Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies.

Venetoclax is the first example of personalized medicine for multiple myeloma (MM), with meaningful clinical activity as a monotherapy and in combination in myeloma patients harboring the t(11:14) translocation. However, despite the high response rates and prolonged PFS, a significant proportion of patients eventually relapse. Here, we aimed to study adaptive molecular responses after the acquisition of venetoclax resistance in sensitive t(11:14) MM cell models. We therefore generated single-cell venetoclax-resistant t(11:14) MM cell lines and investigated the mechanisms contributing to resistance as well as the cells' sensitivity to other treatments. Our data suggests that acquired resistance to venetoclax is characterized by reduced mitochondrial priming and changes in BCL-2 family proteins' expression in MM cells, conferring broad resistance to standard-of-care anti-myeloma drugs. However, our results show that the resistant cells are still sensitive to immunotherapeutic treatments, highlighting the need to consider appropriate sequencing of these treatments following venetoclax-based regimens.

High-dose melphalan treatment significantly increases mutational burden at relapse in multiple myeloma.

High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.

A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth.

Long noncoding RNAs (lncRNAs) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell-growth dependency to lncRNA genes in multiple myeloma (MM) and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that an MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell-growth dependency acting in a microRNA- and DROSHA-independent manner. Lnc-17-92 provides a chromatin scaffold for the functional interaction between c-MYC and WDR82, thus promoting the expression of ACACA, which encodes the rate-limiting enzyme of de novo lipogenesis acetyl-coA carboxylase 1. Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent antitumor effects both in vitro and in vivo in 3 preclinical animal models, including a clinically relevant patient-derived xenograft NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.

In-depth analysis of alternative splicing landscape in multiple myeloma and potential role of dysregulated splicing factors.

Splicing changes are common in cancer and are associated with dysregulated splicing factors. Here, we analyzed RNA-seq data from 323 newly diagnosed multiple myeloma (MM) patients and described the alternative splicing (AS) landscape. We observed a large number of splicing pattern changes in MM cells compared to normal plasma cells (NPC). The most common events were alterations of mutually exclusive exons and exon skipping. Most of these events were observed in the absence of overall changes in gene expression and often impacted the coding potential of the alternatively spliced genes. To understand the molecular mechanisms driving frequent aberrant AS, we investigated 115 splicing factors (SFs) and associated them with the AS events in MM. We observed that ~40% of SFs were dysregulated in MM cells compared to NPC and found a significant enrichment of SRSF1, SRSF9, and PCB1 binding motifs around AS events. Importantly, SRSF1 overexpression was linked with shorter survival in two independent MM datasets and was correlated with the number of AS events, impacting tumor cell proliferation. Together with the observation that MM cells are vulnerable to splicing inhibition, our results may lay the foundation for developing new therapeutic strategies for MM. We have developed a web portal that allows custom alternative splicing event queries by using gene symbols and visualizes AS events in MM and subgroups. Our portals can be accessed at http://rconnect.dfci.harvard.edu/mmsplicing/ and https://rconnect.dfci.harvard.edu/mmleafcutter/ .

IgM-MM is predominantly a pre-germinal center disorder and has a distinct genomic and transcriptomic signature from WM.

Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenström macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and treatment. In this study, we investigated genomic and transcriptomic characteristics of IgM-MM samples using whole-genome and transcriptome sequencing to identify differentiating characteristics from non-IgM-MM and WM. Our results suggest that IgM-MM shares most of its defining structural variants and gene-expression profiling with MM, but has some key characteristics, including t(11;14) translocation, chromosome 6 and 13 deletion as well as distinct molecular and transcription-factor signatures. Furthermore, IgM-MM translocations were predominantly characterized by VHDHJH recombination-induced breakpoints, as opposed to the usual class-switching region breakpoints; coupled with its lack of class switching, these data favor a pre-germinal center origin. Finally, we found elevated expression of clinically relevant targets, including CD20 and Bruton tyrosine kinase, as well as high BCL2/BCL2L1 ratio in IgM-MM, providing potential for targeted therapeutics.

ROBO1 Promotes Homing, Dissemination, and Survival of Multiple Myeloma within the Bone Marrow Microenvironment.

The bone marrow (BM) microenvironment actively promotes multiple myeloma (MM) pathogenesis and therapies targeting both cancer cells and the niche are highly effective. We were interested in identifying novel signaling pathways supporting MM-BM crosstalk. Mutations in the transmembrane receptor Roundabout 1 (ROBO1) were recently identified in MM patients, however their functional consequences are uncertain. Through protein structure-function studies, we discovered that ROBO1 is necessary for MM adhesion to BM stromal and endothelial cells and ROBO1 knock out (KO) compromises BM homing and engraftment in a disseminated mouse model. ROBO1 KO significantly decreases MM proliferation in vitro and intra- and extramedullary tumor growth, in vivo. Mechanistically, ROBO1 C-terminus is cleaved in a ligand-independent fashion and is sufficient to promote MM proliferation. Viceversa, mutants lacking the cytoplasmic domain, including the human-derived G674* truncation, act dominantly negative. Interactomic and RNA sequencing studies suggest ROBO1 may be involved in RNA processing, supporting further studies.

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma.

BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.

Genome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group.

PURPOSE: Multiple myeloma (MM) is accompanied by heterogeneous somatic alterations. The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing (WGS) and develop a model that identifies patients with long survival. METHODS: We analyzed deep WGS data from 183 newly diagnosed patients with MM treated with lenalidomide, bortezomib, and dexamethasone (RVD) alone or RVD + autologous stem cell transplant (ASCT) in the IFM/DFCI 2009 study (ClinicalTrials.gov identifier: NCT01191060). We integrated genomic markers with clinical data. RESULTS: We report significant variability in mutational load and processes within MM subgroups. The timeline of observed activation of mutational processes provides the basis for 2 distinct models of acquisition of mutational changes detected at the time of diagnosis of myeloma. Virtually all MM subgroups have activated DNA repair-associated signature as a prominent late mutational process, whereas APOBEC signature targeting C>G is activated in the intermediate phase of disease progression in high-risk MM. Importantly, we identify a genomically defined MM subgroup (17% of newly diagnosed patients) with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort. This subgroup allowed us to distinguish patients with low- and high-risk hyperdiploid MM and identify patients with prolongation of progression-free survival. Genomic characteristics of this subgroup included lower mutational load with significant contribution from age-related mutations as well as frequent NRAS mutation. Surprisingly, their overall survival was independent of International Staging System and minimal residual disease status. CONCLUSION: This is a comprehensive study identifying genomic markers of a good-risk group with prolonged survival. Identification of this patient subgroup will affect future therapeutic algorithms and research planning.

Deciphering the chronology of copy number alterations in Multiple Myeloma.

Multiple myeloma (MM) and its precursor condition MGUS are characterized by chromosomal aberrations. Here, we comprehensively characterize the order of occurrence of these complex genomic events underlying MM development using 500 MGUS, and MM samples. We identify hyperdiploid MM (HMM) and non-HMM as genomically distinct entities with different evolution of the copy number alterations. In HMM, gains of 9,15 or 19 are the first and clonal events observed as clonal even at MGUS stage. These events are thus early and may underlie initial transformation of normal plasma cells to MGUS cells. However, CNAs may not be adequate for progression to MM except in 15% of the patients in whom the complex subclonal deletion events are observed in MM but not MGUS. In NHMM, besides the driver translocations, clonal deletion of 13 and 1q gain are early events also observed in MGUS. We combined this information to propose a timeline for copy number alteration.

Antibiotic treatment outcomes in community-acquired pneumonia

Background/aim: The optimal empiric antibiotic regimen for patients with community-acquired pneumonia (CAP) remains unclear. This study aimed to evaluate the clinical cure rate, mortality, and length of stay among patients hospitalized with community- acquired pneumonia in nonintensive care unit (ICU) wards and treated with a ß-lactam, ß-lactam and macrolide combination, or a fluoroquinolone. Materials and methods: This prospective cohort study was performed using standardized web-based database sheets from January 2009 to September 2013 in nine tertiary care hospitals in Turkey. Results: Six hundred and twenty-one consecutive patients were enrolled. A pathogen was identified in 78 (12.6%) patients. The most frequently isolated bacteria were S. pneumoniae (21.8%) and P. aeruginosa (19.2%). The clinical cure rate and length of stay were not different among patients treated with ß-lactam, ß-lactam and macrolide combination, and fluoroquinolone. Forty-seven patients (9.2%) died during the hospitalization period. There was no difference in survival among the three treatment groups. Conclusion: In patients admitted to non-ICU hospital wards for CAP, there was no difference in clinical outcomes between ß-lactam, ß-lactam and macrolide combination, and fluoroquinolone regimens.

Does the neutrophil-to-lymphocyte ratio have any importance between subjects with obstructive sleep apnea syndrome with obesity and without obesity?

INTRODUCTION: An increase in the incidence of OSAS (obstructive sleep apnoea syndrome) has been seen due to the reported association between OSAS and obesity. Subjects are predisposed to cardiovascular disease due to systemic inflammation caused by the interactions between obesity and OSA. Inflammatory markers could be used to predict the degree of systemic inflammation, which could be a prognostic factor for future adverse events such as metabolic risks. One marker that has recently started being used as an indicator of systemic inflammation is neutrophil-to-lymphocyte ratio (NLR). MATERIALS AND METHODS: The aim is to evaluate NLR, which is a easily measured parameter of systemic inflammation in OSAS subjects with and without obesity. 155 subjects were assigned to four different groups according to their body mass indices. Comparisons of white blood cell, neutrophil, lymphocyte, NLR values and anthropometric measurements were done for each group. RESULT: The NLR and neutrophil counts of group 4 were statistically significant and higher than those of groups 1, 2 and 3. The lymphocyte counts of group 4 were the lowest amongst all groups, these values were lower than the lymphocyte counts of groups 1, 2 and 3 with statistically significant differences (p< 001). A positive correlation was found between the body mass index and lymphocyte count values of obese OSAS subjects (r= 0.027, p= 353). CONCLUSIONS: The NLR ratio was found to be increasing by obesity grade and reveals that the associated inflammatory response also increases. The NLR ratio might be used as an inflammatory marker in obese OSAS subjects.

Obstructive sleep apnea is associated with increased QT corrected interval dispersion: the effects of continuous positive airway pressure / Apneia obstrutiva do sono está associada a maior dispersão do intervalo QT corrigido: efeitos da pressão positiva contínua nas vias aéreas

Abstract Introduction: Severe obstructive sleep apnea is associated with increased QT corrected interval dispersion and continuous positive airway pressure is thought to improve this arrhythmogenic marker. Objective: The aim of the study was to determine the decrease of ratio of cardiovascular risk in patients with obstructive sleep apnea. Methods: The study included 65 patients with severe obstructive sleep apnea who had an apnea-hypopnea index score of >30. Each patient underwent 12-channel electrocardiogram monitoring and polysomnography. Patients with an apnea-hypopnea index score of <5 were used as the control group. The control group also underwent electrocardiogram monitoring and polysomnography testing. The QT corrected interval dispersion levels of both groups were calculated. Three months after continuous positive airway pressure treatment, electrocardiogram recordings were obtained from the 65 patients with severe obstructive sleep apnea again, and their QT corrected interval dispersion values were calculated. Results: There were 44 male and 21 female patients with severe obstructive sleep apnea syndrome. The age, gender, body mass index, initial saturation, minimum saturation, average saturation, and desaturation index were determined in both groups. The QT corrected intervals of the obstructive sleep apnea patients (62.48 ± 16.29 ms) were significantly higher (p = 0.001) than those of the control group (29.72 ± 6.30 ms). There were statistically significant differences between the QT corrected values before and after the continuous positive airway pressure treatment, with pretreatment QT corrected intervals of 62.48 ± 16.29 ms and 3-month post-treatment values of 41.42 ± 16.96 ms (p = 0.001). There was a positive and significant correlation between QT corrected interval dispersion periods and the apnea-hypopnea index and hypopnea index in obstructive sleep apnea patients (p = 0.001; r = 0.71; p = 0.001; r = 0.679, respectively). Conclusion: Continuous positive airway pressure treatment reduced the QT corrected interval dispersion in patients with severe obstructive sleep apnea. In addition, shortening the QT corrected interval dispersion periods in patients with severe obstructive sleep apnea may reduce their risk of arrhythmias and cardiovascular disease.

Resumo Introdução: A apneia obstrutiva do sono grave está associada a uma maior dispersão do intervalo QT corrigido e acredita-se que a pressão positiva contínua nas vias aéreas melhore esse marcador arritmogênico. Objetivo: Determinar a diminuição da razão de risco cardiovascular em pacientes com apneia obstrutiva do sono. Método: O estudo incluiu 65 pacientes com apneia obstrutiva do sono grave que apresentavam índice de apneia-hipopneia > 30. Cada paciente foi submetido à monitoração por eletrocardiograma de 12 derivações e polissonografia. Os pacientes com escore de índice de apneia-hipopneia < 5 foram utilizados como o grupo de controle. O grupo de controle também foi submetido à monitoração por eletrocardiograma e teste de polissonografia. Os níveis de dispersão do intervalo QT corrigido dos dois grupos foram calculados. Três meses após o tratamento com pressão positiva contínua nas vias aéreas, os registros de eletrocardiograma foram novamente obtidos dos 65 pacientes com apneia obstrutiva do sono grave e seus valores de dispersão do intervalo QT corrigido foram calculados. Resultados: Havia 44 pacientes do sexo masculino e 21 do feminino com síndrome de apneia obstrutiva do sono grave. Idade, sexo, índice de massa corporal, saturação inicial, saturação mínima, saturação média e índice de dessaturação foram determinados em ambos os grupos. Os intervalos QT corrigido dos pacientes com apneia obstrutiva do sono (62,48 ± 16,29 ms) foram significativamente maiores (p = 0,001) do que os do grupo controle (29,72 ± 6,30 ms). Houve diferenças estatisticamente significativas entre os valores de QT corrigido antes e após o tratamento com pressão positiva contínua nas vias aéreas, com intervalos QT corrigido pré-tratamento de 62,48 ± 16,29 ms e três meses pós-tratamento, de 41,42 ± 16,96 ms (p = 0,001). Houve uma correlação positiva e significativa entre os períodos de dispersão do intervalo QT corrigido e o índice de apneia-hipopneia e índice de hipopneia em pacientes com apneia obstrutiva do sono (p = 0,001; r = 0,71; p = 0,001; r = 0,679, respectivamente). Conclusão: O tratamento com pressão positiva contínua nas vias aéreas reduziu a dispersão do intervalo QT corrigido em pacientes com apneia obstrutiva do sono grave. Além disso, o encurtamento de dispersão do intervalo QT corrigido em pacientes com apneia obstrutiva do sono grave pode reduzir o risco de arritmias e doenças cardiovasculares.

Long intergenic non-coding RNAs have an independent impact on survival in multiple myeloma.

Although long intergenic non-coding RNAs (lincRNA) role in various cancers is described, their significance in Multiple Myeloma (MM) remains poorly defined. Here we have studied the lincRNA profile and their clinical impact in MM. We performed RNA-seq on MM cells from 308 newly diagnosed and uniformly treated patients, 16 normal plasma cells and utilized RNA-seq data from 532 newly diagnosed patients from CoMMpass study to analyze for lincRNAs. We observed 869 differentially expressed lincRNAs in MM compared to normal plasma cells. We identified 14 lincRNAs associated with PFS and calculated a risk score to stratify patients. The median PFS between high vs low-risk groups was 17 months vs not-reached (NR); and OS 30 months vs NR, respectively (p < 0.0001 for both). In the independent validation dataset between high and low-risk groups, PFS was 27 vs 42 months (HR 2.06 [1.44-2.96]; p < 0.0005); and 4-year OS 62% vs 86% (HR 2.76 [1.51-5.05]; p < 0.0005) confirming significant clinical relevance of lincRNA in MM. Importantly, lincRNA signature was able to further identify patients with significant differential outcomes within each low and high-risk categories identified using standard risk categorization including cytogenetic/FISH, ISS, and MRD negative or positive. Our results suggest that lincRNAs have an independent effect on MM outcome and provide a rationale to evaluate its molecular and biological impact.

Obstructive sleep apnea is associated with increased QT corrected interval dispersion: the effects of continuous positive airway pressure.

INTRODUCTION: Severe obstructive sleep apnea is associated with increased QT corrected interval dispersion and continuous positive airway pressure is thought to improve this arrhythmogenic marker. OBJECTIVE: The aim of the study was to determine the decrease of ratio of cardiovascular risk in patients with obstructive sleep apnea. METHODS: The study included 65 patients with severe obstructive sleep apnea who had an apnea-hypopnea index score of >30. Each patient underwent 12-channel electrocardiogram monitoring and polysomnography. Patients with an apnea-hypopnea index score of <5 were used as the control group. The control group also underwent electrocardiogram monitoring and polysomnography testing. The QT corrected interval dispersion levels of both groups were calculated. Three months after continuous positive airway pressure treatment, electrocardiogram recordings were obtained from the 65 patients with severe obstructive sleep apnea again, and their QT corrected interval dispersion values were calculated. RESULTS: There were 44 male and 21 female patients with severe obstructive sleep apnea syndrome. The age, gender, body mass index, initial saturation, minimum saturation, average saturation, and desaturation index were determined in both groups. The QT corrected intervals of the obstructive sleep apnea patients (62.48±16.29ms) were significantly higher (p=0.001) than those of the control group (29.72±6.30ms). There were statistically significant differences between the QT corrected values before and after the continuous positive airway pressure treatment, with pretreatment QT corrected intervals of 62.48±16.29ms and 3-month post-treatment values of 41.42±16.96ms (p=0.001). There was a positive and significant correlation between QT corrected interval dispersion periods and the apnea-hypopnea index and hypopnea index in obstructive sleep apnea patients (p=0.001; r=0.71; p=0.001; r=0.679, respectively). CONCLUSION: Continuous positive airway pressure treatment reduced the QT corrected interval dispersion in patients with severe obstructive sleep apnea. In addition, shortening the QT corrected interval dispersion periods in patients with severe obstructive sleep apnea may reduce their risk of arrhythmias and cardiovascular disease.

Serum telomerase levels in smokers and smokeless tobacco users as Maras powder.

INTRODUCTION: To the best of our knowledge, no previous study regarding the serum telomerase levels in Maras powder users (MPUs) has been founded. The aim of the current study was to investigate serum telomerase levels in smokers and MPUs. MATERIALS AND METHODS: The study was carried out with 98 patients (36 MPUs, 32 smokers and 30 non-smokers). Blood samples were collected, and after having measured the serum telomerase and malondialdehyde (MDA) levels of the patients, comparison were made between the groups. RESULT: It has been observed that the serum telomerase and MDA levels of smokers (p< 0.001) and MPUs (p< 0.001) were significantly higher compared to those of the non-smoker control subjects. In addition, the levels of serum telomerase and MDA were observed to be higher in the MPU group compared to those of the smoker group (p< 0.001). CONCLUSIONS: The levels of serum telomerase and MDA were observed to be higher among MPUs and smokers. In this context, it may be useful to further measure and assess telomerase activity in such patients in order to better determine the harmful effects associated with these habits.

ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma.

Amplification of 1q21 occurs in approximately 30% of de novo and 70% of relapsed multiple myeloma (MM) and is correlated with disease progression and drug resistance. Here, we provide evidence that the 1q21 amplification-driven overexpression of ILF2 in MM promotes tolerance of genomic instability and drives resistance to DNA-damaging agents. Mechanistically, elevated ILF2 expression exerts resistance to genotoxic agents by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65, which promotes mRNA processing and the stabilization of transcripts involved in homologous recombination in response to DNA damage. The intimate link between 1q21-amplified ILF2 and the regulation of RNA splicing of DNA repair genes may be exploited to optimize the use of DNA-damaging agents in patients with high-risk MM.

Microalbuminuria in Subjects With COPD: Relationship to the New Version of Global Initiative for Chronic Obstructive Lung Disease Staging.

BACKGROUND: Microalbuminuria, used as a marker of endothelial dysfunction, is a predictor of mortality for any reason and of cardiovascular events. Recent research on the management of COPD has focused more on comorbidities, including cardiovascular events. The objective of this study was to investigate the incidence of microalbuminuria and whether it is associated with physiological and clinical features in a subject group that was classified in line with the new version of the Global Initiative for Chronic Obstructive Lung Disease stages. METHODS: The study included 105 stable subjects with mild to very severe COPD. The urinary albumin/creatinine ratio was calculated using a previously defined formula. The presence of microalbuminuria was accepted as a urinary albumin/creatinine ratio ≥20 in males and ≥30 in females. RESULTS: Urinary albumin/creatinine ratios were significantly higher in subjects grouped as having more symptoms and high future risk than in those with fewer symptoms and low future risk. In addition, significant differences were observed when the subjects were grouped based on PaO2 (≤65 mm Hg vs >65 mm Hg), PaCO2 (≤41 mm Hg vs >41 mm Hg), arterial oxygen saturation (≤92% vs >92%), and median split C-reactive protein (≤4.6 mg/L vs >4.6 mg/L). Pearson correlation analysis revealed that the urinary albumin/creatinine ratio was significantly inversely correlated with percent-of-predicted FEV1 (r = -0.56, P = .001), percent-of-predicted SaO2 (r = -0.48, P = .001), and PaO2 (r = 0.60, P = .001). A positive correlation was also found between urinary albumin/creatinine ratio and COPD assessment test scores (r = 0.53, P = .001). CONCLUSIONS: The results of this study indicate a strong relationship between microalbuminuria and cardiovascular events in subjects with COPD, particularly in subjects with more symptoms and high future risk. Therefore, microalbuminuria should be regularly monitored in this subgroup of subjects with COPD for risk of cardiovascular morbidity or mortality.

The effect of obstructive sleep apnea syndrome and hypothyroidism to intima-media thickness of carotid artery.

AIM: Obstructive sleep apnea syndrome (OSAS) is a common disorder and in subjects with OSAS the prevalence of hypothyroidism is approximately 1.2-11 %. The episodes of hypoxia/reoxygenation associated with the respiratory disturbances observed in subjects with OSAS increases the risk of cardiovascular diseases. Hypothyroidism; primary or subclinical, has several effects on cardiovascular system. In our study, we investigated carotid artery intima-media thickness (IMT) which is an early sign of atherosclerosis, in OSAS subjects with hypothyroidism. MATERIALS AND METHOD: Subjects who admitted to Kahramanmaras Necip Fazil City State Hospital Chest Diseases out-patient clinic between May 2014 and January 2016 for snoring and had polysomnographic evaluation at the sleep laboratory were included in this study. Each subject was evaluated for serum thyroid function tests and carotid artery IMT was measured by a Doppler ultrasound. RESULTS: Mean carotid artery IMT values in the isolated OSAS, OSAS plus hypothyroidism, and control groups were 0.67 ± 0.12, 0.8 ± 0.12, and 0.54 ± 0.08 mm, respectively; difference between groups was statistically significant (p < .05). A poXsitive correlation was found between thyroid stimulating hormone levels and IMT (r = 0.426, p = .002), while free T3 levels and IMT were negatively correlated (r = -0.463, p = .001). IMT and apnea-hypopnea index were also positively correlated (r = 0.403, p = .003). CONCLUSION: We suggest, physicians should be alert for hypothyroidism comorbidity in OSAS, and suspected subjects with OSAS should be screened for hypothyroidism considering the potential cardiovascular complications.

Serum Gamma-Glutamyl Transferase Activity as a Potential Novel Cardiovascular Biomarker in COPD.

BACKGROUND: Gamma-glutamyl transferase (gamma-GT) is an enzyme present in the cell membranes, which is used as a new biomarker in prediction of inflammation, myocardial infarction, stroke, and cardiac death. The objective of this study was to investigate the relationship between serum levels of gamma-GT and cardiovascular disease in subjects with COPD and the correlation between serum gamma-GT level and degree of the limitation of air flow in COPD. METHODS: A total of 70 subjects (46.1%) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) A-B and normal function of the liver and biliary tract (mean age [IQR] 59 [51.75-70] y; 77.1% men) and 82 subjects (53.9%) with GOLD C-D (mean age [IQR] 59 [56-66] y; 79.3% men) participated. Serum levels of gamma-GT and C-reactive protein were measured and compared between the 2 groups. RESULTS: The serum level of gamma-GT was found to be significantly (P < .001) higher in the GOLD stage C and D group than in the GOLD stage A and B group. Mean values of C-reactive protein, aspartate aminotransferase, and alanine aminotransferase did not differ significantly between the 2 groups. The prevalence of cardiovascular disease was statistically significantly higher in subjects in the GOLD stage C and D group than in the GOLD stage A and B group (P < .001). The serum level of gamma-GT was higher in subjects with COPD with coexisting cardiovascular disease than in those without cardiovascular disease (64 units/L [interquartile range 57-72.5] vs 17.5 units/L [interquartile range 10-25]). CONCLUSIONS: Our results demonstrate that serum levels of gamma-GT may be helpful in grading the severity of COPD as the marker of oxidative stress, and there is a strong correlation between high serum levels of gamma-GT and cardiovascular events in subjects with COPD.