Interval between Intra-Arterial Infusion Chemotherapy and Surgery for Locally Advanced Oral Squamous Cell Carcinoma: Impacts on Effectiveness of Chemotherapy and on Overall Survival

Background. The interval between intra-arterial infusion chemotherapy (IAIC) and surgery was investigated in terms of its effects on survival in patients with locally advanced oral squamous cell carcinoma (OSCC). Methods. This retrospective study analyzed 126 patients who had completed treatment modalities for stage IV OSCC. All patients were followed up for 3 years. Kaplan-Meier and Cox regression methods were used to determine how survival was affected by general factors, primary tumor volume, TNM stage, and duration of neoadjuvant chemotherapy. Results. In 126 patients treated for locally advanced OSCC by preoperative induction IAIC using methotrexate, multivariate analysis of relevant prognostic factors showed that an IAIC duration longer than 90 days was significantly associated with poor prognosis (hazard ratio, 1.77; P=0.0259). Conclusions. Duration of IAIC is a critical factor in the effectiveness of multimodal treatment for locally advanced OSCC. Limiting the induction course to 90 days improves overall survival

Prenatal diagnosis and molecular cytogenetic characterization of de novo partial monosomy 3p (3p26.3→pter) and partial trisomy 16q (16q23.1→qter)

AbstractObjectiveTo present the prenatal diagnosis and molecular cytogenetic characterization of a de novo unbalanced reciprocal translocation.Case ReportA 37-year-old woman, G3P1, underwent amniocentesis at 17 weeks of gestation because of her advanced maternal age. Her husband was 38 years old. Amniocentesis revealed a derivative chromosome 3 with the deletion of terminal 3p and the addendum of an unknown extra chromosomal segment on the distal 3p. The parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. Array comparative genomic hybridization (aCGH) analysis using cultured amniocytes revealed a 2.38-Mb deletion in 3p26.3 [arr 3p26.3 (1-2,380,760)×1] encompassing 15 genes, which included 3 OMIM genes CHL1, CNTN6, and CNTN4, and a 13.17-Mb duplication in 16q23.1-q24.3 [arr 16q23.1q24.3 (76,999,082-90,170,596)×3] encompassing 207 genes, which included 81 OMIM genes. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism. Postnatal cord blood analysis revealed a karyotype of 46,XY,der(3)t(3;16)(p26.3;q23.1)dn. Polymorphic DNA marker analysis by quantitative fluorescent polymerase chain reaction (QF-PCR) on the DNAs extracted from the placenta and parental blood showed a paternal origin of the aberrant chromosome.ConclusionThe aCGH and QF-PCR analyses helped in delineating the genomic imbalance and parental origin of prenatally detected de novo unbalanced reciprocal translocation

Evolution of carbapenem resistance in Acinetobacter baumannii: An 18-year longitudinal study from a medical center in northern Taiwan

BackgroundCarbapenem-resistant Acinetobacter baumannii has emerged as an important cause of nosocomial infections with high morbidity and mortality. The carbapenemases, especially class D carbapenem-hydrolyzing oxacillinases (CHDLs), play an important role, but the relationship between their prevalence trend and carbapenem resistance remains unclear.Materials and methodsBetween 1995 and 2012, we collected 667 isolates of A. baumannii from a single medical center in northern Taiwan. Pulsed-field gel electrophoresis (PFGE) was used to determine clonality. Antimicrobial susceptibility was determined. Carbapenemase genes and associated genetic structures were detected by polymerase chain reaction.ResultsIsolates were heterogeneous on PFGE. Susceptibility to carbapenem decreased steadily over the study period from 88.1% (2001–2003) to <25% (2010–2012), whereas the isolates remained susceptible to colistin (nearly 100%) and partially susceptible to tigecycline (80%). Starting in 2001, isolates carrying the ISAba1-blaOXA-51-like allele were consistently identified. Isolates containing the transposons Tn2006 or Tn2008 first appeared in 2007 with increasing carriage rates from 17.5% (2007–2009) to 50.0% (2010–2012). The IS1008-ΔISAba3-blaOXA-58-like, blaOXA-72 and metallo-β-lactamase genes were detected only sporadically. Isolates carrying CHDL genes were resistant to multiple drugs, including carbapenem, but remained susceptible to colistin (100.0%).ConclusionIncreased carbapenem resistance in A. baumannii may be caused by the increased prevalence of isolates containing the ISAba1-blaOXA-51-like allele and the transposons Tn2006 and Tn2008

Hospital Mortality of Septic Acute Kidney Injury Requiring Renal Replacement Therapy in the Postoperative Elderly

SummaryBackgroundSeptic acute kidney injury (AKI) is a common complication in intensive care units (ICU), it and portends a higher risk of morbidity and death than nonseptic AKI. However, its outcome and prognostic factors among elderly postoperative patients remain unknown. We aimed to determine the risk factors and predictors of mortality among postoperative elderly patients (≥ 65 years) with septic AKI requiring acute dialysis.MethodsThe study protocol was based on that of a clinical cohort study of renal failure patients in the database of the National Taiwan University Surgical ICU Acute Renal Failure (NSARF) Study Group. From January 2002 to July 2009, patients (aged > 18 years) with postoperative AKI requiring renal replacement therapy (RRT) were recruited for this study. Each case of septic AKI before operation was identified and patients with end-stage renal disease were excluded.ResultsA total of 292 postoperative patients with septic AKI requiring dialysis were identified during the study period. The mean (SD) age was 65.9 (11.9) years and 68.2% were men. Abdominal surgery was the most common type of surgery (42.8%), followed by cardiovascular (28.8%) and chest surgery (15.4%). The most common indications for RRT in this study cohort were azotemia in 223 patients (76.4%) and fluid overload in 62 patients (21.2%); 92 (31.5%) patients had one indication, 170 (58.2%) had two indications, and 30 (10.3%) had more than three indications. The elderly patients (those ≥ 65 years) had anemia, underwent abdominal surgery, and received dialysis for fluid overload more frequently than the young adults. By contrast, the young adults were more likely to present with shock requiring vasopressor use and have abnormal liver functions. In the elderly subgroup, the outcome was found to be associated with mechanical ventilator use, but not with disease severity, comorbidities, types of surgery and the indication for dialysis.ConclusionsThe hospital mortality of postoperative elderly patients with septic AKI was more than 60% and was not affected by age. Mechanical ventilator use was the major risk factor and prognostic factor for elderly patients in this clinical setting

Evaluation of Oral Antiretroviral Drugs in Mice With Metabolic and Neurologic Complications

Antiretroviral (ART) drugs has previously been associated with lipodystrophic syndrome, metabolic consequences, and neuropsychiatric complications. ART drugs include three main classes of protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our previous work demonstrated that a high risk of hyperlipidemia was observed in HIV-1-infected patients who received ART drugs in Taiwan. Patients receiving ART drugs containing either Abacavir/Lamivudine (Aba/Lam; NRTI/NRTI), Lamivudine/Zidovudine (Lam/Zido; NRTI/NRTI), or Lopinavir/Ritonavir (Lop/Rit; PI) have the highest risk of hyperlipidemia. The aim of this study was to investigate the effects of Aba/Lam (NRTI/NRTI), Lam/Zido (NRTI/NRTI), and Lop/Rit (PI) on metabolic and neurologic functions in mice. Groups of C57BL/6 mice were administered Aba/Lam, Lam/Zido, or Lop/Rit, orally, once daily for a period of 4 weeks. The mice were then extensively tested for metabolic and neurologic parameters. In addition, the effect of Aba/Lam, Lam/Zido, and Lop/Rit on lipid metabolism was assessed in HepG2 hepatocytes and during the 3T3-L1 preadipocyte differentiation. Administration with Aba/Lam caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in leptin serum levels. Administration with Lop/Rit also caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in serum levels of total cholesterol, and HDL-c. Treatment of mice with Aba/Lam and Lop/Rit enhanced the lipid accumulation in the liver, and the decrease in AMP-activated protein kinase (AMPK) phosphorylation and/or its downstream target acetyl-CoA carboxylase (ACC) protein expression. In HepG2 hepatocytes, Aba/Lam, Lam/Zido, and Lop/Rit also enhanced the lipid accumulation and decreased phosphorylated AMPK and ACC proteins. In 3T3-L1 pre-adipocyte differentiation, Aba/Lam and Lop/Rit reduced adipogenesis by decreasing expression of transcription factor CEBPb, implicating the lipodystrophic syndrome. Our results demonstrate that daily oral administration of Aba/Lam and Lop/Rit may produce cognitive, motor, and metabolic impairments in mice, regardless of HIV-1 infection

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Isoaaptamine Induces T-47D Cells Apoptosis and Autophagy via Oxidative Stress

Aaptos is a genus of marine sponge which belongs to Suberitidae and is distributed in tropical and subtropical oceans. Bioactivity-guided fractionation of Aaptos sp. methanolic extract resulted in the isolation of aaptamine, demethyloxyaaptamine, and isoaaptamine. The cytotoxic activity of the isolated compounds was evaluated revealing that isoaaptamine exhibited potent cytotoxic activity against breast cancer T-47D cells. In a concentration-dependent manner, isoaaptamine inhibited the growth of T-47D cells as indicated by short-(MTT) and long-term (colony formation) anti-proliferative assays. The cytotoxic effect of isoaaptamine was mediated through apoptosis as indicated by DNA ladder formation, caspase-7 activation, XIAP inhibition and PARP cleavage. Transmission electron microscopy and flow cytometric analysis using acridine orange dye indicated that isoaaptamine treatment could induce T-47D cells autophagy. Immunoblot assays demonstrated that isoaaptamine treatment significantly activated autophagy marker proteins such as type II LC-3. In addition, isoaaptamine treatment enhanced the activation of DNA damage (γH2AX) and ER stress-related proteins (IRE1 α and BiP). Moreover, the use of isoaaptamine resulted in a significant increase in the generation of reactive oxygen species (ROS) as well as in the disruption of mitochondrial membrane potential (MMP). The pretreatment of T-47D cells with an ROS scavenger, N-acetyl-l-cysteine (NAC), attenuated the apoptosis and MMP disruption induced by isoaaptamine up to 90%, and these effects were mediated by the disruption of nuclear factor erythroid 2-related factor 2 (Nrf 2)/p62 pathway. Taken together, these findings suggested that the cytotoxic effect of isoaaptamine is associated with the induction of apoptosis and autophagy through oxidative stress. Our data indicated that isoaaptamine represents an interesting drug lead in the war against breast cancer

Matrin3 (MATR3) Expression Is Associated with Hemophagocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by prolonged fever, cytopenia, hepatosplenomegaly, and hemophagocytosis. This occurs as a result of activated macrophages and impaired function of natural killer cells and/or cytotoxic T lymphocytes. The NF-κB pathway plays a crucial role in hyperinflammation. Matrin3 (MATR3) is a nuclear RNA/DNA-binding protein that plays multiple roles in the regulation of gene expression. We enroll 62 patients diagnosed with secondary HLH and hemophagocytosis. Peripheral blood (PB) from 25 patients and 30 healthy volunteers and good quality bone marrow (BM) samples from 47 patients are collected and used for analysis. Clinical parameters, including age, sex, etiology, ferritin, fibrinogen, triglyceride, and viral infection status, had no association with survival prediction. Patients with downregulation of NF-κB and MATR3mRNA expression in the BM had a higher mortality rate. MATR3mRNA expression in PB was lower in patients compared to that in healthy volunteers. We use shRNA-MATR3-KD-THP1 cells to determine the efficacy of phagocytosis. We note that shRNA-MATR3-KD-THP1 cells had a higher phagocytic effect on necrotic Jurkat E6 cells and carboxylate modified polystyrene latex beads. Herein, we provide evidence of a new marker for clinical translation that can serve as a potential treatment target for secondary HLH