FOXP1 gene in chronic myeloproliferative neoplasms

UVOD: Kronične mijeloproliferativne neoplazme (MPN) poremećaji su koštane srži koji se očituju abnormalnom proliferacijom i nakupljanjem zrelih krvnih stanica. FOXP1 gen transkripcijski je faktor važan za normalan razvoj embrionalnog tkiva, te neurološkog i imunološkog sustava. Moguća je povezanost ekspresije FOXP1 gena s nastankom i progresijom kroničnih MPN-ova. ISPITANICI I METODE: Istraživanje je provedeno na 35 pacijenata dijagnosticiranih i liječenih u KB Dubrava, u Zagrebu, u razdoblju između 2006. i 2014. godine, te na 4 zdrava donora koštane srži. Pacijenti su podijeljeni u 5 skupina, prema kliničkim entitetima, te su analizirane njihove demografske i kliničke karakteristike. Iz stanica tkiva koštane srži izolirana je ribonukleinska kiselina (RNA), te podvrgnuta reakciji reverzne transkripcije u svrhu dobivanja komplementarne deoksiribonukleinske kiseline (cDNA), nakon čega je provedeno umnažanje sekvence FOXP1 lančanom reakcijom polimeraze u realnom vremenu (RT-PCR). REZULTATI: Uočavamo kako Philadelphia-negativni (Ph-negativni) klinički i hematološki stabilni MPN-ovi pokazuju nižu relativnu ekspresiju FOXP1 gena u usporedbi s kontrolnom koštanom srži, dok istovremeno pokazuju višu relativnu ekspresiju gena u usporedbi s transformiranim entitetima. Statističkom analizom pokazalo se kako rezultat nije statistički značajan. Smanjena ekspresija gena mogla bi biti povezana s agresivnijom biologijom i sklonošću transformaciji. Analizom preživljenja utvrdili smo kako je smrtnost najviša u transformiranim entitetima, približno jednaka u kroničnim stabilnim oblicima MPN-ova, a najmanja kod reaktivnih eritrocitoza (RE) i reaktivnih trombocitoza (RT). RASPRAVA: Zanimljiva je dvojna funkcija FOXP1 gena, ovisno o vrsti stanica, kao onkogena ili tumor supresorskog gena. Nema mnogo radova o povezanosti FOXP1 gena s MPN-ovima. Usporedno s drugim radovima koji govore u prilog tumor supresorskoj funkciji FOXP1 gena mi nalazimo smanjenu ekspresiju FOXP1 gena kod svih Ph-negativnih MPN-ova, s time da se ekspresija dodatno smanjuje u transformiranim entitetima, što također govori u prilog tumor supresorskoj funkciji gena. ZAKLJUČAK: Ekspresija FOXP1 gena smanjena je kod svih Ph-negativnih MPN-ova u odnosu na kontrolne skupine. Ekspresija FOXP1 gena smanjena je u transformiranim kliničkim entitetima u odnosu na klinički i hematološki stabilne Ph-negativne MPN-ove. Razina ekspresije FOXP1 gena slična je kod policitemije vere (PV), esencijalne trombocitemije (ET) i primarne mijelofibroze (PMF), dok je minimalna ekspresija gena nađena kod leukemijske transformacije u sekundarnu akutnu mijeloičnu leukemiju (sAML).INTRODUCTION: Chronic myeloproliferative neoplasms (MPN) are bone marrow disorders, revealed by abnormal proliferation and accumulation of mature blood cells. FOXP1 gene is a transcription factor important for normal development of embryonal tissue and for neurological and immune systems. There is a possible connection of FOXP1 gene expression with the occurrence as well as progression of chronic MPNs. SUBJECTS AND METHODS: The research included 35 patients diagnosed and treated in Clinical Hospital Dubrava, Zagreb, from 2006 to 2014, as well as 4 healthy bone marrow donors. Patients were divided in 5 groups, according to clinical entities. Their demographic and clinical characteristics were analyzed. From the cells of bone marrow tissue ribonucleid acid (RNA) was isolated and subjected to reverse trascription to obtain complementary deoxyribonucleid acid (cDNA). After that FOXP1 sequence was multiplied with polymerase chain reaction in real time (RT-PCR). RESULTS: We noticed Philadelphia-negative (Ph-negative) clinical and hematological stable MPNs show lower relative FOXP1 gene expression compared to control bone marrow, while also show higher relative gene expression compared to transformed entities. Statistical analysis showed the result was not statistically significant. It is possible lower gene expression is connected to more aggressive biology and greater possibility of transformation. Survival analysis found mortality is the highest in transformed entities, approximately equal in chronic stable MPNs and the lowest in reactive erythrocytosis (RE) and reactive thrombocytosis (RT). DISCUSSION: Dual function of FOXP1 gene as oncogene or tumor suppressor gene depending on the cell type is of interest. There is only a handful of papers on connection between FOXP1 gene and MPNs all indicating tumor suppressing function of FOXP1 gene. We found lower FOXP1 gene expression in all Ph-negative MPNs with the expression further reducing in transformed entities, supporting the tumor suppressing function of the gene. CONCLUSION: FOXP1 gene expression is lower in all Ph-negative MPNs compared to the control group. FOXP1 gene expression is lower in transformed clinical entities compared to clinical and hematological stable Ph-negative MPNs. Level of expression of FOXP1 gene is similar in policitemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Minimal gene expression was found in leukemic transformation in secondary acute myeloid leukemia (sAML)

FOXP1 gene in chronic myeloproliferative neoplasms

UVOD: Kronične mijeloproliferativne neoplazme (MPN) poremećaji su koštane srži koji se očituju abnormalnom proliferacijom i nakupljanjem zrelih krvnih stanica. FOXP1 gen transkripcijski je faktor važan za normalan razvoj embrionalnog tkiva, te neurološkog i imunološkog sustava. Moguća je povezanost ekspresije FOXP1 gena s nastankom i progresijom kroničnih MPN-ova. ISPITANICI I METODE: Istraživanje je provedeno na 35 pacijenata dijagnosticiranih i liječenih u KB Dubrava, u Zagrebu, u razdoblju između 2006. i 2014. godine, te na 4 zdrava donora koštane srži. Pacijenti su podijeljeni u 5 skupina, prema kliničkim entitetima, te su analizirane njihove demografske i kliničke karakteristike. Iz stanica tkiva koštane srži izolirana je ribonukleinska kiselina (RNA), te podvrgnuta reakciji reverzne transkripcije u svrhu dobivanja komplementarne deoksiribonukleinske kiseline (cDNA), nakon čega je provedeno umnažanje sekvence FOXP1 lančanom reakcijom polimeraze u realnom vremenu (RT-PCR). REZULTATI: Uočavamo kako Philadelphia-negativni (Ph-negativni) klinički i hematološki stabilni MPN-ovi pokazuju nižu relativnu ekspresiju FOXP1 gena u usporedbi s kontrolnom koštanom srži, dok istovremeno pokazuju višu relativnu ekspresiju gena u usporedbi s transformiranim entitetima. Statističkom analizom pokazalo se kako rezultat nije statistički značajan. Smanjena ekspresija gena mogla bi biti povezana s agresivnijom biologijom i sklonošću transformaciji. Analizom preživljenja utvrdili smo kako je smrtnost najviša u transformiranim entitetima, približno jednaka u kroničnim stabilnim oblicima MPN-ova, a najmanja kod reaktivnih eritrocitoza (RE) i reaktivnih trombocitoza (RT). RASPRAVA: Zanimljiva je dvojna funkcija FOXP1 gena, ovisno o vrsti stanica, kao onkogena ili tumor supresorskog gena. Nema mnogo radova o povezanosti FOXP1 gena s MPN-ovima. Usporedno s drugim radovima koji govore u prilog tumor supresorskoj funkciji FOXP1 gena mi nalazimo smanjenu ekspresiju FOXP1 gena kod svih Ph-negativnih MPN-ova, s time da se ekspresija dodatno smanjuje u transformiranim entitetima, što također govori u prilog tumor supresorskoj funkciji gena. ZAKLJUČAK: Ekspresija FOXP1 gena smanjena je kod svih Ph-negativnih MPN-ova u odnosu na kontrolne skupine. Ekspresija FOXP1 gena smanjena je u transformiranim kliničkim entitetima u odnosu na klinički i hematološki stabilne Ph-negativne MPN-ove. Razina ekspresije FOXP1 gena slična je kod policitemije vere (PV), esencijalne trombocitemije (ET) i primarne mijelofibroze (PMF), dok je minimalna ekspresija gena nađena kod leukemijske transformacije u sekundarnu akutnu mijeloičnu leukemiju (sAML).INTRODUCTION: Chronic myeloproliferative neoplasms (MPN) are bone marrow disorders, revealed by abnormal proliferation and accumulation of mature blood cells. FOXP1 gene is a transcription factor important for normal development of embryonal tissue and for neurological and immune systems. There is a possible connection of FOXP1 gene expression with the occurrence as well as progression of chronic MPNs. SUBJECTS AND METHODS: The research included 35 patients diagnosed and treated in Clinical Hospital Dubrava, Zagreb, from 2006 to 2014, as well as 4 healthy bone marrow donors. Patients were divided in 5 groups, according to clinical entities. Their demographic and clinical characteristics were analyzed. From the cells of bone marrow tissue ribonucleid acid (RNA) was isolated and subjected to reverse trascription to obtain complementary deoxyribonucleid acid (cDNA). After that FOXP1 sequence was multiplied with polymerase chain reaction in real time (RT-PCR). RESULTS: We noticed Philadelphia-negative (Ph-negative) clinical and hematological stable MPNs show lower relative FOXP1 gene expression compared to control bone marrow, while also show higher relative gene expression compared to transformed entities. Statistical analysis showed the result was not statistically significant. It is possible lower gene expression is connected to more aggressive biology and greater possibility of transformation. Survival analysis found mortality is the highest in transformed entities, approximately equal in chronic stable MPNs and the lowest in reactive erythrocytosis (RE) and reactive thrombocytosis (RT). DISCUSSION: Dual function of FOXP1 gene as oncogene or tumor suppressor gene depending on the cell type is of interest. There is only a handful of papers on connection between FOXP1 gene and MPNs all indicating tumor suppressing function of FOXP1 gene. We found lower FOXP1 gene expression in all Ph-negative MPNs with the expression further reducing in transformed entities, supporting the tumor suppressing function of the gene. CONCLUSION: FOXP1 gene expression is lower in all Ph-negative MPNs compared to the control group. FOXP1 gene expression is lower in transformed clinical entities compared to clinical and hematological stable Ph-negative MPNs. Level of expression of FOXP1 gene is similar in policitemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Minimal gene expression was found in leukemic transformation in secondary acute myeloid leukemia (sAML)

Reduced renal function strongly affects survival and thrombosis in patients with myelofibrosis

We retrospectively investigated a cohort of 176 myelofibrosis patients (128 primary-PMF; 48 secondary-SMF) from five hematology centers. The presence of chronic kidney disease (CKD) was determined in addition to other clinical characteristics. CKD was present in 26.1% of MF patients and was significantly associated with older age (P 0.05 for all analyses). The presence of CKD was significantly associated with shorter time to arterial (HR = 3.49; P = 0.041) and venous thrombosis (HR = 7.08; P = 0.030) as well as with shorter overall survival (HR 2.08; P = 0.009). In multivariate analyses, CKD (HR = 1.8; P = 0.014) was associated with shorter survival independently of the DIPSS (HR = 2.7; P < 0.001); its effect being more pronounced in lower (HR = 3.56; P = 0.036) than higher DIPSS categories (HR = 2.07; P = 0.023). MF patients with CKD should be candidates for active management aimed at the improvement of renal function. Prospective studies defining the optimal therapeutic approach are highly needed

C reactive protein to albumin ratio as prognostic marker in primary and secondary myelofibrosis

We retrospectively investigated C reactive protein to albumin ratio (CAR) in a cohort of 142 patients with myelofibrosis [101 primary (PMF); 41 secondary (SMF)] and compared it to hematological and clinical parameters. Among other associations, higher CAR was significantly associated with higher grade of bone marrow fibrosis, lower frequency of Calreticulin (CALR) mutations, presence of constitutional symptoms, massive splenomegaly, transfusion dependency, blast phase disease, lower hemoglobin, lower platelets, higher ferritin and higher lactate dehydrogenase (LDH) (p < .05 for all analyses). Higher CAR was able to predict inferior survival in PMF independently of DIPSS [hazard ratio (HR)=2.17; p = .015 for high CAR and HR = 2.05; p < .001 for DIPSS] and in SMF independently of Mysec-PM (HR = 6.48; p = .022 for high CAR and HR = 2.63; p = .013 for Mysec-PM) demonstrating its good prognostic potential. CAR seems to be an independent and prognostically relevant parameter, both in PMF and SMF, and might aid in timely recognition of most vulnerable patients

Hypoosmolar and hyperosmolar COVID-19 patients are predisposed to dismal clinical outcomes

We aimed to investigate the associations of hypo- and hyperosmolarity at hospital admission with clinical characteristics and outcomes in 5645 consecutive hospitalized COVID-19 patients treated at a tertiary-level institution. Serum osmolarity was calculated as 2x Na (mmol/L) + urea (mmol/L) + glucose (mmol/L), with normal range from 275 to 295 mOsm/L. Median serum osmolarity was 292.9 mOsm/L with 51.8% normoosmolar, 5.3% hypoosmolar and 42.9% hyperosmolar patients present at the time of hospital admission. Hypoosmolarity was driven by hyponatremia, and was associated with the presence of chronic liver disease, liver cirrhosis, active malignancy and epilepsy. Hyperosmolarity was driven by an increase in urea and glucose and was associated with the presence of chronic metabolic and cardiovascular comorbidities. Both hypo- and hyperosmolar patients presented with more severe COVID-19 symptoms, higher inflammatory status, and experienced higher mortality in comparison to normoosmolar patients. In multivariate analysis, hypoosmolarity (adjusted odds ratio (aOR)=1.39, p = 0.024) and hyperosmolarity (aOR = 1.9, p < 0.001) remained significantly associated with higher mortality independently of older age, male sex, higher Charlson Comorbidity Index and more severe COVID-19. Disruptions in serum osmolarity are frequent in COVID-19 patients, may be easy to detect and target therapeutically, and thus potentially moderate associateds poor prognosis

Asymptomatic deep vein thromboses in prolonged hospitalized COVID-19 patients

High incidence of venous thromboembolic (VTE) events in coronavirus disease 2019 (COVID-19) patients has been reported despite pharmacologic thromboprophylaxis. We performed prospective bilateral lower extremity ultrasound evaluation of prolonged hospitalized COVID-19 ward patients from our institution without clinical suspicion of deep vein thrombosis (DVT).A total of 102 patient were included in the study. All patients were receiving pharmacologic thromboprophylaxis, the majority in intermediate or therapeutic doses. Asymptomatic DVT was detected in 26/102 (25.5%) patients: 22 had distal and four had proximal DVT, six had bilateral leg involvement. Pulmonary embolism was highly prevalent (17/70, 24.3%) but similarly grouped among patients with and without asymptomatic DVT. In total 37.2% of patients included in the study were recognized as having VTE.Asymptomatic DVT events were more common in intensive care unit (ICU) survivors (60% in postmechanically ventilated ICU survivors, 21.2% in ward patients, 22% in high-flow oxygen treated patients; P = 0.031), in patients with higher modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk-score (median 3 vs. 2 points with and without DVT; P = 0.021) and higher body temperature on admission (median 38.7 °C vs. 37.7 °C with and without DVT; P = 0.001). No clear associations with Padua VTE risk score, demographic and other clinical characteristics, intensity of thromboprophylaxis, severity of other COVID-19 symptoms, degree of systemic inflammation or D‑dimers on admission were found (P > 0.05 for all analyses).Systematic ultrasound assessment in prolonged hospitalized severe COVID-19 patients prior to hospital discharge is needed, especially in ICU survivors, to timely recognize and appropriately treat patients with asymptomatic DVT