Platelet-to-Lymphocyte Ratio (PLR), Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), and Eosinophil-to-Lymphocyte Ratio (ELR) as Biomarkers in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD).

Purpose: The study comprehensively evaluated the prognostic roles of the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR), and eosinophil-to-lymphocyte ratio (ELR) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Patients and Methods: Six hundred and nineteen patients with AECOPD and 300 healthy volunteers were retrospectively included into the study. The clinical characteristics of the patients with AECOPD and the complete blood counts (CBCs) of the healthy volunteers were collected. The associations of PLR, NLR, MLR, BLR, and ELR with airflow limitation, hospital length of stay (LOS), C-reactive protein (CRP), and in-hospital mortality in patients with AECOPD were analyzed. Results: Compared with the healthy volunteers, PLR, NLR, MLR, BLR, and ELR were all elevated in COPD patients under stable condition. PLR, NLR, MLR, and BLR were further elevated while ELR was lowered during exacerbation. In the patients with AECOPD, PLR, NLR, and MLR were positively correlated with hospital LOS as well as CRP. In contrast, ELR was negatively correlated with hospital LOS as well as CRP. Elevated PLR, NLR, and MLR were all associated with more severe airflow limitation in AECOPD. Elevated PLR, NLR, and MLR were all associated with increased in-hospital mortality while elevated ELR was associated with decreased in-hospital mortality. Binary logistic regression analysis showed that smoking history, FEV1% predicted, pneumonia, pulmonary heart disease (PHD), uric acid (UA), albumin, and MLR were significant independent predictors ofin-hospital mortality. These predictors along with ELR were used to construct a nomogram for predicting in-hospital mortality in AECOPD. The nomogram had a C-index of 0.850 (95% CI: 0.799-0.901), and the calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) further demonstrated its good predictive value and clinical applicability. Conclusion: In summary, PLR, NLR, MLR, and ELR served as useful biomarkers in patients with AECOPD.

Efficacy and Safety of Different Doses of Rivaroxaban and Risk Factors for Bleeding in Elderly Patients with Venous Thromboembolism: A Real-World, Multicenter, Observational, Cohort Study.

INTRODUCTION: Venous thromboembolism (VTE) consists of deep vein thrombosis (DVT) and pulmonary embolism (PE). Rivaroxaban is a direct oral anticoagulant (DOAC) inhibiting activated coagulation factor X (FXa), and exerts several advantages in the treatment of VTE compared to conventional therapy. However, the efficacy and safety of rivaroxaban in elderly patients with VTE was still poorly understood. METHODS: The study was carried out using an observational and non-interventional approach. A total of 576 patients aged ≥ 60 years with newly diagnosed VTE were included in the study. All patients received rivaroxaban with recommended treatment duration of ≥ 3 months for secondary prevention. In addition, 535 elderly patients with various diseases except VTE were included in the study in a retrospective and randomized way. RESULTS: The total bleeding rate was 12.2% (70/576). Major bleeding and non-major clinically relevant (NMCR) bleeding occurred in 4 (0.69%) patients and 5 (0.87%) patients, respectively. The rate of recurrent VTE was 5.4%. The mean level of D-dimers was increased by 467.2% in the elderly patients with VTE compared with the elderly patients without VTE. The elderly patients with VTE receiving rivaroxaban at a dose of 10 mg once daily (n = 134) had lower risk for bleeding (3.7% vs 14.7%; P = 0.001) and a similar rate of recurrent VTE (4.5% vs 5.7%; P = 0.596) as compared to the elderly patients with VTE receiving rivaroxaban at higher doses including 15 mg once daily and 20 mg once daily (n = 442). In addition, age, concomitant aspirin, hemoglobin, activated partial thromboplastin time (APTT), and rivaroxaban doses were independent predictive factors for bleeding events. CONCLUSIONS: The study suggested that a dose of 10 mg once daily should be the priority in elderly patients with VTE receiving long-term rivaroxaban anticoagulation therapy in view of reduced bleeding risk.

Efficacy and safety evaluation of Azvudine in the prospective treatment of COVID-19 based on four phase III clinical trials.

Azvudine (FNC) is a synthetic nucleoside analog used to treat adult patients living with human immunodeficiency virus-1 (HIV-1) infection with high viral load. After phosphorylation, Azvudine inhibits RNA-dependent RNA polymerase, leading to the discontinuation of RNA chain synthesis in viruses. In addition, Azvudine is the first dual-target nucleoside oral drug worldwide to simultaneously target reverse transcriptase and viral infectivity factors in the treatment of HIV infection. On 9 August 2022, Azvudine was incorporated into the Guidelines for the Diagnosis and Treatment of Coronavirus Disease 2019 (version ninth) issued by the National Health Commission and the National Administration of Traditional Chinese Medicine. The recommended oral dose of Azvudine for the treatment of moderate coronavirus disease 2019 (COVID-19) is 5 mg once daily, and the duration of Azvudine treatment should not exceed 14 days. Four phase III clinical trials were performed during 2020-2022 to evaluate the efficacy and safety of Azvudine in the treatment of COVID-19. The results revealed that Azvudine could reduce nucleic acid-negative conversion time, viral load, and time to improvement in clinical conditions in patients with moderate COVID-19. In addition, Azvudine exhibited good safety and tolerance. Thereafter, Azvudine was incorporated into the Chinese guidelines and expert consensus for the treatment of COVID-19 and was highly approbated. Furthermore, Azvudine was also included in the Chinese guidelines for HIV infection.

Deuremidevir and Simnotrelvir-Ritonavir for the Treatment of COVID-19.

Deuremidevir hydrobromide tablets and simnotrelvir tablets/ritonavir tablets (co-packaged) were approved by the Chinese National Medical Products Administration for the treatment of mild to moderate COVID-19 in January 2023. Both formulations contain small-molecule anti-SARS-CoV-2 agents. Deuremidevir, an oral nucleoside analog, is a broad-spectrum virus replication inhibitor targeting the highly conserved RNA-dependent RNA polymerase. Simnotrelvir-ritonavir is a co-packaged combination drug consisting of simnotrelvir tablets and ritonavir tablets. Simnotrelvir is an oral antiviral agent targeting the 3-chymotrypsin-like protease, which is essential for SARS-CoV-2 viral replication. Previous clinical trials revealed that both deuremidevir and simnotrelvir-ritonavir were effective and well tolerated in the treatment of COVID-19.

Why is it necessary to improve COVID-19 vaccination coverage in older people? How to improve the vaccination coverage?

In accordance with the COVID-19 surveillance data from Hong Kong, over 95% fatal cases were elderly patients aged ≥60 years, and the median age of the dead cases was 86 years in the fifth COVID-19 wave. COVID-19 case fatality rates increased with age, vaccinations offered notable protection against COVID-19 death, and the protection was enhanced as the doses of vaccinations increased. The data fully demonstrated that elderly people were the main group of victims in the COVID-19 pandemic, and the vaccination was a vital weapon against COVID-19 in elderly people. In light of the experience of China's COVID-19 response, the measures to improve COVID-19 vaccination coverage in older people were shown as follows: dispatching volunteers into residential communities to urge older people to complete COVID-19 vaccinations; ascertaining the vaccination status of elderly people suffering from underlying diseases; mobilizing various public institutions to participate in COVID-19 response; releasing a great deal of news via mass media every day to educate the elderly about COVID-19 prevention and control measures; assisting elderly people in rural and remote areas through drug distribution and emergency reserves.

Whole-brain connectivity to the bed nucleus of the stria terminalis calretinin-expressing interneurons in male mice.

The bed nucleus of the stria terminalis (BNST) is a neuropeptide-enriched brain region that modulates a wide variety of emotional behaviours and states, including stress, anxiety, reward and social interaction. The BNST consists of diverse subregions and neuronal ensembles; however, because of the high molecular heterogeneity within BNST neurons, the mechanisms through which the BNST regulates distinct emotional behaviours remain largely unclear. Prior studies have identified BNST calretinin (CR)-expressing neurons, which lack neuropeptides. Here, employing virus-based cell-type-specific retrograde and anterograde tracing systems, we mapped the whole-brain monosynaptic inputs and axonal projections of BNST CR-expressing neurons in male mice. We found that BNST CR-expressing neurons received inputs mainly from the amygdalopiriform transition area, central amygdala and hippocampus and moderately from the medial preoptic area, basolateral amygdala, paraventricular thalamus and lateral hypothalamus. Within the BNST, plenty of input neurons were primarily located in the oval and interfascicular subregions. Furthermore, numerous BNST CR-expressing neuronal boutons were observed within the BNST but not in other brain regions, thus suggesting that these neurons are a type of interneuron. These results will help further elucidate the neuronal circuits underlying the elaborate and distinct functions of the BNST.

Esophageal Ulcer After Intravitreal Ranibizumab Injection in a Patient With Age-Related Macular Degeneration.

Ranibizumab is a monoclonal antibody fragment targeted against vascular endothelial growth factor (VEGF) A isoform (VEGF-A). This study aimed to report a case of esophageal ulcer that developed soon after intravitreal ranibizumab injection in a patient with age-related macular degeneration (AMD). A 53-year-old male patient diagnosed with AMD received ranibizumab through intravitreal injection in the left eye. Mild dysphagia occurred 3 days after receiving intravitreal ranibizumab injection for the second time. The dysphagia exacerbated remarkably and was accompanied by hemoptysis 1 day after receiving ranibizumab for the third time. Severe dysphagia accompanied by intense retrosternal pain and pant emerged after injecting ranibizumab for the fourth time. An esophageal ulcer was observed through ultrasound gastroscopy, covered with fibrinous tissue, and surrounded by flushing and congestive mucosae. The patient received proton pump inhibitor (PPI) therapy combined with traditional Chinese medicine (TCM) after discontinuation of ranibizumab. The dysphagia and retrosternal pain were gradually relieved after treatment. Afterwards, the esophageal ulcer has not relapsed since permanent discontinuation of ranibizumab. To our best knowledge, this was the first case of esophageal ulcer related to intravitreal ranibizumab injection. Our study indicated that VEGF-A played a potential role in the development of esophageal ulceration.

Long-Term Prognostic Factors in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A 15-Year Multicenter Retrospective Study.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multisystem autoimmune disease with small-vessel involvement. In AAV, microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are major clinicopathologic variants. In addition, myeloperoxidase (MPO) and proteinase 3 (PR3) are major target antigens. The objective of the study was to explore the predictive factors for long-term survival in AAV patients. Materials and Methods: A multicenter retrospective study was carried out on 407 patients between 2005 and 2020. Clinical parameters were obtained from laboratory tests including the ANCA types, antinuclear antibody (ANA), extractable nuclear antigen (ENA), anti-streptolysin O (ASO), glomerular filtration rate (GFR), and the laboratory examinations for the blood routine, liver function, renal function, and immunity, etc. The data for clinical parameters were collected from electronic medical records (EMRs), and the data for patient survival were acquired through regular follow-up. The association of clinical parameters with overall survival (OS) along with 3-year and 5-year survival rates was analyzed, and the nomogram as a predictive model was established according to the analysis results. Results: In the present study, 336 (82.6%) patients and 46 (11.3%) patients were diagnosed with MPA and GPA, respectively. The mean and median OS for all the patients were 2,285 and 2,290 days, respectively. The 1-year, 3-year, 5-year, and 10-year cumulative survival rates for all the patients were 84.2%, 76.3%, 57.2%, and 32.4%, respectively. Univariate and multivariate survival analyses indicated that the independent prognostic factors included age, pathological categories (MPA, GPA, and other types), serum ANCA types (negative or positive for MPO and/or PR3), ANA, ASO, GFR, lymphocyte, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and these clinical parameters except for ASO were used to construct a nomogram. The nomogram for 3-year and 5-year survival rates had a C-index of 0.721 (95% CI 0.676-0.766). The calibration curves showed that the predicted values of the nomogram for 3-year and 5-year survival rates were generally consistent with practical observed values, and decision curve analysis (DCA) further demonstrated the practicability and accuracy of the predictive model. Conclusion: Laboratory tests at diagnosis have great significance in the prediction of long-term survival in AAV patients.

Pharmacokinetics and Bioequivalence of Two Formulations of Rosuvastatin Following Single-dose Administration in Healthy Chinese Subjects Under Fasted and Fed Conditions.

The main objective of the study was to evaluate the bioequivalence of two rosuvastatin calcium tablets in healthy Chinese subjects under fasted and fed conditions. The study was carried out using a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design, with a washout period of 7 days. Both the fasted study and fed study enrolled 28 subjects. In each study period, the subjects were administrated a single oral dose of the test product or reference product of rosuvastatin 10 mg. Blood samples were collected from pre-dose to 72 hours after administration with 16 time points in total. Bioequivalence evaluation was performed using ln-transformed pharmacokinetic parameters of rosuvastatin, including Cmax , AUC0-t , and AUC0-∞ . In the present study, 95% confidence intervals (CIs) of test/reference geometric mean ratios (GMRs) of Cmax , AUC0-t , and AUC0-∞ under the fasted and fed conditions were all within the acceptance range of 80%-125%. Additionally, only one subject experienced one adverse event (AE). High-fat meals reduced the Cmax , AUC0-t , and AUC0-∞ , but had no significant effects on the λz, t1/2 , or Tmax of rosuvastatin. In the current study, the test product was bioequivalent to the reference product, and a single dose of rosuvastatin (10 mg) was well-tolerated. Food decreased the systemic exposure of rosuvastatin without the effects on the Tmax or elimination rate.

Pharmacokinetics and bioequivalence study of two ciprofloxacin hydrochloride tablets in healthy Chinese subjects under fasting and fed conditions: A randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover study.

OBJECTIVE: The study mainly aimed to determine the bioequivalence of two branded ciprofloxacin hydrochloride tablets (250 mg) under fasting and fed conditions. MATERIALS AND METHODS: The study was carried out in 48 healthy Chinese subjects under fasting and fed conditions with a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design. In each period of the study, the subjects were assigned to receive a single oral dose of 250 mg ciprofloxacin hydrochloride. Blood samples were collected from 1 hour before dosing to 36 hours after administration with 16 timepoints in total. The bioequivalence analysis was performed after ln-transformation of the ciprofloxacin pharmacokinetic parameters including Cmax, AUC0-t, and AUC0-∞. RESULTS: A total of 48 subjects were enrolled in the fasting and fed studies, and 1 of the subjects was excluded before drug administration. In the fasting study, the 90% CIs for the test/reference geometric mean ratios (GMRs) of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 85.41 - 100.97%, 95.40 - 100.27%, and 95.48 - 100.30%, respectively. For the fed study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 90.15 - 113.75%, 99.10 - 103.77%, and 99.11 - 103.80%, respectively. These values all fell within the standard acceptance range of 80 - 125%. CONCLUSION: In the study, the generic (test) product of ciprofloxacin hydrochloride 250 mg was bioequivalent to the innovator (reference) product after single-, oral-dose administration under fasting and fed conditions.

TBC1D16 predicts chemosensitivity and prognosis in adult acute myeloid leukemia (AML) patients.

Acute myeloid leukemia (AML) is a hematopoietic disease with poor survival. Chemotherapy resistance is one of the determinant factors influencing AML prognosis. To identify genes possibly affecting the drug responses in AML, the Illumina Infinium MethylationEPIC (850K) was used to screen for differential DNA methylation loci between patients achieved complete remission (CR) or not (non-CR) after induction therapy in 37 AML patients. Then, 32 differentially methylated sites (DMS) were selected for replication in another 86 AML patients by next-generation sequencing. Nine sites including cg03988660, cg16804603, cg18166936, cg11308319, cg09095403, cg18493214, cg01443536, cg16030878 and cg10143426 were replicated. Analysis of the Gene Expression Omnibus (GEO) database showed that mRNA expression of TBC1D16 and HDAC4 was associated with AML prognosis. Methylation level of the cg16030878 in TBC1D16 3'-UTR correlated positively with TBC1D16 mRNA expression in samples both in the TCGA database and clinically collected in the study. Both higher cg16030878 methylation and higher TBC1D16 mRNA expression were associated with increased risk of non-CR and worse overall survival (OS) in AML patients. In AML cells, knockdown of TBC1D16 decreased cell proliferation and ERK phosphorylation levels, as well as increased sensitivity to mitoxantrone and decitabine indicated by IC50. In patients with combined use of decitabine, those patients with CR showed significantly lower TBC1D16 mRNA expression. On the contrary, knockdown of TBC1D16 resulted in decreased sensitivity to cytarabine in U937 cells. Our findings implicated that TBC1D16 is a potential predictor for chemosensitivity and prognosis in adult AML patients.

Salidroside inhibits NLRP3 inflammasome activation and apoptosis in microglia induced by cerebral ischemia/reperfusion injury by inhibiting the TLR4/NF-κB signaling pathway.

BACKGROUND: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an important mediator of neuroinflammatory responses that regulates inflammatory injury following cerebral ischemia and may be a potential target. Salidroside (Sal) has good anti-inflammatory effects; however, it remains unclear whether Sal can regulate NLRP3 inflammasome activation through the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway after cerebral ischemia to alleviate inflammatory injury. METHODS: We established an oxygen-glucose deprivation and reoxygenation (OGD/R) model of BV2 cells and a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model. Cell Counting Kit-8 (CCK-8), flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay were used to detect the viability and apoptosis of BV2 cells. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of inflammatory factors. 2,3,5-triphenyltetrazolium chloride (TTC) staining and modified Neurological Severity Score (mNSS) were used to detect cerebral infarction volume and neurological deficit in rats. Western blot, immunohistochemistry and immunofluorescence staining were used to detect the protein expression levels. RESULTS: Our results showed that Sal increased viability, inhibited lactate dehydrogenase (LDH) release, and reduced apoptosis in OGD/R-induced BV2 cells. Sal reduced the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-8. Following induction by OGD/R, BV2 cells exhibited NLRP3 inflammasome activation and increased protein levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, IL-1ß, and IL-18. Protein levels of key TLR4 signaling pathway elements, such as TLR4, myeloid differentiation primary response 88 (MyD88), and phosphorylated nuclear factor kappa B p65 (p-NF-κB p65)/NF-κB p65 were upregulated. Interestingly, it was revealed that Sal could reverse these changes. In addition, TAK242, a specific inhibitor of TLR4, had the same effect as Sal treatment on BV2 cells following induction by OGD/R. In the MCAO/R rat model, Sal was also observed to inhibit NLRP3 inflammasome activation in microglia, reduce cerebral infarction volume, and inhibit apoptosis. CONCLUSIONS: In summary, we found that Sal inhibited NLRP3 inflammasome activation and apoptosis in microglia induced by cerebral ischemia/reperfusion injury by inhibiting the TLR4/NF-κB signaling pathway, thus playing a protective role. Therefore, Sal may be a promising drug for the clinical treatment of ischemic stroke.

Erdheim-Chester disease with asymmetric talus involvement: A case report.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare multi-system or multi-organ histiocytic proliferative disease with diverse clinical manifestations, and the development of the disease is complex, which makes clinical diagnosis and treatment difficult. The characteristic clinical manifestations include multi-organ involvement, especially in the symmetrical diaphysis and metaphysis of the bilateral extremities. ECD with a unilateral talus lesion is extremely rare. Here, we report an unusual case of ECD invading the asymmetric talus and tibia without involving other organs. The patient had good outcome after surgery. CASE SUMMARY: We report a case of a 67-year-old man who was referred to our outpatient department because of left ankle chronic pain for 5 years, which exacerbated after a foot sprain 6 mo previously. We discovered multiple sclerotic lesions of the tibia and talus on his previous X-ray films, which were initially missed in a local hospital. Therefore, enhanced computer computed tomography (CT) and magnetic resonance imaging were performed. These examinations showed multiple lesions in the bone marrow cavity of the left tibia, and cortical sclerosis and osteonecrosis of the left talus. Specimens were collected via bone puncture from the two lesions, and a final diagnosis of ECD was confirmed by pathological and immunohistochemical examinations. In addition, other auxiliary examinations including head CT, pulmonary CT, spinal CT, abdominal CT, cardiac ultrasound and thyroid ultrasound showed no obvious abnormalities. The patient underwent surgery for the tibia lesion scraping and talus lesion scraping combined with cement casting. The patient started on a progressive rehabilitation at 4 wk, and felt no pain after surgery. During a 2-year follow-up period, the patient exercised normally without pain, and there were no signs of recurrence. CONCLUSION: This study shows that surgery treatment may also achieve good results for ECD patients with only bone involvement.

Influence of DNMT3A R882 mutations on AML prognosis determined by the allele ratio in Chinese patients.

BACKGROUND: The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. Besides, it is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations. METHODS: DNMT3A R882 mutations in 870 adult AML patients receiving standard induction therapy were detected by pyrosequencing. Associations of the mutants with responses to induction therapy and disease prognosis were analyzed. RESULTS: DNMT3A R882 mutations were detected in 74 (8.51%) patients and allele ratio of the mutations ranged from 6 to 50% in the cohort. After the first and second courses of induction therapy including aclarubicin, complete remission rates were significantly lower in carriers of the DNMT3A R882 mutants as compared with R882 wildtype patients (P = 0.022 and P = 0.038, respectively). Compared with R882 wild-type patients, those with the R882 mutations showed significantly shorter overall survival (OS) and disease-free survival (DFS) (P = 1.92 × 10-4 and P = 0.004, respectively). Patients with higher allele ratio of R882 mutations showed a significantly shorter OS as compared with the lower allele ratio group (P = 0.035). CONCLUSION: Our results indicate that the impact of DNMT3A R882 mutations on AML prognosis was determined by the mutant-allele ratio and higher allele ratio could predict a worse prognosis, which might improve AML risk stratification. In addition, DNMT3A R882 mutations were associated with an inferior response to induction therapy with aclarubicin in Chinese AML patients.

Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens.

BACKGROUNDS: UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver. METHODS: UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated. RESULTS: After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379-0.737, P = 1.7 × 10-4) and better overall survival (HR = 0.787, 95% CI 0.627-0.990, P = 0.040) as compared with homozygotes for both polymorphisms. CONCLUSION: Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.

Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML).

BACKGROUND: Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara-CTP. METHODS: A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients. CONCLUSION: Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China.

Long non-coding RNA GAS5 polymorphism predicts a poor prognosis of acute myeloid leukemia in Chinese patients via affecting hematopoietic reconstitution.

Whether long non-coding RNA (lncRNA) single-nucleotide polymorphisms (SNPs) affect prognosis of acute myeloid leukemia (AML) remains unknown. To search the association between lncRNA SNPs and AML outcomes, thirty tagSNPs in five lncRNAs were genotyped in 313 AML patients. Survival analysis indicated that GAS5 rs55829688 (T > C) was significantly associated with prognosis of AML (p = 0.018). Patients with rs55829688 CC genotype showed higher GAS5 expression in peripheral blood mononuclear cells (PBMCs) (p = 0.025) and harbored a longer platelets recovery (p = 0.040) than carriers of rs55829688T allele. In vitro study indicated that GAS5 promoter harboring the rs55829688C allele showed marginally increased reporter gene activity (p = 0.019), and the promoter activity was increased by TP63 in a dose-dependent manner (P = 0.001). Moreover, GAS5 higher expression predict shorter AML overall survival (OS), which validated in GEO GSE12417 dataset (p = 0.011). In conclusion, rs55829688 polymorphism could increase GAS5 expression by interacting with TP63, which might aggravate the myelosuppression and in turn lead to poor prognosis in AML. Trail registration number: ChiCTR-PPC-14005297.

Evaluation of DNMT3A genetic polymorphisms as outcome predictors in AML patients.

DNMT3A mutation is known as a recurrent event in acute myelogenous leukemia (AML) patients. However, association between DNMT3A genetic polymorphisms and AML patients' outcomes is unknown. DNMT3A 11 SNPs (rs11695471, rs2289195, rs734693, rs2276598, rs1465825, rs7590760, rs13401241, rs7581217, rs749131, rs41284843 and rs7560488) were genotyped in 344 diagnostic non-FAB-M3 AML patients from southern China. Patients underwent combined chemotherapy with cytarabine and anthracyclines. DNMT3A mRNA expression was analyzed in PBMCs from randomly selected AML patients. Multivariate analysis and combined genotype analysis showed that rs2276598 was associated with increased while rs11695471 and rs734693 were associated with decreased chemosensitivity (P<0.05), while rs11695471 (worse for OS), rs2289195 (favorable for OS and DFS) and rs2276598 (favorable for DFS) were significantly associated with disease prognosis (P<0.05). In conclusion, DNMT3A polymorphisms may be potential predictive markers for AML patients' outcomes, which might improve prognostic stratification of AML.

A systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma.

Vascular endothelial growth factor (VEGF) plays an important role in the tumor angiogenesis, and its expression has been supposed to be a biomarker of prognosis in patients with osteosarcoma. There are many studies assessing the prognostic role of VEGF expression in osteosarcoma, and no consistent outcomes are reported. To provide a comprehensive assessment of the prognostic role of VEGF expression, we performed a systematic review and meta-analysis of published studies. We assessed the effect of VEGF expression on the overall survival rate and the disease-free survival rate by calculating the pooled odds ratio (OR) with corresponding 95 % confidence interval (95 %CI). Finally, 12 studies with a total of 559 osteosarcoma patients were included into the systematic review and meta-analysis. Compared with osteosarcoma patients with low or negative VEGF expression, patients with high VEGF expression were obviously associated with lower disease-free survival (OR=0.25, 95 %CI 0.11-0.58, P=0.001, I (2) =56.4 %). In addition, patients with high VEGF expression were obviously associated with lower overall survival (OR=0.22, 95 %CI 0.13-0.35, P<0.001, I (2) =0.0 %). Therefore, the findings from this systematic review suggest that VEGF expression is an effective biomarker of prognosis in patients with osteosarcoma.