Pharmacogenomics in Lebanon: current status, challenges and opportunities.

Pharmacogenomics (PGx) research and applications are of utmost relevance in Lebanon considering its population genetic diversity. Moreover, as a country with regional leadership in medicine and higher education, Lebanon holds a strong potential in contributing to PGx research and clinical implementation. In this manuscript, we first review and evaluate the available PGx research conducted in Lebanon, then describe the current status of PGx practice in Lebanon while reflecting on the local and regional challenges, and highlighting areas for action, and opportunities to move forward. We specifically expand on the status of PGx at the American University of Beirut Faculty of Medicine and Medical Center as a case study and guide for the further development of local and regional comprehensive PGx research, teaching, and clinical implementation programs. We also delve into the status of PGx knowledge and education, and prospects for further advancement such as with online courses and certificates.

Patterns and predictors of positive multiplex polymerase chain reaction respiratory panel among patients with acute respiratory infections in a single center in Lebanon.

BACKGROUND: Infectious agents associated with community-acquired acute respiratory infections (ARIs) remain understudied in Lebanon. We aim to assess the microbiological profiles of ARIs by employing polymerase chain reaction (PCR) and identifying predictors of positive PCR results among patients admitted for ARI. METHODS AND RESULTS: We conducted a retrospective single-center study at the American University of Beirut Medical Center, including all respiratory PCR panels performed on pediatric (< 18) and adult (≥ 18) patients presenting with an ARI from January 2015 to March 2018, prior to the onset of the COVID-19 pandemic. We aimed to identify the epidemiological patterns of ARIs and the factors associated with positive PCRs in both adult and pediatric patients. Among 281 respiratory PCRs, 168 (59.7%) were positive for at least one pathogen, with 54.1% positive PCR for viruses, 7.8% for bacteria species, and 3.9% with virus-bacteria codetection. Almost 60% of the patients received antibiotics prior to PCR testing. PCR panels yielded more positive results in pediatric patients than in adults (P = 0.005). Bacterial detection was more common in adults compared to pediatrics (P < 0.001). The most common organism recovered in the entire population was Human Rhinovirus (RhV) (18.5%). Patients with pleural effusion on chest CT were less likely to have a positive PCR (95% Cl: 0.22-0.99). On multivariate analysis, pediatric age group (P < 0.001), stem cell transplant (P = 0.006), fever (P = 0.03) and UTRI symptoms (P = 0.004) were all predictive of a positive viral PCR. CONCLUSION: Understanding the local epidemiology of ARI is crucial for proper antimicrobial stewardship. The identification of factors associated with positive respiratory PCR enhances our understanding of clinical characteristics and potential predictors of viral detection in our population.

Using comprehensive genomic and functional analyses for resolving genotype-phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study.

Constitutional mismatch repair deficiency (CMMRD) is an aggressive and highly penetrant cancer predisposition syndrome. Because of its variable clinical presentation and phenotypical overlap with neurofibromatosis, timely diagnosis remains challenging, especially in countries with limited resources. Since current tests are either difficult to implement or interpret or both we used a novel and relatively inexpensive functional genomic assay (LOGIC) which has been recently reported to have high sensitivity and specificity in diagnosing CMMRD. Here we report the clinical and molecular characteristics of nine patients diagnosed with cancer and suspected to have CMMRD and highlight the challenges with variant interpretation and immunohistochemical analysis that led to an uncertain interpretation of genetic findings in 6 of the 9 patients. Using LOGIC, we were able to confirm the diagnosis of CMMRD in 7 and likely exclude it in 2 patients, resolving ambiguous result interpretation. LOGIC also enabled predictive testing of asymptomatic siblings for early diagnosis and implementation of surveillance. This study highlights the varied manifestations and practical limitations of current diagnostic criteria for CMMRD, and the importance of international collaboration for implementing robust and low-cost functional assays for resolving diagnostic challenges.

The Impact of an Educational Video in Arabic Language on Patients' Knowledge and Attitudes Towards Genetic Testing for Cancer Therapy.

Rapid advances in cancer genetics are paving the way towards personalized cancer management, and genetic testing is now an important decision-making tool. Despite the advantages, genetic testing adds a layer of complexity in the management which is difficult to communicate with patients. The variability health literacy among patients may restrict their engagement in genetic procedures. Improving the language and presentation of genomic concepts can influence patients' risk assessment and willingness to undergo testing. The study aimed to compare the knowledge and attitudes of cancer patients presenting to oncology clinics at The American University of Beirut Medical Center before and after watching a short educational video that clarifies the concepts of genetic mutations, genetic testing technique, and its purposes.Twenty-nine adult patients presenting to the oncology clinics and due to receive somatic or germline genetic testing filled a questionnaire which assesses their knowledge and attitudes before and after the educational video was played. The majority of patients had poor baseline knowledge before the intervention. After watching the video, the percentage of patients with poor knowledge decreased to a minimum of 3.4% and a maximum of 39% for each concept. Mean score for attitude questions also increased significantly. Effective patient education and counseling programs in the patients' native language prior to genetic testing can increase knowledge, decrease hesitancy, and improve clinical decision making. A short educational video is an example of a simple intervention towards an inclusive approach in patient care all over the world.

Heritable cancer predisposition testing in pediatric cancer patients excluding retinoblastoma in a middle-income country.

Resource-limited settings often have financial barriers to genetic testing for heritable cancer. This retrospective study investigated the pattern of heritable cancer predisposition testing in a middle-income country over the period 2014-2021, excluding retinoblastoma. After establishing a specific fund in 2019, rate of tests increased from 1.1% to 10.9% of new diagnoses. Most common testing was for constitutional mismatch repair deficiency (CMMRD), rhabdoid predisposition syndrome, TP53 (tumor protein 53) mutation, and hereditary cancer panel. Of 33 patients, 13 (39%) tested positive, 12 (36%) negative, and eight (24%) had variants of unknown significance. Positivity rate was 43% for a clinical phenotype and 44% for a tumor type indication.

PD-L1 expression in sebaceous carcinomas.

BACKGROUND: Traditional systemic treatments for unresectable, recurrent, and/or advanced sebaceous carcinoma (SC) are ineffective. Tumoral immune microenvironment characterization is essential for considering immune checkpoint inhibitors as a treatment option. METHODS: A total of 173 resected SCs were reviewed. Clinical information, lesion size, and location were collected. Microscopic examination documented histopathologic features and expression of immunohistochemical markers PD-L1 and CD8. PD-L1 percentage was assessed amongst tumor (PD-L1 + Tu) and immune infiltrating cells (PD-L1 + Inf). Each case was attributed a combined positive score (CPS) following Head and Neck squamous cell carcinoma recommendations. PD-L1 expression was evaluated according to clinicopathologic parameters. Human Papilloma Virus presence (HPV) was analyzed using PCR microarray scanning. RESULTS: A therapeutically relevant CPS was seen in 51.4% of cases. Higher PD-L1 + Tu, PD-L1 + Inf, and CPSs were positively associated with greater lesion size and an extraocular location. No association was seen with patient age or gender. 9.2% of SCs showed PD-L1 + Tu ≥ 1, while 52.0% showed PD-L1 + Inf ≥ 1. A higher CD8 + T-lymphocyte density was significantly associated with a higher CPS, PD-L1 + Tu, and PD-L1 + Inf. Tumor-associated T-cell infiltrate's density was higher along tumor periphery. HPV-16, HPV-43, HPV-52, and HPV-66 were detected in 8.4% of SCs. There was no significant association between HPV status, PD-L1 expression, and CPS. A significant number of SCs express PD-L1 at therapeutic levels. Nevertheless, PD-L1 expression shows a higher intertumoral heterogeneity, in extraocular than in biologically distinct periocular cases. CONCLUSION: Our data support the need for large-scale prospective studies evaluating anti-PD-L1 immunotherapy mainly in extraocular SC treatment.

Use of Chest Imaging in the Diagnosis and Management of COVID-19: A WHO Rapid Advice Guide.

The World Health Organization (WHO) undertook the development of a rapid guide on the use of chest imaging in the diagnosis and management of coronavirus disease 2019 (COVID-19). The rapid guide was developed over 2 months by using standard WHO processes, except for the use of "rapid reviews" and online meetings of the panel. The evidence review was supplemented by a survey of stakeholders regarding their views on the acceptability, feasibility, impact on equity, and resource use of the relevant chest imaging modalities (chest radiography, chest CT, and lung US). The guideline development group had broad expertise and country representation. The rapid guide includes three diagnosis recommendations and four management recommendations. The recommendations cover patients with confirmed or who are suspected of having COVID-19 with different levels of disease severity, throughout the care pathway from outpatient facility or hospital entry to home discharge. All recommendations are conditional and are based on low certainty evidence (n = 2), very low certainty evidence (n = 2), or expert opinion (n = 3). The remarks accompanying the recommendations suggest which patients are likely to benefit from chest imaging and what factors should be considered when choosing the specific imaging modality. The guidance offers considerations about implementation, monitoring, and evaluation, and also identifies research needs. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Treatment-induced cerebral sinus venous thrombosis in childhood acute lymphoblastic malignancies: New risk factors to consider.

BACKGROUND: Cerebral sinus venous thrombosis (CSVT) is one of the many side effects encountered during acute lymphoblastic leukemia (ALL) therapy. Due to the rarity of cases, lack of data, and consensus management, no recommendations exist to target the population at risk. METHODS: This is a retrospective chart review of 229 consecutive patients diagnosed with ALL with an age range of 1-21 years, treated at the Children's Cancer Center of Lebanon between October 2007 and February 2018. RESULTS: The incidence of CSVT was 10.5%. Using univariate analysis, increased risk of CSVT was observed with male gender, age >10 years, T-cell immunophenotype, intermediate/high-risk disease, maximum triglyceride (TG) level of >615 mg/dl, presence of mediastinal mass, and larger body surface area (BSA). With multivariate analysis, the only statistically significant risk factors were maximum TG level, BSA, presence of mediastinal mass, and risk stratification (intermediate/high risk). CONCLUSION: Our study was able to unveil TG level of >615 mg/dl, mediastinal mass, and a larger BSA as novel risk factors that have not been previously discussed in the literature.

The burden of laboratory-confirmed influenza infection in Lebanon between 2008 and 2016: a single tertiary care center experience.

BACKGROUND: Influenza is a major cause of morbidity and mortality worldwide. Following the 2009 pandemic, there was widened interest in studying influenza burden in all regions. However, since data from the World Health Organization (WHO) Middle East and North Africa (MENA) region remain limited, we aimed to contribute to the understanding of influenza burden in Lebanon. METHODS: A retrospective chart review extending over a period of 8 seasons from Jan 1st, 2008 till June 30th, 2016 at a tertiary care center in Beirut was performed. All cases confirmed to have influenza based on rapid antigen detection or/and polymerase chain reaction on a respiratory sample were included for analysis. Data on epidemiology, clinical presentation, complications, antiviral use and mortality were collected for analysis. RESULTS: A total of 1829 cases of laboratory-confirmed influenza were identified. Average annual positivity rate was 14% (positive tests over total requested). Both influenza A and B co-circulated in each season with predominance of influenza A. Influenza virus started circulating in December and peaked in January and February. The age group of 19-50 years accounted for the largest proportion of cases (22.5%) followed by the age group of 5-19 years (18%). Pneumonia was the most common complication reported in 33% of cases. Mortality reached 3.8%. The two extremes of age (< 2 years and ≥ 65 years) were associated with a more severe course of disease, hospitalization, intensive care unit (ICU) admission, complications, and mortality rate. Of all the identified cases, 26% were hospitalized. Moderate-to-severe disease was more likely in influenza B cases but no difference in mortality was reported between the two types. Antivirals were prescribed in 68.8% and antibiotics in 41% of cases. There seemed to be an increasing trend in the number of diagnosed and hospitalized cases over the years of the study. CONCLUSION: Patients with laboratory-confirmed influenza at our center had a high rate of hospitalization and mortality. A population based prospective surveillance study is needed to better estimate the burden of Influenza in Lebanon that would help formulate a policy on influenza control.

Inflammatory bowel disease: between genetics and microbiota.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease that can involve any part of the gastrointestinal tract. It includes two main disorders: Crohn's disease (CD) and Ulcerative colitis (UC). CD and UC often share a similar clinical presentation; however, they affect distinct parts of the GI Tract with a different gut wall inflammatory extent. Ultimately, IBD seems to emanate from an uncontrollably continuous inflammatory process arising against the intestinal microbiome in a genetically susceptible individual. It is a multifactorial disease stemming from the impact of both environmental and genetic components on the intestinal microbiome. Furthermore, IBD genetics has gained a lot of attention. Around 200 loci were identified as imparting an increased risk for IBD. Few of them were heavily investigated and determined as highly linked to IBD. These genes, as discussed below, include NOD2, ATG16L1, IRGM, LRRK2, PTPN2, IL23R, Il10, Il10RA, Il10RB, CDH1 and HNF4α among others. Consequently, the incorporation of a genetic panel covering these key genes would markedly enhance the diagnosis and evaluation of IBD.

Primary vulvar Ewing sarcoma/peripheral primitive neuroectodermal tumor with pelvic lymph nodes metastasis: A case report and review of literature.

Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumors (pPNET) are soft tissue tumors that generally affect the bones. Extraosseous ES/pPNET has been rarely reported. Our patient presented with a 6 × 4 cm right subcutaneous solid vulvar lesion causing pain and discomfort. Pathology and immunohistochemistry staining showed strong positivity for CD99 and vimentin, favoring the diagnosis of ES/pPNET. Magnetic resonance imaging showed a 6-cm lesion in the right vulvar region with enlarged bilateral inguinal and right iliac lymph nodes. Fluorescence in situ hybridization test for translocation t(11;22)(q24;q12) was positive, confirming the diagnosis. The patient received three cycles of neoadjuvant chemotherapy with vincristine, adriamycin, cyclophosphamide alternating with ifosfamide and etoposide with complete response. The patient underwent vulvar radical local excision. Residual tumor measured 1.6 cm with free margins. She received four additional cycles of adjuvant chemotherapy and 30 sessions radiotherapy. She is currently disease free after 37 months. No ES/pPNET cases with pelvic lymph nodes metastasis were ever reported.

Myocardial regeneration: role of epicardium and implicated genes.

Lower invertebrates' hearts such as those of zebrafish have the capacity for scarless myocardial regeneration which is lost by mammalian hearts as they form a fibrotic scar tissue instead of regenerating the injured area. However, neonatal mammalian hearts have a remarkable capacity for regeneration highlighting conserved evolutionary mechanisms underlying such a process. Studies investigated the underlying mechanism of myocardial regeneration in species capable to do so, to see its applicability on mammals. The epicardium, the mesothelial outer layer of the vertebrate heart, has proven to play an important role in the process of repair and regeneration. It serves as an important source of smooth muscle cells, cardiac fibroblasts, endothelial cells, stem cells, and signaling molecules that are involved in this process. Here we review the role of the epicardium in myocardial regeneration focusing on the different involved; Activation, epithelial to mesenchymal transition, and differentiation. In addition, we will discuss its contributory role to different aspects that support myocardial regeneration. Of these we will discuss angiogenesis and the formation of a regenerate extracellular matrix. Moreover, we will discuss several factors that act on the epicardium to affect regeneration. Finally, we will highlight the utility of the epicardium as a mode of cell therapy in the treatment of myocardial injury.

Molecular profiling of adult acute myeloid and lymphoid leukemia in a major referral center in Lebanon: a 10-year experience report and review of the literature.

Recurrent genetic abnormalities confer distinct morphologic features and play a role in determining the clinical behavior, prognosis and adequate treatment of acute leukemia. In the MENA region, only one study targets the frequency of genetic modifications in AML, reporting a higher occurrence of acute promyelocytic leukemia in Lebanon. Determining the frequency of translocations and gene mutations in acute myeloid and lymphoid leukemia cases in an adult patients' population in Lebanon and comparing the resultant genetic profile with the published international molecular profile of adult acute leukemia. Laboratory results of adult patients diagnosed with AML or ALL presenting to AUBMC for genetic profiling between years 2006 until June 2016 were reviewed. Genetic profiling of AML cases in our CAP accredited molecular diagnostics laboratory consists of a validated lab developed RT-PCR for the detection of RUNX1/RUNX1T1, CBFB/MYH11, KMT2A/MLLT3, PML-RARA, and BCR-ABL and mutations in the FLT3 receptor, NPM1, c-kit and CEPBA genes. The ALL panel tests for the presence of BCR-ABL1, ETV6/RUNX1; KMT2A/AFF1, and TCF3-PBX1. We reviewed 580 AML and 175 ALL cases. In the AML cohort, the M:F ratio was 1.3:1 with a mean age of 50 years. t(15;17) was present in 7.6%, t(8;21) in 4.2%, inv(16) in 3.7%, t(9;22) in 2.2% and t(9;11) in 1.7% of cases. FLT3 mutation (ITD or TKD) was present in 25.2% of all cases and 30.1% of Cytogenetics-normal (CN) patients. Mutations of the NPM1 gene was present in 31.4% of AML cases and in 43.8% of CN patients. Double positive (NPM1+/FLT3+) cases accounted for 20% of NK patients. CEBPA and c-kit mutations were detected in 7.3% and 2.4% respectively. In the ALL cohort, the mean age was 37 years. B- and T-lymphoblastic leukemia constituted 84.6% and 15.4% of ALL cases and the M:F ratio was 1.2:1 and 2.86:1 respectively. B-ALL patients were positive for t(9;22) in 14.2%, t(4;11) in 5.4%, t(1;19) in 2.7% and t(12;21) in 1.4%. T-ALL patients were negative for translocations found in our ALL panel. A lower mean age was found in our adult leukemic Lebanese population as compared to the Western cases. Other interesting findings were the lower percentage of inv(16), lower incidence of TCF3-PBX1, and the mild increase in Philadelphia positivity in our AML cohort. In our ALL cohort, t(9;22) positivity was less than expected for adult lymphoblastic leukemia. Full molecular profiling by next generation sequencing is required for further classification of cases into prognostic categories. This study will be a baseline reference for future research and epidemiological data useful for transplant centers and oncologists both in Lebanon and the region.

Prevalence of T790M mutation among TKI-therapy resistant Lebanese lung cancer patients based on liquid biopsy analysis: a first report from a major tertiary care center.

Lung adenocarcinoma patients have variable prognosis due to many factors. Detection of epidermal growth factor receptor (EGFR) activating mutations is one of the factors that implies the need for initiating a first-line EGFR tyrosine kinase inhibitor (TKI) treatment. However, T790M resistance mutation emergence during treatment accounts for most EGFR-TKI drug resistance. The traditional sample taken for T790M mutation analysis is tissue biopsy, but its numerous disadvantages have introduced liquid biopsy as a preferred method for testing. We studied the prevalence of T790M mutation among pulmonary adenocarcinoma patients in Lebanese patients based on liquid biopsy testing the circulating tumor DNA (ctDNA). We have reviewed the laboratory charts of 52 patients who developed resistance on treatment and referred to AUBMC for EGFR T790M Liquid Biopsy to analyze the mutational analysis results for EGFR T790M. In total, 82.6% of the tested lung cancer patients were positive for a specific EGFR mutation. Among these patients, a total 26.9% were positive for T790M, which is comparable to the international prevalence of this mutation. However, for those cases who developed resistance with circulating DNA showing an EGFR mutation, 50% were positive for T790M that is also comparable to the international literature. This is the first report from Lebanon to discuss the prevalence of T790M mutation using liquid biopsy among Lebanese population. An important landmark molecular epidemiology study that will be a reference to all oncologists in Lebanon and the region in assessing the potential for targeted therapy options in the country. In addition, the data will be of an asset to the building international literature related to this disease.

Molecular characterization, toxin detection and resistance testing of human clinical Clostridium difficile isolates from Lebanon.

Clostridium (Clostridioides) difficile is the main cause for nosocomial diarrhoea in industrialised nations. Epidemiologic data on the pathogen's occurrence in other world regions are still scarce. In this context we characterized with phenotypic and molecular genetic methods C. difficile isolates stemming from hospitalised patients with diarrhoea in Lebanon. From 129 stool samples of symptomatic patients at a tertiary care University hospital in Lebanon, a total of 107 C. difficile strains were cultivated and underwent ribotyping, toxin gene detection and antibiotic resistance testing. Ribotype 014 (RT014, 16.8%) predominated, followed by RT002 (9.3%), RT106 (8.4%) and RT070 (6.5%). Binary toxin gene-positive isolates (RT023, RT078 and RT126) were rarely detected and RT027 was absent. Interestingly, within one isolate only the toxin A gene (tcdA) was detected. Multiple-locus variable-number tandem repeat analysis (MLVA) revealed strong strain diversity in most RTs. The isolates were sensitive to metronidazole and vancomycin, and only a small proportion of strains displayed resistance against moxifloxacin, rifampicin, and clarithromycin (5.6%, 1.9%, and 2.8%), respectively. The data indicate that the genetic strain composition of Lebanese strains differs markedly from the situation seen in Europe and North America. Especially the epidemic RTs seen in the latter regions were almost absent in Lebanon. Interestingly, most strains showed almost no resistance to commonly used antibiotics that are suspected to play a major role in the development of C. difficile infection, despite frequent use of these antibiotics in Lebanon. Thus, the role of antimicrobial resistance as a major driving force for infection development remains uncertain in this area.

The association between cardiovascular disease gene mutations and recurrent pregnancy loss in the Lebanese population.

Recurrent pregnancy loss (RPL) is a problem affecting up to 5% of women of childbearing age due to many factors. Studies have shown that RPL and cardiovascular disease (CVD) may have shared risk factors. We compared the prevalence of 12 cardiovascular disease related gene mutations in patients with a history of RPL to normal controls in a major tertiary care center in Lebanon. The CVD StripAssay (ViennaLab, Austria) was used to analyze the CVD genes on 70 women with RPL history as part of the initial routine workup for recurrent miscarriage at the American University of Beirut Medical Center. The obtained results were compared with data of controls from the Lebanese population using Fisher's exact test and Chi square analysis. Two genes of the CVD panel demonstrated a strong relationship with RPL, including, MTHFR (C677T homozygosity, A1298C homozygosity, and compound heterozygosity for C677T and A1298C) and Factor II (heterozygosity for G20210A). Moreover, a protective role of positive APO-E3 isoform was observed. This study is the first in the Lebanese population in associating RPL with a large panel of CVD related genes.

Primary synovial sarcoma of the kidney: a case report of complete pathological response at a Lebanese tertiary care center.

BACKGROUND: Primary synovial sarcoma of the kidney is a rare type of soft tissue sarcoma. Its presenting features can resemble those of other renal tumors; rendering its early diagnosis, a dilemma. Several cases of renal synovial sarcoma have been reported in the literature with varying treatment options and outcomes. This article describes a rare case of primary renal synovial sarcoma and reviews all cases in the literature. CASE PRESENTATION: A 26-year-old male presented with flank pain and hematuria. Initially diagnosed with Wilm's tumor, revision of pathology and histology, along with the immunohistochemical profile, confirmed, nevertheless, the diagnosis of primary monophasic synovial sarcoma of the kidney with the SYT-SSX2 fusion transcript. Follow-up, post nephrectomy, revealed recurrence within the lungs and at the surgical bed. Surgical resection followed by adjuvant chemotherapy regimen constituting of Doxorubicin and Ifosfamide, achieved complete pathological response. CONCLUSION: In this case report, we emphasize the need for accurate diagnosis and prompt treatment. We propose multimodality treatment approach including surgery along with anthracycline-based chemotherapy to induce complete remission.

SLC35B4, an Inhibitor of Gluconeogenesis, Responds to Glucose Stimulation and Downregulates Hsp60 among Other Proteins in HepG2 Liver Cell Lines.

SLC35B4, solute receptor for UDP-N-acetylglucosamine and UDP-xylose, is associated with diabetes and predisposing conditions. This study investigated the localization of SLC35B4 and compared the differential expression between a knockdown of SLC35B4 and controls in HepG2. Responsiveness to glucose, expression, and localization were assayed using Western blot and immunostaining. Localization was confirmed using a proximity ligation assay. Two-dimensional (2D) gel electrophoresis and MALDI-TOF were used to identify differentially expressed proteins and pathway analysis was performed. SLC35B4 was increased by 60% upon glucose stimulation and localized in Golgi apparatus and endoplasmic reticulum. Presence of SLC35B4 in the Golgi apparatus suggests its involvement in the biosynthesis of glycoconjugate proteins. Four proteins were markedly under-expressed (Hsp60, HspA8, TUBA1A, and ENO1) and linked to the pathogenesis of diabetes or post-translationally modified by O-GlcNAc. Glucose levels activate SLC35B4 expression. This triggers a downstream effect via Hsp60 and other proteins. We hypothesize that the downstream effect on the proteins is mediated via altering the glycosylation pattern inside liver cells. The downstream cascade ultimately alters the ability of cultured liver cells to inhibit endogenous glucose production, and this could play a role in the association of the above-listed genes with the pathogenesis of diabetes.

NUDT15 and TPMT genetic polymorphisms are related to 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon.

BACKGROUND: Interindividual variability in thiopurine-related toxicity could not be completely explained by thiopurine S-methyltransferase (TPMT) polymorphisms, as a number of patients who are homozygous wild type or normal for TPMT still develop toxicity that necessitates 6-mercaptopurine (MP) dose reduction or protocol interruption. Recently, few studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T low-function variant that is associated with decreased thiopurine metabolism and leukopenia in childhood acute lymphoblastic leukemia (ALL) and other diseases. PROCEDURES: The aim of this study is to measure the frequency of TPMT and NUDT15 polymorphisms and assess whether they are predictors of MP intolerance in children treated for ALL. One hundred thirty-seven patients with ALL of whom 121 were Lebanese were evaluated. MP dose intensity was calculated as the ratio of the tolerated MP dose to planned dose during continuation phase to maintain an absolute neutrophil count (ANC) dose above 300 per µl. RESULTS: One patient was NUDT15 heterozygous TC and tolerated only 33.33% of the planned MP dose, which was statistically significantly different from the median-tolerated MP dose intensity of the rest of the cohort (76.00%). Three patients had the TPMT*3A haplotype and tolerated 40.00-66.66% of the planned MP dose, which was also statistically significantly different from the rest of the cohort. CONCLUSIONS: This is the first report on the association of TPMT and NUDT15 polymorphisms with MP dose intolerance in Arab patients with ALL. Genotyping for additional polymorphisms may be warranted for potential gene/allele-dose effect.

Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha.

Imatinib is the standard of care in chronic meloid leukemia (CML) therapy. However, imatinib is not curative since most patients who discontinue therapy relapse indicating that leukemia initiating cells (LIC) are resistant. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. Arsenic trioxide was suggested to decrease CML LIC. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction/transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Finally, in vivo, combined interferon and arsenic treatment, but not single agents, prolonged the survival of primary CML mice. Importantly, the combination severely impaired engraftment into untreated secondary recipients, with some recipients never developing the disease, demonstrating a dramatic decrease in CML LIC activity. Arsenic/IFN effect on CML LIC activity was significantly superior to that of imatinib. These results support further exploration of this combination, alone or with imatinib aiming at achieving CML eradication rather than long-term disease control.