We investigated the association of genetic polymorphisms in drug metabolizing enzymes (DMEs) and transporters in patients with docetaxel-induced febrile neutropenia, by a new high-throughput DMEs and transporters (DMETPlus) microarray platform, characterizing 1936 single nucleotide polymorphisms (SNPs) in 225 genes. We recruited 100 Lebanese breast cancer patients from a consecutive cohort of 277 patients who received docetaxel either alone, or in combination with trastuzumab. Out of 100 patients, 18 had developed febrile neutropenia (cases). They were age- and treatment- matched with 18 patients who did not develop febrile neutropenia on docetaxel (controls). We found that 12 SNPs in seven genes (ABCC6, ABCG1, ABCG2, CYP1A2, CYP2D6, FMO2, and FMO3) were significantly associated with febrile neutropenia after docetaxel treatment. Many of these SNPs have not been previously reported to be associated with toxicity due to docetaxel treatment. Interestingly, one SNP in the FMO3 gene (rs909530) was significantly associated with three clinical endpoints: febrile neutropenia, reduced absolute neutrophil count, and hemoglobin reduction. To the best of our knowledge, this is the first study that evaluated the effect of a large array of nearly 2000 polymorphisms in DMEs and transporters on docetaxel toxicity in breast cancer patients, and in a previously understudied population. Additionally, it attests to the feasibility of genomics research in low- and middle-income countries (LMICs). In light of the current global epidemic of noncommunicable diseases (NCDs) such as breast cancer impacting LMICs, we suggest pharmacogenomics is considered as an integral part of the global health research agenda for NCDs and personalized therapeutics.

This study showed a difference in 25(OH)D levels between CYP2R1 genotypes that equates a daily supplementation of 400-800 IU vitamin D, depending on genotype. It underscores possible important genetic contributions for the high prevalence of hypovitaminosis D in the Middle East.

Background: Bisphenol A (BPA), an estrogen-like endocrine disruptor used in plastics, has been associated with development and promotion of breast cancer, so plastic manufacturers shifted towards less-studied analogs, BPF and BPS. Studying the associated DNA methylome-wide mechanisms of these derivatives is timely, particularly in comparison with BPA. Methods: We assessed proliferation, cell cycle, and migration of breast cancer cells (estrogen receptor (ER)-positive: MCF-7 and ER-negative: MDA-MB-231) treated with BPF and BPS ± estrogen receptor inhibitor (ERI) in comparison to BPA ± ERI. RNA expression and activity of DNA (de)methylation enzymes and LINE-1 methylation were quantified. DNA methylome-wide analysis was evaluated in bisphenol-exposed cells and compared to clinical breast cancer data. Results: The three bisphenols caused ER-dependent increased proliferation and migration of MCF-7 but not MDA-MB-231 cells, with BPS being 10 times less potent than BPA and BPF. Although they have similar chemical structures, the three bisphenols induced differential DNA methylation alterations at several genomic clusters of or single CpG sites, with the majority of these being ER-dependent. At equipotent doses, BPA had the strongest effect on the methylome, followed by BPS then BPF. No pathways were enriched for BPF while BPA-and BPS-induced methylome alterations were enriched in focal adhesion, cGMP-PKG, and cancer pathways, which were also dysregulated in methylome-wide alterations comparing ER-positive breast cancer samples to adjacent normal tissues. Conclusions: The three bisphenols have important epigenetic effects in breast cell lines, with those of BPA and BPS overlapping with cancer-related pathways in clinical breast cancer models. Hence, further investigation of their safety is warranted.

A brain abscess is defined as a focal intracerebral infection consisting of an encapsulated collection of pus, which can be a life-threatening complication of infections, trauma, or surgery. While immunocompromised patients can have a wide array of causative organisms, bacterial species represent the most common etiology in immunocompetent individuals. The incidence of brain abscesses ranges from 0.4 to 0.9 per 100,000, with a high predisposition among immunocompromised patients and in those with disruption of the blood-brain barrier.The most common causative organisms found were Streptococcus species, particularly S. viridians and S. pneumonia, Enterococcus, and Staphylococcus species, mainly S. aurieus and S. epidermidis. Microorganism can invade the brain through different mechanisms, either directly by contiguous spread and odontogenic infections, which usually cause a single brain abscess, or indirectly through hematogenous spread which can cause multiple brain abscesses. Both surgical and conservative dental procedures contribute to hematogenous spreading of oral microorganisms. Although most of those organisms are eliminated shortly after they gain access to the bloodstream, some can persist and contribute to the pathogenesis of abscesses in the appropriate environment. Odontogenic origins are rarely implicated in the formation of brain abscesses, and oral foci comprise approximately 5% of identified cases. We report a case of brain and diverticular abscesses due to S. intermidius occurring two months after dental extraction. This case highlights the fact that even usual dental workup can result in the development of bacteremia and disseminated abscesses including but not restricted to the brain. Consequently, in addition to identifying the possible source of bacteremia with an extensive history and physical exam, the diagnosis of Streptococcus milleri organisms should prompt the physicians to screen for sites of possible metastatic infection spread.

Ultraviolet radiation (UV) is causally linked to cutaneous melanoma, yet the underlying epigenetic mechanisms, known as molecular sensors of exposure, have not been characterized in clinical biospecimens. Here, we integrate clinical, epigenome (DNA methylome), genome and transcriptome profiling of 112 cutaneous melanoma from two multi-ethnic cohorts. We identify UV-related alterations in regulatory regions and immunological pathways, with multi-OMICs cancer driver potential affecting patient survival. TAPBP, the top gene, is critically involved in immune function and encompasses several UV-altered methylation sites that were validated by targeted sequencing, providing cost-effective opportunities for clinical application. The DNA methylome also reveals non UV-related aberrations underlying pathological differences between the cutaneous and 17 acral melanomas. Unsupervised epigenomic mapping demonstrated that non UV-mutant cutaneous melanoma more closely resembles acral rather than UV-exposed cutaneous melanoma, with the latter showing better patient prognosis than the other two forms. These gene-environment interactions reveal translationally impactful mechanisms in melanomagenesis.