The Status Quo of Pharmacogenomics of Tyrosine Kinase Inhibitors in Precision Oncology: A Bibliometric Analysis of the Literature.

Precision oncology and pharmacogenomics (PGx) intersect in their overarching goal to institute the right treatment for the right patient. However, the translation of these innovations into clinical practice is still lagging behind. Therefore, this study aimed to analyze the current state of research and to predict the future directions of applied PGx in the field of precision oncology as represented by the targeted therapy class of tyrosine kinase inhibitors (TKIs). Advanced bibliometric and scientometric analyses of the literature were performed. The Scopus database was used for the search, and articles published between 2001 and 2023 were extracted. Information about productivity, citations, cluster analysis, keyword co-occurrence, trend topics, and thematic evolution were generated. A total of 448 research articles were included in this analysis. A burst of scholarly activity in the field was noted by the year 2005, peaking in 2017, followed by a remarkable decline to date. Research in the field was hallmarked by consistent and impactful international collaboration, with the US leading in terms of most prolific country, institutions, and total link strength. Thematic evolution in the field points in the direction of more specialized studies on applied pharmacokinetics of available and novel TKIs, particularly for the treatment of lung and breast cancers. Our results delineate a significant advancement in the field of PGx in precision oncology. Notwithstanding the practical challenges to these applications at the point of care, further research, standardization, infrastructure development, and informed policymaking are urgently needed to ensure widespread adoption of PGx.

PTEN loss is not a determinant of time to castration-resistance following androgen-deprivation therapy in prostate cancer: a study from Jordan.

Androgen deprivation therapy (ADT) remains the principal treatment of advanced prostate cancer. However, most patients eventually experience treatment failure, resulting in castrate-resistant prostate cancer (CRPC). Loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) has been linked to poor survival in prostate cancer. We have recently shown that PTEN loss is evident in approximately 60% of prostate cancer cases in Jordan. However, the correlation between PTEN loss and response to ADT remains unclear. This study aimed to determine the relationship between PTEN loss and time to CRPC in Jordan. We conducted a retrospective analysis of confirmed CRPC cases at our institution from 2005 to 2019 (N=104). PTEN expression was assessed using immunohistochemistry. Time to CRPC was calculated from the initiation of ADT to the confirmed diagnosis of CRPC. Combination/sequential ADT was defined as the use of two or more classes of ADT concomitantly or switching from one class to another. We found that PTEN loss was evident in 60.6% of CRPC. Mean time to CRPC was not different between patients with PTEN loss (24.8 months) and those with intact PTEN (24.2 months; p=0.9). However, patients receiving combination/sequential ADT had a significantly delayed onset of CRPC compared to patients on monotherapy ADT (log-rank Mantel-Cox p=0.000). In conclusion, PTEN loss is not a major determinant of time to CRPC in Jordan. The use of combination/sequential ADT procures a significant therapeutic advantage over monotherapy regimens, delaying the onset of CRPC.

A Comparative Piloting of Determinants of Self-Medication Among University Students in the MENA Region; UAE and Jordan as an Example.

Purpose: Unsupervised self-medication (SM) is a global public health concern. University students are particularly vulnerable due to misperceptions of improved academic performance and thus are at risk of dependence, addiction, and drug overdose. Past studies have shown an alarming prevalence of SM among university students in the Middle East and North Africa (MENA) region. However, there is a scarcity of reports from the region dissecting determinants of SM. Therefore, this study aimed to determine the prevalence and epidemiological correlates of SM among university students and its perceived impact on their academic performance. Methods: Two countries in the MENA region were surveyed in a cross-sectional design; UAE and Jordan. Through a stratified sampling technique, undergraduate students in both healthcare and non-healthcare majors of study were recruited to participate. A structured, self-administered questionnaire developed for the purpose of this study was distributed to consented participants via the university's official email. Statistical analyses were performed using SPSS. Descriptive and inferential statistics were used to analyze data. A p-value <0.05 was considered statistically significant. Results: A total of 362 students participated in the study (74% were females, 60% were from the UAE, and 59% were in healthcare majors). Significantly higher prevalence rates and adjusted odds of SM were found among females, students from Jordan, and those in healthcare majors, particularly for paracetamol (90.2% of females [p=0.001], 88.3% from Jordan [p=0.03], 92.5% in healthcare majors [p=0.001]) and antibacterial drugs (48.9% of females [p=0.01], 60.7% from Jordan [p=0.001], 53.3% in healthcare majors [p=0.001]). Majoring in healthcare fields was the most consistent determinant of such practice, while social influences of family and friends represented the chief source of recommendation. Only 21% of respondents assumed SM boosts their academic performance. Conclusion: Our pilot study underlines the predominant determinants of SM among university students in the MENA region, namely female gender, students from Jordan, and those in healthcare majors. Informed data-driven awareness campaigns to mitigate such practice should be designed to focus on these susceptible populations.

Jordan's Pandemic Influenza Preparedness (PIP): A Reflection on COVID-19 Response.

The COVID-19 pandemic made it clear to the world that better preparedness for future pandemics is paramount. This study aims to explore how the 2018 Jordan's Pandemic Influenza Preparedness (PIP) assessment plan (conducted utilizing a standardized tool of the CDC National Inventory of Core Capabilities for Pandemic Influenza Preparedness and Response) reflected on the initial COVID-19 response. A qualitative, single intrinsic case study design, utilizing interpretivist approach, was utilized to interview subject-matter experts and explore the potential reflection of PIP assessment on COVID-19 response. Utilizing a mini-Delphi approach, the interviews aimed at generating an in-depth understanding of how the Jordan's PIP risk assessment reflects on the country's response to COVID-19. The following 12 core capabilities, along with their reflections on COVID-19, were assessed: country planning, research and use of findings, communications, epidemiologic capability, laboratory capability, routine influenza surveillance, national respiratory disease surveillance, outbreak response, resources for containment, community-based interventions to prevent the spread of influenza, infection control (IC), and health sector pandemic response. Jordan's experience and preparedness for influenza may have served as a crucial guide to establishing success in COVID-19 control and mitigation. Surveillance, outbreak, and research activities were very well established in Jordan's PIP, whereas surge capacity in human capital and health facility were identified as two high-risk areas. However, the limitation in these two areas was met during the COVID-19 response. Still, human capital suffered fatigue, and there was an evident lack of laboratory testing plans when COVID-19 cases increased. Jordan's experience with PIP may have served as a guide for establishing successful COVID-19 control and mitigation. The established PIP principles, systems, and capacities seem to have reflected well on fighting against COVID-19 in terms of more efficient utilization of available surveillance, laboratory, outbreak management, and risk communications. This reflection facilitated a better mitigation and control of COVID-19.

Effectiveness of interactive teaching intervention on medical students' knowledge and attitudes toward stem cells, their therapeutic uses, and potential research applications.

BACKGROUND: Stem cell science is rapidly developing with the potential to alleviate many non-treatable diseases. Medical students, as future physicians, should be equipped with the proper knowledge and attitude regarding this hopeful field. Interactive teaching, whereby the teachers actively involve the students in the learning process, is a promising approach to improve their interest, knowledge, and team spirit. This study aims to evaluate the effectiveness of an interactive teaching intervention on medical students' knowledge and attitudes about stem cell research and therapy. METHODS: A pre-post test study design was employed. A six-session interactive teaching course was conducted for a duration of six weeks as an intervention. Pre- and post-intervention surveys were used. The differences in the mean scores of students' knowledge and attitudes were examined using paired t-test, while gender differences were examined using an independent t-test. RESULTS: Out of 71 sixth-year medical students from different nationalities invited to participate in this study, the interactive teaching course was initiated by 58 students resulting in a participation rate of 81.7%. Out of 58 students, 48 (82.8%) completed the entire course. The mean age (standard deviation) of students was 24 (1.2) years, and 32 (66.7%) were males. The results showed poor knowledge about stem cells among the medical students in the pre-intervention phase. Total scores of stem cell-related knowledge and attitudes significantly improved post-intervention. Gender differences in knowledge and attitudes scores were not statistically significant post-intervention. CONCLUSIONS: Integrating stem cell science into medical curricula coupled with interactive learning approaches effectively increased students' knowledge about recent advances in stem cell research and therapy and improved attitudes toward stem cell research and applications.

Effects of Elemental Mercury Vapor Inhalation on Arterial Blood Gases, Lung Histology, and Interleukin-1 Expression in Pulmonary Tissues of Rats.

We investigated the effects of elemental mercury vapor inhalation on arterial blood gases (ABGs), lung histology, and interleukin-1 (IL-1) expression in pulmonary tissues in rats. A total of 42 Sprague Dawley rats were divided randomly into three groups. Rats in the first group were used as the control (CG). A short-term group (STG) and a long-term group (LTG) were exposed to 500 µg/m3 of mercury vapor 2 hrs/day for 21 days and 65 days, respectively. After exposure periods were completed, arterial blood samples were obtained, and ABGs were measured. Lung tissue sections were prepared for histology evaluation and immune-stained to detect IL-1 expression. There was a significant decrease in body weight in both STG (15%) and LTG (22%) compared with the CG. In the LTG, six out of 14 (43%) rats died, including two males and four females, while none of the rats in the STG died during the experiment. In both STG and LTG, a significant acid-base imbalance was characterized by a significant decrease in blood pH values and a significant increase in PCO2 values. Both PO2 and SpO2 blood values were significantly decreased in the STG and LTG, while no changes were observed in HCO3 values in all groups. Histological evaluation of lung tissues revealed severe lesions characterized by pulmonary emphysema and inflammatory cellular infiltrate. IL-1 expression in lung tissues was not significantly different between exposed rats and control subjects. These results indicate significant alterations in blood acid-base status characterized by severe respiratory acidosis with hypoxemia and no evidence of compensatory alkalosis in rats after exposure to short- and long-term elementary mercury vapor.

Stem cell-related knowledge and attitudes among physicians in Jordan.

BACKGROUND: Rapid advancement of stem cell (SC) therapies provides both opportunities and risks for patients and physicians alike. Physicians have a role in counselling patients about unproven SC therapies, requiring a basic level of knowledge and access to information about SCs. OBJECTIVE: This study sought to assess SC-related knowledge of and attitudes among physicians in Jordan to elucidate areas of deficiency that can be addressed. METHODS: A cross-sectional survey, comprising questions on demographics and SC knowledge and attitudes, was designed as a scoring system to evaluate physicians' knowledge and attitudes. Participants were recruited from 10 major hospitals in Jordan over 3 months between February and April 2019. The internal consistency of the scoring scales was calculated using Cronbach's alpha reliability coefficient. Gender differences were evaluated with an independent t-test. RESULTS: In total, 382 physicians in Jordan completed the survey (59.9% response rate). They demonstrated a low/moderate level of overall SC knowledge (51.3%), but most lacked confidence in their ability to answer patients' questions about SC therapies (64.7%). However, the total attitude score was moderate/high positive (66.8%) and most were interested in learning more about SCs (80.8%). Male physicians reported significantly more knowledge than females (P < .0001). CONCLUSIONS: This study reveals Jordanian physicians' hesitancy to counsel patients about SC therapies, largely because of gaps in knowledge. However, overall attitudes toward SC research and therapies are positive. The results of this study demonstrate a need to cover SC-related information in medical curricula in Jordan, as well as to support initiatives to regulate SC tourism in Jordan.

Knowledge, attitude, future expectations and perceived barriers of medical students and physicians regarding pharmacogenomics in Jordan.

BACKGROUND: Pharmacogenomics (PG) is a modern tool of personalising treatment protocols to improve the efficacy and safety of drug prescriptions. These benefits are offset by a slow uptake in clinical application due to a host of physician factors, patient factors and/or health system factors. Our study, thus, aimed to determine the knowledge, attitude, future expectations and perceived barriers of medical students and physicians in Jordan regarding PG testing. METHODS: A descriptive, cross-sectional study was conducted between February and August 2019. Physicians and senior medical students from academic and non-academic institutions in North Jordan (n = 424) were surveyed. A structured, self-administered questionnaire was designed and piloted for the purpose of the study. A scoring system for each dimension assessed was calculated and presented using means. Mean scores were compared by sociodemographic and professional variables. RESULTS: The response rate was 70.7%. The mean total PG knowledge score (±SD) was 5.42 (±1.51) out of 10, with a significantly higher mean among respondents aged <30 years (5.54 ± 1.43) compared with those ≥30 years old (5.21 ± 1.62; P = .03). The mean total PG attitude score was 21.18 (±2.58) out of 24, with significant differences by seniority levels evident (P = .03). The future expectations of PG among our sample were high, with a mean score of 10.44 (±1.64) out of 12. The top three perceived barriers in applying PG were the high cost, lack of clinical guidelines, and limited knowledge and awareness. CONCLUSION: Physicians and medical students in Jordan have low overall knowledge, albeit strongly positive attitude and future expectations towards PG, despite the perceived high cost and lack of clinical guidelines. Thus, we strongly recommend adopting a comprehensive educational strategy that aims to integrate PG concepts into medical curricula, and promote the culture of continuous medical education about PG among practitioners.

The relationship between depression and metabolic control parameters in type 2 diabetic patients: A cross-sectional and feasibility interventional study.

BACKGROUND: Substantial evidence supports a bidirectional relationship between diabetes and clinical depression. However, little is known about the effect of treating one condition on the control of the other. Thus, this study aimed to determine the prevalence of depression among Type II diabetes mellitus (T2DM) patients and to assess the efficacy and feasibility of escitalopram treatment of depression on their metabolic control parameters. METHODS: T2DM patients attending primary care clinics in the North of Jordan were enrolled in a cross-sectional study during the period from February to December 2019 (n = 157). Depressive symptoms were screened utilising the patient health questionnaire-9 (PHQ-9) tool. Metabolic control was assessed by measurement of glycated haemoglobin (HbA1c), triglycerides, cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Patients with moderate to severe depressive symptoms by PHQ-9 (n = 58) were interviewed by a psychiatrist to confirm a clinical diagnosis of depression. Eligible depressed patients were administered escitalopram 10 mg orally once daily for 3 months (n = 12). Thereafter, depressive symptoms and metabolic control measures were reassessed. RESULTS: The prevalence of moderate to severe depressive symptoms among T2DM patients, according to PHQ-9, was 36.94%, while the prevalence of clinical depression based on interview was 7.64%. Baseline PHQ-9 scores correlated significantly with baseline levels of HbA1c, HDL, cholesterol and triglycerides. Escitalopram treatment intervention resulted in significant improvement of PHQ-9 scores without significantly improving any of the metabolic control measures. CONCLUSION: The relationship between depression and T2DM in the context of metabolic syndrome is plausible. However, our results show that escitalopram treatment may not be associated with significant improvement in metabolic control parameters among these patients. Our study has laid the groundwork for future randomised clinical trials with larger sample size and longer follow-up.

The Effect of Strict State Measures on the Epidemiologic Curve of COVID-19 Infection in the Context of a Developing Country: A Simulation from Jordan.

COVID-19 has posed an unprecedented global public health threat and caused a significant number of severe cases that necessitated long hospitalization and overwhelmed health services in the most affected countries. In response, governments initiated a series of non-pharmaceutical interventions (NPIs) that led to severe economic and social impacts. The effect of these intervention measures on the spread of the COVID-19 pandemic are not well investigated within developing country settings. This study simulated the trajectories of the COVID-19 pandemic curve in Jordan between February and May and assessed the effect of Jordan's strict NPI measures on the spread of COVID-19. A modified susceptible, exposed, infected, and recovered (SEIR) epidemic model was utilized. The compartments in the proposed model categorized the Jordanian population into six deterministic compartments: suspected, exposed, infectious pre-symptomatic, infectious with mild symptoms, infectious with moderate to severe symptoms, and recovered. The GLEAMviz client simulator was used to run the simulation model. Epidemic curves were plotted for estimated COVID-19 cases in the simulation model, and compared against the reported cases. The simulation model estimated the highest number of total daily new COVID-19 cases, in the pre-symptomatic compartmental state, to be 65 cases, with an epidemic curve growing to its peak in 49 days and terminating in a duration of 83 days, and a total simulated cumulative case count of 1048 cases. The curve representing the number of actual reported cases in Jordan showed a good pattern compatibility to that in the mild and moderate to severe compartmental states. The reproduction number under the NPIs was reduced from 5.6 to less than one. NPIs in Jordan seem to be effective in controlling the COVID-19 epidemic and reducing the reproduction rate. Early strict intervention measures showed evidence of containing and suppressing the disease.

PTEN Loss in a Prostate Cancer Cohort From Jordan.

Deletion of phosphatase and tensin homolog (PTEN) in prostate cancer has been associated with early biochemical recurrence, increased metastatic potential, and androgen independence. We evaluated the status of PTEN loss in a cohort of prostate cancer patients from Jordan. We investigated 71 patients with prostate cancer and 52 control subjects with benign prostatic hyperplasia (BPH). PTEN status was assessed by immunohistochemistry. PTEN mutations on exons 1, 2, 5, and 8 were also evaluated by polymerase chain reaction single-stranded conformation polymorphism (PCR-SSCP). We found PTEN loss in 42 of 71 (59.2%) evaluated prostate cancer cases by immunohistochemistry. In contrast, 51 of 52 BPH (98.1%) cases had an intact PTEN. In a subset of 24 prostate cancer cases evaluated by PCR-SSCP, we found PTEN mutations in 15 (62.5%) cases, whereas 22 (91.7%) of BPH controls lacked PTEN mutations. Exon 5 was the most frequently mutated exon (37.5%). Although the loss of PTEN was not significantly correlated with the Gleason Score (GS) or the World Health Organization (WHO)-International Society of Urological Pathology (ISUP) Grade Group (GG), we found higher frequency of PTEN loss (64%) in patients with GS≥4+3/GG≥3, compared with patients with GS≤3+4/GG≤2 (47.6%). In this first study to address the question of PTEN loss in a predominantly Arab population, we documented the frequency of PTEN loss in prostate cancer patients from Jordan, which was found to be higher than in comparable cohorts from East Asia, and was at the higher end of the range of reported frequency of PTEN loss in respective cohorts from North America and Western Europe. Although there was more frequent PTEN loss in cancers with higher GS/GG, this was not statistically significant.

Trauma exposure, mental health and tobacco use among vulnerable Syrian refugee youth in Jordan.

BACKGROUND: Little is known about tobacco use among youth exposed to armed conflicts, or the influence of trauma on tobacco use in this context. This study examined patterns of smoking by tobacco product and gender among Syrian refugee youth living in host communities in Jordan and assessed the associations of post-traumatic stress disorder (PTSD) and depression symptoms, trauma exposure and social support with current smoking status in boys and girls. METHODS: Syrian refugee students (mean [standard deviation] age = 14.9 [1.33] years) were identified through the public school system. Data were collected using an online Arabic questionnaire that included questions about demographics, trauma exposure, current smoking (cigarette and waterpipe), PTSD, depression and perceived social support. Logistic regression was used to assess the adjusted effects of independent variables on current smoking status. RESULTS: One in 7 boys and one in 14 girls were current smokers, with boys reporting greater tobacco use than girls. Among boys, current smokers reported significantly higher family member loss and lower perceived family social support than nonsmokers; among girls, current smokers also reported significantly higher family member loss as well as greater PTSD symptoms and lower perceived significant other/special person social support. CONCLUSIONS: Tobacco use is established among this vulnerable group. The findings highlight the potential role of psychosocial support for tobacco prevention and cessation strategies.

The Effects of Laparoscopic Sleeve Gastrectomy on the Parameters of Leptin Resistance in Obesity.

Obesity is a growing public health problem worldwide. Bariatric surgical procedures achieve the most sustainable and efficacious outcomes in the treatment of morbid obesity. However, little is known about the underlying molecular pathways modulated by these surgical interventions. Since leptin resistance is implicated in the pathogenesis of obesity, we herein report the effects of laparoscopic sleeve gastrectomy (LSG) on the serum levels of leptin and leptin receptor, in addition to its overall effect on leptin resistance. This was an interventional and follow-up clinical study. In the first part, patients attending the general surgery outpatient clinics at our university hospital were first stratified according to their Body-Mass Index (BMI) into cases (n = 38) with BMI ≥ 35 who were scheduled to undergo LSG, and controls (n = 75) with a normal BMI. Serum leptin and leptin receptor levels were measured by sandwich ELISA technique. A leptin resistance index was estimated by adjusting leptin to BMI ratio to leptin receptor concentration. In the second part of the study, cases who underwent LSG were followed up one year postoperatively to assess their BMI and serum leptin and leptin receptor levels. Leptin to BMI ratio was significantly higher, while serum leptin receptor was significantly lower, in obese patients compared to controls. This translated into a significantly higher leptin resistance index in obese patients. LSG resulted in a significant reduction of BMI, leptin to BMI ratio, and leptin resistance index, as it significantly increased leptin receptor levels. In conclusion, LSG showed significant decrease in leptin resistance in obese patients after one year. Further studies are needed to determine the clinical impact of this finding on LSG outcomes.

The Bidirectional Relationship between Diabetes and Depression: A Literature Review.

Diabetes is a major public health problem worldwide. Depression is a serious mental condition that decreases mental and physical functioning and reduces the quality of life. Several lines of evidence suggest a bidirectional relationship between diabetes and depression: diabetes patients are twice as likely to experience depression than nondiabetic individuals. In contrast, depression increases the risk of diabetes and interferes with its daily self-management. Diabetes patients with depression have poor glycemic control, reduced quality of life, and an increased risk of diabetes complications, consequently having an increased mortality rate. Conflicting evidence exists on the potential role of factors that may account for or modulate the relationship between diabetes and depression. Therefore, this review aims to highlight the most notable body of literature that dissects the various facets of the bidirectional relationship between diabetes and depression. A focused discussion of the proposed mechanisms underlying this relationship is also provided. We systematically reviewed the relevant literature in the PubMed database, using the keywords "Diabetes AND Depression". After exclusion of duplicate and irrelevant material, literature eligible for inclusion in this review was based on meta-analysis studies, clinical trials with large sample sizes (n≥1,000), randomized clinical trials, and comprehensive national and cross-country clinical studies. The evidence we present in this review supports the pressing need for long, outcome-oriented, randomized clinical trials to determine whether the identification and treatment of patients with these comorbid conditions will improve their medical outcomes and quality of life.

Correction: Lower Levels of Serum Adiponectin and the T Allele of rs1501299 of the ADIPOQ Gene Are Protective against Polycystic Ovarian Syndrome in Jordan.

[This corrects the article on p. 108 in vol. 39.].

Lower Levels of Serum Adiponectin and the T Allele of rs1501299 of the ADIPOQ Gene Are Protective against Polycystic Ovarian Syndrome in Jordan.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive disorder. Obesity, which is linked with lower adiponectin levels, increases a woman's risk of developing PCOS; however, the association between adiponectin and PCOS is controversial. Adiponectin levels could be affected by single nucleotide polymorphisms (SNPs) in the ADIPOQ gene. This study aimed to test the relationship between serum adiponectin and PCOS in Jordan and the association between the rs2241766, rs1501299, and rs266729 SNPs in the ADIPOQ gene and PCOS. METHODS: One hundred and fifty-four women with PCOS and 149 age- and body mass index-matched normally menstruating controls were recruited. Serum adiponectin levels were measured using enzyme-linked immunosorbent assay. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Serum adiponectin levels were significantly lower (P=0.0064) in PCOS women and rs1501299 (+276 G/T) genotype distributions were significantly different (P=0.01) between them and normally menstruating women. Multivariate analysis revealed that adiponectin levels remained significantly lower in PCOS women (P=0.001; odds ratio [OR], 0.9; 95% confidence interval [CI], 0.84-0.96). The GT genotype of rs1501299 increased the risk of PCOS (P<0.001; OR, 5.46; 95% CI, 2.42-12.33) and increased the risk of PCOS by three-fold (P<0.001; OR, 3.00; 95% CI, 1.36-6.60) relative to the TT genotype. The GG genotype increased the risk of PCOS as well (P<0.001; OR, 3:00; 95% CI, 1.36-6.60). CONCLUSION: PCOS is associated with lower serum adiponectin levels independent of age and body mass index. The T allele of the rs1501299 (+276 G/T) SNP of the ADIPOQ gene protects against PCOS.

Changes of serum growth factors profiles in patients with venous thromboembolism.

BACKGROUND AND RATIONALE: Venous thromboembolism (VTE) is a multifactorial disorder. Multiple hits to the tightly regulated blood hemostasis systems are required to trigger VTE. Growth factors, such as angiopoietins 1 and 2 (Ang-1 and Ang-2), and the epidermal growth factor (EGF) are critically involved in the maintenance of endothelial activity and vascular stability. The aim of this study was to evaluate the changes of these serum growth factors in patients with VTE. METHODS: This is a multi-institutional retrospective case-control study. The first arm included 50 patients diagnosed with deep vein thrombosis (DVT), pulmonary embolism (PE) or both. The control arm included 25 healthy subjects with no current or previous VTE. Both arms were investigated for changes in their serum levels of Ang-1, Ang-2 and EGF. RESULTS: Compared to healthy controls, Ang-2 was significantly higher (p = .001) while Ang-1 and EGF were significantly lower (p = .001 and p = .004; respectively) in VTE patients compared to healthy subjects. The type of VTE (DVT vs. PE) did not affect the observed changes in serum growth factors profiles. These changes were not time- or frequency-dependent, as there were no significant differences between acute versus chronic, or between the first-time versus recurrent cases of VTE. CONCLUSIONS: Serum profiles of Ang-1, Ang-2 and EGF change dramatically during VTE. This hints the significant role that these growth factors played in the pathogenesis of VTE. Thus, serum levels of growth factors may help in the first-time diagnosis of VTE, but not in diagnosing a recurrent episode of VTE. Larger studies are required to determine 'threshold levels' or 'likelihood ranges' of each biomarker for accurate diagnosis.

Increased reactive oxygen species, metabolic maladaptation, and autophagy contribute to pulmonary arterial hypertension-induced ventricular hypertrophy and diastolic heart failure.

Pulmonary arterial hypertension (PAH) is a debilitating and deadly disease with no known cure. Heart failure is a major comorbidity and a common cause of the premature death of patients with PAH. Increased asymmetrical right ventricular hypertrophy and septal wall thickening compress the left ventricular cavity and elicit diastolic heart failure. In this study, we used the Sugen5416/hypoxia/normoxia-induced PAH rat to determine whether altered pyridine nucleotide signaling in the failing heart contributes to 1) increased oxidative stress, 2) changes in metabolic phenotype, 3) autophagy, and 4) the PAH-induced failure. We found that increased reactive oxygen species, metabolic maladaptation, and autophagy contributed to the pathogenesis of right ventricular remodeling and hypertrophy that lead to left ventricular diastolic dysfunction. In addition, arterial elastance increased in PAH rats. Glucose-6-phosphate dehydrogenase is a major source of pyridine molecule (nicotinamide adenine dinucleotide phosphate), which is a substrate for nicotinamide adenine dinucleotide phosphate oxidases in the heart. Dehydroepiandrosterone, a 17-ketosteroid that reduces pulmonary hypertension and right ventricular hypertrophy, inhibited glucose-6-phosphate dehydrogenase, decreased oxidative stress, increased glucose oxidation and acetyl-coA, and reduced autophagy in the hearts of PAH rats. It also decreased arterial stiffness and improved left ventricular diastolic function. These findings demonstrate that pyridine nucleotide signaling, at least partly, mediates PAH-induced diastolic heart failure, and that reduction of glucose-6-phosphate dehydrogenase-derived nicotinamide adenine dinucleotide phosphate is beneficial to improve left ventricle diastolic function.

Glucose-6-phosphate dehydrogenase plays a critical role in hypoxia-induced CD133+ progenitor cells self-renewal and stimulates their accumulation in the lungs of pulmonary hypertensive rats.

Although hypoxia is detrimental to most cell types, it aids survival of progenitor cells and is associated with diseases like cancer and pulmonary hypertension in humans. Therefore, understanding the underlying mechanisms that promote survival of progenitor cells in hypoxia and then developing novel therapies to stop their growth in hypoxia-associated human diseases is important. Here we demonstrate that the proliferation and growth of human CD133(+) progenitor cells, which contribute to tumorigenesis and the development of pulmonary hypertension, are increased when cultured under hypoxic conditions. Furthermore, glucose-6-phosphate dehydrogenase (G6PD) activity was increased threefold in hypoxic CD133(+) cells. The increased G6PD activity was required for CD133(+) cell proliferation, and their growth was arrested by G6PD inhibition or knockdown. G6PD activity upregulated expression of HIF1α, cyclin A, and phospho-histone H3, thereby promoting CD133(+) cell dedifferentiation and self-renewal and altering cell cycle regulation. When CD133(+) cells were cocultured across a porous membrane from pulmonary artery smooth muscle cells (PASMCs), G6PD-dependent H2O2 production and release by PASMCs recruited CD133(+) cells to the membrane, where they attached and expressed smooth muscle markers (α-actin and SM22α). Inhibition of G6PD reduced smooth muscle marker expression in CD133(+) cells under normoxia but not hypoxia. In vivo, CD133(+) cells colocalized with G6PD(+) cells in the perivascular region of lungs from rats with hypoxia-induced pulmonary hypertension. Finally, inhibition of G6PD by dehydroepiandrosterone in pulmonary arterial hypertensive rats nearly abolished CD133(+) cell accumulation around pulmonary arteries and the formation of occlusive lesions. These observations suggest G6PD plays a key role in increasing hypoxia-induced CD133(+) cell survival in hypertensive lungs that differentiate to smooth muscle cells and contribute to pulmonary arterial remodeling during development of pulmonary hypertension.

A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension.

A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH.