that serious ADRs and systemic toxicity may occur not only with systemic use of anti-VEGF drugs in patients with cancer but also with intravitreal administration. Close monitoring of cardio/cerebrovascular adverse events should be considered during treatment with all anti-VEGF drugs.

PMID: 28585152 [PubMed - as supplied by publisher]

[Use of pharmacogenetic testing to prevent adverse drug reactions during statin therapy].

Ter Arkh. 2017;89(1):82-88

Authors: Rumyantsev NA, Kukes VG, Kazakov RE, Rumyantsev AA, Sychev DA

Abstract
The number of patients receiving statins increases every year and due to the fact that they should take statins during their lives, the problem of their safety use comes to the forefront. The paper analyzes the safety of using the medications of this group and discusses the diagnosis of myopathies induced by statins and the occurrence of immune-mediated statin myopathies. It considers a personalized approach to prescribing statins, analyzes Russian and foreign experience in using pharmacogenetics to reduce the risk of myopathies, publishes the results of the authors' experience in clinically introducing pharmacogenetic testing at hospitals, and analyzes the long-term results of determining the polymorphism of the SLCO1B1 gene for the prediction of the risk of adverse events when using statins and estimating patient compliance to prescribed treatment.

PMID: 28252633 [PubMed - indexed for MEDLINE]

Stemming the Rising Tide of Drug Burden.

Consult Pharm. 2016 Nov 01;31(11):612

Authors: Edward Davidson H

PMID: 28107117 [PubMed - indexed for MEDLINE]