Hypomagnesemia May Predict Better Survival and Reduced Nonrelapse Mortality in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

BACKGROUND: Magnesium (Mg) is an essential element that is required as a cofactor for many cellular reactions, including immunologic pathways. The aim of this study was to investigate the potential impact of serum Mg levels on allogeneic hematopoietic stem cell transplantation (alloHSCT) outcomes. METHODS: Medical records of 340 alloHSCT recipients (median age: 45 [18-71] years; M/F: 210/130) were reviewed for this retrospective study. Serum Mg levels on days -28, -7, 0, +7, +14, +21, +30, +60, and +90 were included in the analysis. RESULTS: Serum Mg+14 levels predicted nonrelapse mortality (NRM) (P = .025) and had a significant impact on the development of mucositis (P = .027), fungal infection (P = .006), engraftment syndrome (P < .001), sinusoidal obstruction syndrome (SOS) (P = .001), cytomegalovirus (CMV) reactivation (P = .039), and acute graft vs host disease (GvHD) (P < .001). Based on the optimal threshold of serum Mg+14 level (1.33 mg/dL; area under the curve: 0.581 [0.515-0.648]; P = .018), the study group was divided into 2 subgroups as low- and high-Mg+14. The incidence of acute GvHD (P = .002), SOS (P = .013), engraftment syndrome (P = .013), CMV reactivation (P = .001), and Epstein Barr virus reactivation (P = .005) was significantly lower in low-Mg+14 group. The probability of overall survival (OS) was significantly better (P = .002), whereas NRM was lower in the low-Mg+14 group (P = .001). CONCLUSION: Hypomagnesemia seems to provide a considerable advantage for the post-transplant outcome, which may confirm its potential role in the immunologic microenvironment and adaptive immunity.

A metagenomic survey of bacterial communities from kurut: The fermented cow milk in Kyrgyzstan.

Kurut is a traditional dry dairy product mostly consumed in Central Asia. In this study, the distribution of the dominant bacteria present in kurut samples (n=84) originated from seven (Chuy, Issyk-Kul, Talas, Naryn, Jalal-Abad, Osh, and Batken) regions in Kyrgyzstan were analyzed with Illumina iSeq100 platform. The dominant phylum detected was Firmicutes followed by Proteobacteria, Actinobacteria, Cyanobacteria/Chloroplast, and Tenericutes. The most abundant family detected was Lactobacillaceae followed by Streptococcaceae, Enterococcaceae, Chloroplast, and Leuconostocaceae. At the genus level, Lactobacillus was the predominant one in samples and Streptococcus, Enterococcus, Lactococcus, and Streptophyta followed this. Further comprehensive characterization analyses in kurut samples may have potential applications both in industrial starter culture developments and also future therapeutic approaches based on potential strains with probiotic properties.

Expression of GRP78 and its copartners in HEK293 and pancreatic cancer cell lines (BxPC-3/PANC-1) exposed to MRI and CT contrast agents.

Endoplasmic reticulum (ER) stress-associated chaperones trigger a defense mechanism called as unfolded protein response (UPR) which can manage apoptosis and be determinative in cell fate. Both anticancer drug effects and potential toxicity effects of magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents were aimed to be evaluated. For this purpose, we investigated expression profiles of endoplasmic reticulum stress-associated chaperone molecules in human pancreatic tumor lines BxPC-3 and PANC-1 and control human embryonic kidney cells 293 (HEK293) induced with a variety of gadolinium and iohexol contrast agents. Protein expression levels of ER stress-associated chaperones (master regulator: GRP78/Bip and its copartners: Calnexin, Ero1, PDI, CHOP, IRE1α and PERK) were evaluated with Western blotting. Expression levels at mRNA level were also assessed for GRP78/Bip and CHOP with real-time PCR. Induction of cells was carried out with four different Gd-based contrast agents (GBCAs): (Dotarem, Optimark, Primovist and Gadovist) and two different iohexol agents (Omnipol, Omnipaque). CT contrast agents tested in the study did not result in significant ER stress in HEK293 cells. However, they do not seem to have theranostic potential in pancreas cancer through ER pathway. The potential efficiency of macrocyclic MRI contrast agents to provoke apoptosis via ER stress-associated chaperones in BxPC-3 cells lends credibility for their future theranostic use in pancreas cancer as long as undesired toxicity effects were carefully considered. ER stress markers and/or contrast agents seem to have promising potential to be translated into the clinical practice to manage pancreas cancer progression.

Clinical factors associated with autologous stem cell transplantation outcomes in multiple myeloma: upfront transplant with MEL200 remains the standard of care.

Autologous stem cell transplantation (ASCT) remains the mainstay of the treatment in newly diagnosed transplant-eligible multiple myeloma (MM) patients. This retrospective study was performed to investigate the potential prognostic markers which may modify transplant course in a total of 256 ASCT recipients [median age: 58 (30-74) years; male/female: 138/118], including pretransplant (PET0) and day + 60 (PET2) PET/CT assessments and comparative analysis of melphalan (Mel) dose. Better responses with significantly higher complete response/very good partial response rates were achieved in patients who proceeded to transplant within 301 days from diagnosis (p < 0.001). Patients who had received < 1.5 lines of treatment prior to transplant had significantly higher probability of overall survival (OS) (p = 0.004) and progression-free survival (PFS) (p < 0.001). The probability of OS was significantly higher in patients with low Eastern Cooperative Oncology Group (ECOG) performance score (PS = 0-1) (p = 0.003) and HCT-Comorbidity Index (HCT-CI = 0) (p = 0.011). The number of involved areas (p = 0.028) and maximum standardized uptake value (SUVmax) (p = 0.021) in PET0 represented significant impact on OS. The probabilities of OS (p < 0.001) and PFS (p = 0.01) were significantly better with Mel200 mg/m2 conditioning compared to Mel140 mg/m2. Conditioning with Mel200 mg/m2, early and upfront ASCT and low pretransplant treatment burden were found to be significantly associated with ASCT outcome in MM patients. Despite its predictor impact on survival and prognosis, further studies are warranted to standardize PET/CT-based response assessments before being used as a guide for treatment decisions in clinical practice.

Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party.

Background: Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. Methods: We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. Findings: 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA: (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01). Interpretation: Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. Funding: There was no external funding source for this study.

Preconditioning Modified-Easix as a Predictor of Prognosis in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Allogeneic hematopoietic stem cell transplantation (alloHCT) is associated with severe complications, most of which share a common physiopathological background characterized by endothelial dysfunction. A novel risk assessment model, endothelial activation and stress index (EASIX), has been introduced as a predictor of endothelial activation. This retrospective study was performed to evaluate the predictive impact of EASIX/modified-EASIX (mEASIX) on transplant outcome. Medical records of 398 alloHCT recipients [median age: 43(17-71) years; M/F: 243/155] were examined. EASIX/mEASIX were calculated at specific time points before and after transplantation. EASIX/mEASIX were significantly associated with transplant complications including engraftment syndrome, sinusoidal obstruction syndrome, febrile neutropenia and transplant associated thrombotic microangiopathy. The probability of overall survival was significantly higher in low-preconditioning mEASIX (day -7) group (37% vs 25.2%; p = 0.008; HR: 2.057; 95% CI: 1.208-3.504). The probabilities of day30 mortality (2.9% vs 19.4%; p = 0.017; HR: 7.028; 95% CI: 1.418-34.836), day100 mortality (9% vs 33%; p = 0.004; HR: 4.469; 95% CI: 1.619-12.336) and non relapse mortality (44.8% vs 61.4%; p = 0.005; HR: 2.551; 95% CI: 1.318-4.941) were lower in low-preconditioning mEASIX (day -7) group. This retrospective cohort analysis demonstrates the significant impact of EASIX/mEASIX on transplant complications and survival. Prospective analyses are mandatory to assess the predictive role of EASIX/mEASIX in clinical practice.

Elevated expression levels of COX-2, IL-8 and VEGF in colon adenocarcinoma.

There is growing evidence of a connection between inflammation and tumor development and NF-κB is an important transcription factor in the inflammation pathway. Genetic approaches have proven the role of NF-κB responsive genes in tumorigenesis. The NF-κB responsive genes products such as IL-8, VEGF and COX-2 are the key components of angiogenesis. MMP-2 and MMP-9 are playing important roles in the disruption of the extracellular matrix that may contribute to the metastasis of tumor cells. This study aimed to investigate gene expression levels of COX-2, IL-8, VEGF, MMP-2 and MMP-9 in colon tumors. A total of 34 fresh colon carcinoma specimens and paired normal adjacent tissues (NAT) were collected during the surgery and RNA isolations were carried out from specimens. Synthesis of cDNA was carried out from these RNAs with oligo dT18 primers. The transcribed cDNA was used for PCR amplification reactions for the investigated genes with ß-actin being the internal reference via the semi-quantitative RT-PCR method. A statistically significant difference was observed for COX-2, IL-8 and VEGF which were all upregulated in colon tumors compared with adjacent normal tissues (p<0.05). However, MMP-2 and MMP-9 expression levels did not change between tumor and normal tissues (p>0.05). Upregulated expression levels of COX-2, IL-8 and VEGF might occur in the early stages of tumorigenesis and detection of these mRNA levels may be beneficial for early diagnosis and management of colon tumors.

Is flow cytometry useful in determining central nervous system involvement in patients with hematological malignancy? Analysis with a prospective cohort.

Central nervous system (CNS) involvement occurs in approximately 5-15% of patients in hematological malignancies. Early diagnosis and treatment is essential for a successful approach to CNS involvement. The gold standard method for diagnosis is cytological evaluation, but its sensitivity is low. Flow cytometry (FCM) from cerebrospinal fluid(CSF) is another method used to identify small groups of cells with abnormal phenotype. In our study, we compared FCM and cytological findings in the evaluation of CNS involvement in our patients with hematological malignancies. 90 patients [58 males, 32 females] were included in the study. CNS involvement was positive in 35(%38.9) patients, negative in 48(%53.3) patients, and suspicious (atypical) in 7(%7.8) patients by flow cytometry and it was positive in 24(%26.7) patients, negative in 63(%70) patients, and atypical in 3(%3.3) patients by cytology. While the sensitivity and specificity were found to be respectively 68.5% and 100% by cytology, it was found to be 94.2% and 85.4% by flow cytometry. Flow cytometry, cytology and MR findings were significantly correlated with each other in both prophylaxis (p < 0.001) and patients with prediagnosis of CNS involvement. Although the gold standard diagnostic method in the diagnosis of CNS involvement is cytological, its sensitivity is low and it can give false negative results at a rate of 20-60%. Flow cytometry is an ideal objective and quantitative method for identifying small groups of cells with abnormal phenotype. Flow cytometry can be used routinely in the diagnosis of CNS involvement in patients with hematological malignancies with cytology, since it can detect fewer malignant cells, has a higher sensitivity, and provides easy and faster results.

[Comparison of the Results of Galactomannan and Beta Glucan Antigen Tests in the Suspicion of Invasive Pulmonary Aspergillosis]. / Invaziv Pulmoner Aspergilloz Süpheli Hastalarda Galaktomannan ve Beta Glukan Antijen Testlerinin Karsilastirilmasi.

Opportunistic fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Invasive aspergillosis (IA) has an important place among these infections with ~ 250.000 cases annually. Reducing the mortality rate due to invasive aspergillosis is possible with early diagnosis and treatment of the disease. Because of the low sensitivity in microscopic examination, the time consuming of culture growth, and the difficulties in distinguishing colonization/infection, serological methods are frequently used in the diagnosis of invasive aspergillosis. The aim of this study was to determine the diagnostic performance of galactomannan and beta glucan tests for the diagnosis of invasive pulmonary aspergillosis (IPA). Sixty patients, followed up with the suspicion of invasive pulmonary aspergillosis in Gazi University Hospital were included in the study. The clinical classification of the patients was made according to the revised European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) criteria. A total of 10 patients were classified as probable invasive aspergillosis and 20 patients were classified as possible invasive fungal disease. Demographic data of the patients and various risk factors were recorded. One hundred and thirty serum and nine bronchoalveolar lavage (BAL) fluid samples were studied with Plateliaᵀᴹ Aspergillus Ag (Bio-Rad, France), Dynamiker Aspergillus Galactomannan and Dynamiker Fungus (1-3)-beta-D-Glucan (Dynamiker, China) kits. Sensitivity and specificity values were calculated according to U.S. Food and Drug Administration (FDA) approved Plateliaᵀᴹ Aspergillus Ag test. According to this study, the most important risk factors in the development of IPA were the use of steroids and immunomodulatory drugs. The sensitivity of the galactomannan test in the probable group was 77.8%, the specificity was 96.7%, the sensitivity of the beta glucan test was 61.1%, and the specificity was 92.6%. When these two tests were evaluated together, it was observed that the sensitivity in the probable group increased to 83.3% and the specificity decreased to 89.3%. The combined use of galactomannan and beta glucan tests increases the diagnostic sensitivity. Although the presence of prolonged neutropenia is an important risk factor for IA, the use of steroids and immunomodulatory drugs should be kept in mind in non-neutropenic patients.

Risk factors for ICU mortality in patients with hematological malignancies: a singlecenter, retrospective cohort study from Turkey.

BACKGROUND: Patients with hematological malignancies (HM) often require admission to the intensive care unit (ICU) due to organ failure, disease progression or treatment-related complications, and they generally have a poor prognosis. Therefore, understanding the factors affecting ICU mortality in HM patients is important. In this study, we aimed to identify the risk factors for ICU mortality in our critically ill HM patients. METHODS: We retrospectively reviewed the medical records of HM patients who were hospitalized in our medical ICU between January 1, 2010 and December 31, 2018. We recorded some parameters of these patients and compared these parameters by statistically between survivors and nonsurvivors to determine the risk factors for ICU mortality. RESULTS: The study included 368 critically ill HM patients who were admitted to our medical ICU during a 9-year period. The median age was 58 (49-67) years and 63.3% of the patients were male. Most of the patients (43.2%) had acute leukemia. Hematopoietic stem cell transplantation (HSCT) was performed in 153 (41.6%) patients. The ICU mortality rate was 51.4%. According to univariable analyses, a lot of parameters (e.g., admission APACHE II and SOFA scores, length of ICU stay, some laboratory parameters at the ICU admission, the reason for ICU admission, comorbidities, type of HM, type of HSCT, infections on ICU admission and during ICU stay, etc.) were significantly different between survivors and nonsurvivors. However, only high SOFA scores at ICU admission (OR:1.281, p = 0.004), presence of septic shock (OR:17.123, p = 0.0001), acute kidney injury (OR:48.284, p = 0.0001), and requirement of invasive mechanical ventilation support during ICU stay (OR:23.118, p = 0.0001) were independent risk factors for ICU mortality. DISCUSSION: In our cohort, critically ill HM patients had high ICU mortality. We found four independent predictors for ICU mortality. Yet, there is still a need for further research to better understand poor outcome predictors in critically ill HM patients.

Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry.

Introduction: COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. Methods: This study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic. Results: The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 - 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022. Discussion: Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.

Determination of Bacterial Diversity of Propolis Microbiota.

Propolis is a natural resinous mixture produced by the excretions of honeybees. PCR amplification of the 16S rRNA gene region was achieved using DNA of pre-enriched propolis samples collected from Apis mellifera production hives (n=37) in Eastern Türkiye (Bingöl and its regions). Next-generation sequencing and metabarcoding techniques were used to identify bacterial communities in propolis samples. Firmicutes dominated the phylum structure, with Proteobacteria, Actinobacteria, Tenericutes, and Spirochaetes following. The top three bacterial families were Bacillaceae, Enterobacteriaceae, and Enterococcaceae. Bacillus (dominantly B. badius and B. thermolactis at the species level) was recognized at the genus level, followed by Enterococcus and Clostridium sensu stricto. Our study comprehensively identified the bacterial diversity of propolis samples. Further investigations targeting to enlighten the microbiota of propolis and its potential application fields are required to gain better insight into ecological, nutritional, and medicinal perspectives.

Allogeneic hematopoietic cell transplantation in patients with chronic phase chronic myeloid leukemia in the era of third generation tyrosine kinase inhibitors: A retrospective study by the chronic malignancies working party of the EBMT.

Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for chronic phase (CP) chronic myeloid leukemia (CML) has dramatically decreased. Imatinib was the first TKI introduced to the clinical arena, predominantly utilized in the first line setting. In cases of insufficient response, resistance, or intolerance, CML patients can subsequently be treated with either a second or third generation TKI. Between 2006 and 2016, we analyzed the impact of the use of 1, 2, or 3 TKI prior to allo-HCT for CP CML in 904 patients. A total of 323-, 371-, and 210 patients had 1, 2, or 3 TKI prior to transplant, respectively; imatinib (n = 778), dasatinib (n = 508), nilotinib (n = 353), bosutinib (n = 12), and ponatinib (n = 44). The majority had imatinib as first TKI (n = 747, 96%). Transplants were performed in CP1, n = 549, CP2, n = 306, and CP3, n = 49. With a median follow-up of 52 months, 5-year OS for the entire population was 64.4% (95% CI 60.9-67.9%), PFS 50% (95% CI 46.3-53.7%), RI 28.7% (95% CI 25.4-32.0%), and NRM 21.3% (95% CI 18.3-24.2%). No difference in OS, PFS, RI, or NRM was evident related to the number of TKI prior to allo-HCT or to the type of TKI (p = ns). Significant factors influencing OS and PFS were > CP1 versus CP1 and Karnofsky performance (KPS) score > 80 versus ≤80, highlighting CP1 patients undergoing allo-HCT have improved survival compared to >CP1 and the importance of careful allo-HCT candidate selection.

Is comprehensive geriatric testing guiding in the identification of multiple myeloma patients who are candidates for autologous stem cell transplantation? A prospective analysis.

Multiple myeloma (MM) is a hematological malignancy of older adults. This study aimed to investigate the differences in performance, comorbidity scores, and comprehensive geriatric assessment (CGA) before and after induction therapy in newly diagnosed MM patients, as well as the factors that may be associated with improved performance status after induction therapy. Thirty-seven consecutive patients aged 50 years and older, who were newly diagnosed with MM, were included in the study. The patients underwent performance status evaluation and CGA when first diagnosed and after 4 cycles of induction chemotherapy. The performance status of 11 patients (40.7%) changed after induction therapy. Improvement in performance status was significantly lower in patients who were frail according to the Fried frailty criteria and IMWG scores (60% vs. 25%, p = 0.04), (30.0% vs. 6.2%, p = 0.02), taking more than 2 medications due to comorbidities (p = 0.01, confidence interval 0.06-0.09) and those with renal involvement (80.0% vs. 18.7%, p = 0.002). Those with bone involvement were more prevalent among the patients whose performance status improved (87.5% and 50.0%, p = 0.03). This study demonstrated that performance status might improve after induction therapy. Results suggest that CGA before induction therapy can predict performance status change. These results might have implications for predicting at the time of diagnosis, whether an MM patient can be a transplant candidate after induction therapy.

A medical and molecular approach to kefir as a therapeutic agent of human microbiota.

The imbalanced microbial composition called as dysbiosis constitutes a tendency related to different kind of human diseases. To overcome the disadvantages of dysbiosis, the consumption of probiotics is an emerging and promising topic of the last decade. Kefir is a probiotic fermented beverage produced from the fermentation of kefir grains with changing varieties of milk and displays a symbiotic association of bacteria and yeast. The discovery of the concept that fermented foods/beverages such as kefir could modify gut microbiota in humans has widened the borders of precision medicine and now microbiome therapeutics can be considered as a significant part of this field. Kefir seems to have potential to guide and manipulate future replacement/complementary therapies with a variety of beneficial biological/medical properties it has. The aim of this review was a comprehensive recapitulation of probiotic beverage kefir's significant properties mainly focusing of antioxidative, immunomodulatory, apoptotic, antitumor, neuroprotective. Apoptotic/antimetastatic effects are regulated at the molecular level by increases in TGF-ß1, caspase-3, p53, Bax, Bax:Bcl-2 ratio, p21 and decreases in TGF-α, Bcl-2 and MMP polarization. Neuroprotective effects are revealed upon upregulation of SOD/catalase and anti-inflammatory Treg cells, decreases in repetitive behavior and modulation of apoptotic genes. Besides these significant features that may offer quite advantages in supplementary cancer therapies, the scope was also extended to recent emerging medical topics and also discussed and evaluated the concept of "psychobiotics". The therapeutic potential of psychobiotic effect is majorly attributed to the increased ratios of Clostridium butyricum, Lactobacillus and Bifidobacterium.

Predictive value of KRAS/NRAS, IL-4 VNTR and HPV alterations in metastases of colorectal cancer.

PURPOSE: The main aim of the study was to evaluate the potential roles of KRAS/NRAS proto-oncogenes, IL-4 VNTR variants and HPV prevalence in colorectal cancer metastasis. As the second aim, the interactions of the analyzed genes and viral sequences with both clinicopathological variables and each other were targeted. METHODS: DNA was extracted using AmoyDx FFPE DNA Extraction kit from paraffin-embedded colorectal tumor tissue samples (n = 60). NRAS/KRAS mutational profiles were determined with real-time polymerase chain reaction using AmoyDx KRAS/NRAS Mutation Detection Kit. Genotyping of IL-4 VNTR was made with PCR. HPV detection was analyzed by PCR with both GP5+/GP6+ consensus primers and type-specific primers for HPV-16 and HPV-18. SPSS v22 (IBM) statistics software was used for all statistical analyses. RESULTS: From the demographical/clinicopathological parameters, age and biopsy specimens revealed an association with metastasis. KRAS mutation rate was as high as 65 % in the patients and the most prevalent mutation type was G12D. Metastasis risk was 3.19-fold increased in KRAS-mutated patients compared to KRAS-negative ones. IL-4 VNTR genotypes/alleles were not associated with metastasis in our analysis.  The frequency of HPVs in our colorectal cancer cohort was 36.7 %, but HPV positivity was not found to be associated with metastasis.  A significant association was found between HPV and NRAS mutations; NRAS wild-type status acted as a protective factor by 7.5-fold for HPV negativity. CONCLUSION: Our study comprehensively and concomitantly evaluated several potential molecular risk factors. Future studies designed in such combined approaches will substantially contribute to better manage colorectal cancer tumorigenesis from molecular biological perspective (Tab. 6, Fig. 2, Ref. 40).

Eltrombopag may induce bone marrow fibrosis in allogeneic hematopoietic stem cell transplant recipients with prolonged thrombocytopenia.

Poor graft function (PGF) and secondary failure of platelet recovery (SFPR) are significant causes of transplant related morbidity and mortality. Although thrombopoietin receptor agonists (TPO-RA), particularly Eltrombopag (EPAG), have been reported to be efficacious in the treatment of prolonged thrombocytopenia, potential long term adverse effects remain to be elucidated. This retrospective study was performed to determine the efficacy and toxicity profile of TPO-RAs in allogeneic hematopoietic stem cell transplant (alloHCT) recipients. Medical records of 27 patients [median age: 55(21-73) years; male/female: 15/12] who received posttransplant EPAG for SFPR or PGF were analysed. Eltrombopag was started on day 110(33-670) after transplant. Median initial dose was 25(25-50) mg/day which was properly escalated to a maximum dose of 75(50-100) mg/day. Duration of the treatment was median 120(31-377) days. Overall response rate (ORR) was 59.3% in the study population. Time-to-treatment response was 42(3-170) days. Mild-to-moderate bone marrow fibrosis was detected in the posttreatment biopsies of 12/22 patients (54.5%), 9 of whom did not represent any grade of myelofibrosis in their inital biopsies. The grade of posttreatment fibrosis was significantly increased when time-to-treatment response was longer (p = 0.008). Long term use of TPO-RAs may be considered as a potential cause of myelofibrosis in alloHCT recipients.

Investigation of the functional vesicular monoamine transporter 1 (VMAT1/SLC18A1) Thr136Ile gene variant in bipolar disorder

Background and objectives: Bipolar disorder (BD) is an episodic and recurrent mood disturbance ranging from mania to severe depression. Because of the heterogeneity of psychiatric disorders, enlightening the possible molecular risk drivers is crucial. Vesicular monoamine transporter 1 (VMAT1) is an important candidate gene to study the underlying molecular mechanisms in BD pathogenesis since it has a significant role in the packaging of monoaminergic neurotransmitters into presynaptic storage vesicles. The aim of this study was to ascertain whether functional and evolutionarily important variant of VMAT1 gene (Thr136Ile (rs1390938)) would affect the susceptibility of the individuals to BD in a Turkish population.MethodOne hundred twenty BD patients and one hundred one healthy control individuals were recruited for the study. Samples were genotyped using PCR-RFLP method to detect VMAT1 gene variant (Thr136Ile (rs1390938)).ResultsContrary to our expectations, VMAT1 Thr136Ile (rs1390938) gene variant was not associated with BD in our population. There was also no relationship between VMAT1 genotypes and some clinically significant parameters in BD patients.ConclusionOur data showed no association between VMAT1 Thr136Ile (rs1390938) and BD in Turkish population. We strongly recommend the analysis of this variant in other populations to draw a precise conclusion about the role of this variant in bipolar disorder. Further large-scale research for the other variants of VMAT1 is also required to clarify the strong hypothesis focused on VMAT1 variants in the development of neuropsychiatric disorders. (AU)

Antecedentes y Objetivos: El trastorno bipolar (TB) es una alteración del ánimo episódica y recurrente, que fluctúa entre la manía y la depresión severa. Debido a la heterogeneidad de los trastornos psiquiátricos, es esencial esclarecer los posibles impulsores del riesgo molecular. El transportador 1 vesicular de monoaminas (VMAT1) es un importante gen candidato para estudiar los mecanismos moleculares subyacentes en la patogenia del TB, dado que tiene un rol significativo de embalaje de los neurotransmisores monoaminérgicos en las vesículas de almacenaje presinápticas. El objetivo de este estudio fue comprobar si la variante funcional y evolutivamente importante del gen VMAT1 (Thr136Ile (rs1390938)) afectaría a la susceptibilidad de los individuos relativa a TB en una población turca.MétodoSe seleccionaron para el estudio ciento veinte pacientes con TB y ciento un individuos sanos. Se genotipificaron las muestras mediante el método PCR-RFLP, para detectar la variante del gen VMAT1 (Thr136Ile (rs1390938)).ResultadosContrariamente a nuestras expectativas, la variante del gen VMAT1 (Thr136Ile (rs1390938)) no estuvo asociada al TB en nuestra población. Tampoco se encontró relación entre los genotipos de VMAT1 y algunos parámetros clínicamente significativos de los pacientes de TB.ConclusiónNuestros datos no reflejaron asociación ninguna entre la variante Thr136Ile (rs1390938) de VMAT1 y el TB en la población turca. Recomendamos encarecidamente el análisis de esta variante en otras poblaciones, para obtener una conclusión precisa sobre el rol de la misma en el trastorno bipolar. También son necesarios más estudios a gran escala sobre las demás variantes de VMAT1 para esclarecer la sólida hipótesis centrada en las variantes de VAT1, en cuanto al desarrollo de trastornos neuropsiquiátricos. (AU)

Comparison of daily oral iron replacement therapy with every other day treatment in female reproductive age patients with iron-deficiency anemia.

Iron-deficiency anemia (IDA) is accepted as the most common cause of anemia in the world. The main goals of iron replacement therapy are to normalize the hemoglobin level and to replace iron stores. Current guidelines for treating iron deficiency recommend daily divided doses of iron to increase absorption. Hepcidin is a key regulator of systemic iron balance and acts in harmony with intracellular iron metabolism. Daily dosing and divided doses may increase serum hepcidin and decrease iron absorption. In this study, it was aimed to compare the effectiveness of daily and every other day oral iron replacement therapy in women of reproductive age with iron-deficiency anemia. We included premenopausal female patients aged between 18 and 50 years with iron-deficiency anemia. Forty patients were given oral iron therapy at a daily dose of 2*80 mg (iron sulfate). Forty-three patients were given iron treatment at a dose of 2*80 mg (iron sulfate) every other day. After 2 months of oral iron therapy, there was a significant improvement in hemoglobin, mean corpuscular volume, serum iron, total iron-binding capacity, and transferrin saturation in both groups. The values of hemoglobin, serum iron, transferrin saturation, and ferritin significantly increased at the end of the treatment for both groups. Although the median hepcidin level on the 15th-day measurement in the every other day treatment group was higher than that in the daily treatment group, there was no significant difference. As a result, the patients' compliance with the treatment can be increased by offering treatment every other day instead of daily, since it provides similar treatment effectiveness.

Association analysis of Epworth Sleepiness Scale (ESS) scores with serotonin transporter (5-HTT- LPR, 5-HTT-VNTR) and circadian (PER3-VNTR) genes.

Excessive daytime sleepiness (EDS) is a common complaint encountered in clinical practice with serious consequences both for individual and society since it can increase the ratio of motor vehicle accidents, work- related incidents, and deaths. Moreover, it also manifests less serious individual consequences. This study aimed to investigate the potential role of PER3-VNTR, 5-HTT-LPR, and 5-HTT-VNTR in terms of constituting liability to EDS. Two hundred eighteen participants (93 complaining about daytime sleepiness and 125 individuals with no serious complaint) were recruited in the study. General daytime of sleepiness was quantified with Epworth sleepiness scale (ESS). DNA extractions were performed from collected blood samples with standart salting-out procedure and genotyped. ESS scores displayed difference between individuals suffering from sleep disturbances and other individuals with values of 12.75±4.55 and 6.34±4.26, respectively. PER3- VNTR and 5-HTT-LPR genotypes did not display association with mean ESS scores. However, 5-HTT-VNTR genotypes showed significant association with mean ESS scores; individuals with 10/10 genotypes had the highest ESS score reflecting this genotype as a liability factor for EDS. We strongly recommend further studies based on circadian/serotonin pathway genes in different populations to reach to a consensus and highlight sleep genetic marker genes which then can be the future targets of pharmacological treatment studies for sleep problems.