The 100 most-cited articles on non-tuberculous mycobacterial infection from 1995 to 2015.

SETTING: Citation analyses aid in assessing quality, trends and future directions of research fields. OBJECTIVE: To identify the most influential articles on infections caused by non-tuberculous mycobacteria (NTM) in the last 20 years. DESIGN: We performed a cited reference search of the Web of Science database from 1995 to 2015. The 100 most cited articles on NTM infections were analysed. RESULTS: The top 100 articles were cited 114-1471 times, and were published from 1995 to 2013. Sixty-five were laboratory-based, basic science articles, with the major topics being pathophysiology (n = 20) and molecular methods for NTM identification (n = 15). Among the 35 non-laboratory studies, major topics were clinical management (n = 15) and epidemiology (n = 14). The top article was a clinical treatise on the management of NTM disease, published in 2007. Although there was a correlation between article rank and journal impact factor (P = 0.043, ρ = -0.202), the five articles from the journals with highest impact factors did not rank among the top 10 articles. CONCLUSION: A large proportion of influential articles on NTM infection are basic scientific studies, and the most influential articles are not always published in high-impact journals.

Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents.

Many human malignancies lack de novo biosynthesis of arginine (Arg) as the key enzyme argininosuccinate synthetase 1 (ASS1) is silenced. These tumors acquire ectopic Arg for survival, and depleting this source by Arg-depleting recombinant enzyme ADI-PEG20 results in cell death. Mechanisms underlying Arg auxotrophy in these tumors and how they respond to Arg-auxotrophic stress are poorly understood. Here, we report that an immediate-early event of Arg-auxotrophic response involves reactive oxygen species-mediated secretion of Gas6, which interacts with its receptor Axl and activates the downstream Ras/PI3K/Akt growth signal leading to accumulation of c-Myc by protein stabilization. Arg-auxotrophic challenge also transcriptionally upregulates c-Myc expression, which provides a feedback mechanism to enhance Axl expression. c-Myc is a positive regulator of ASS1, but elevated ASS1 provides a feedback mechanism to suppress c-Myc and Axl. Our results revealed multiple inter-regulatory pathways in Arg-auxotrophic response, consisting of Axl, c-Myc and ASS1, which regulate Arg homeostasis and ADI-PEG20 sensitivity. These pathways provide potential targets for improving the efficacy of treating Arg-auxotrophic tumors using Arg-deprivation strategies.

Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC-driven neuroblastoma: a Children's Oncology Group study.

BACKGROUND: MYCN amplification with subsequent MYCN protein overexpression is a powerful indicator of poor prognosis of neuroblastoma patients. Little is known regarding the prognostic significance of the homologous MYC protein expression in neuroblastoma. METHODS: Immunostaining for MYCN and MYC protein was performed on 357 undifferentiated/poorly differentiated neuroblastomas. Results were analysed with other prognostic markers. RESULTS: Sixty-seven (19%) tumours were MYCN(+), 38 (11%) were MYC(+), and one(0.3%) had both proteins(+). MYCN(+) tumours and MYC(+) tumours were more likely diagnosed in children>18months with stage4-disease. MYCN(+) tumours were associated with amplified MYCN, Unfavourable Histology (UH), and High-MKI (Mitosis-Karyorrhexis Index). MYC(+) tumours were also frequently UH but not associated with MYCN amplification, and more likely to have low-/intermediate-MKI. Favourable Histology patients without MYC/MYCN expressions exhibited the best survival (N=167, 89.7±5.5% 3-year EFS, 97.0±3.2% 3-year OS), followed by UH patients without MYC/MYCN expressions (N=84, 63.1±13.6% 3-year EFS, 83.5±9.4% 3-year OS). MYCN(+)patients and MYC(+)patients had similar and significantly low (P<0.0001) survivals (46.2±12.0% 3-year EFS, 63.2±12.1% 3-year OS and 43.4±23.1% 3-year EFS, 63.5±19.2% 3-year OS, respectively). Notably, the prognostic impact imparted by MYC expression was independent from other markers. CONCLUSIONS: In this series, ∼30% of neuroblastomas had augmented MYCN or MYC expression with dismal survivals. Prospective study of MYC/MYCN protein expression signature as a new biomarker for high-risk neuroblastomas should be conducted.

Effect of adjunctive dipyridamole to DAPT on platelet function profiles in stented patients with high platelet reactivity. The result of the ACCEL-DIP Study.

Adjunctive use of phosphodiesterase (PDE) inhibitor can enhance antiplatelet and vasoprotective properties in patients with cardiovascular disease. The aim of this study was to evaluate the impact of PDE5 inhibitor dipyridamole on platelet function in stented patients with high platelet reactivity (HPR) during dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Patients with HPR after 600-mg clopidogrel loading were randomly assigned to adjunctive dipyridamole 75 mg twice daily to standard DAPT (DIP group; n = 45) or double-dose clopidogrel of 150 mg daily (DOUBLE group; n = 46) for 30 days. Platelet function was assessed at baseline and 30-day follow-up with platelet reactivity index (PRI) by vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) assay and platelet aggregation (PA) by light transmittance aggregometry (LTA). Primary endpoint was PRI at 30-day follow-up. HPR was defined as PRI > 50%. Baseline platelet function did not differ between the groups. Following 30-day therapy, platelet function was significantly reduced in the DIP and DOUBLE groups (all p-values ≤ 0.004 and ≤ 0.068, respectively). PRI values were not significantly different between the two groups (mean difference: 3.1%; 95% confidence interval: -2.8% to 9.0%: p = 0.295). PA values and prevalence of HPR were similar between the groups. However, a significant number of patients still exhibited HPR in the DIP (75.6%) and DOUBLE (67.4%) groups. In conclusion, among stented HPR patients, adding dipyridamole to DAPT does not reduce platelet reactivity and prevalence of HPR compared with double-dose clopidogrel therapy, and therefore both strategies are inadequate to overcome HPR.

Γ-glutamyl transferase as an early and sensitive marker in ethanol-induced liver injury of rats.

γ-Glutamyl transferase (GGT) has been regarded as a biological marker of heavy alcohol consumption or hepatobiliary disease such as fatty liver. However, the role of GGT is unknown in the molecular pathway during alcohol-induced liver injury. To determine the role of GGT in alcohol-induced liver injury, Sprague-Dawley rats were administered 22% and 38% ethanol for 3 days as acute and 5 weeks as subchronic model. In serologic analysis, the level of GGT was significantly increased and the level of alanine aminotransferase, aspartate aminotransferase, and total bilirubin were not changed at 3 days and 5 weeks. In histologic analysis, ethanol exposure induced granular deposit formation and sinusoidal dilation in the acute model for 3 days. In the subchronic model for 5 weeks, ethanol exposure further increased the granular deposit formation, sinusoidal congestion, and mild fatty liver change. To determine whether ethanol-exposed liver is associated with changes of antioxidants levels, we performed reverse-transcriptase polymerase chain reaction (RT-PCR) analysis on ethanol-exposed livers of rats. In RT-PCR analysis, the mRNA levels of GPX1 and SOD1 were significantly increased as well as up-regulation of CYP2E1. In the glutathione assay, the level of glutathione was significantly reduced in response to ethanol in rats. Therefore, in this study, ethanol increased the level of serum GGT but depleted the level of glutathione. Moreover, the CYP2E1 was rapidly reflected to ethanol in rats. Taken together, our findings suggest that the elevated GGT is associated with cellular antioxidant defense system, and the CYP2E1 can be used for early diagnosis in alcohol-related diseases.

A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1.

Increasing treatment intensity has improved outcomes for children with neuroblastoma. We performed a pilot study in the Children's Oncology Group to assess the feasibility and toxicity of a tandem myeloablative regimen without TBI supported by autologous CD34-selected peripheral blood stem cells. Forty-one patients with high-risk neuroblastoma were enrolled; eight patients did not receive any myeloablative consolidation procedure and seven received only one. Two patients out of 41 (4.9%) experienced transplant-related mortality. CD34 selection was discontinued after subjects were enrolled due to serious viral illness. From the time of study enrollment, the overall 3-year EFS and OS were 44.8 ± 9.6% and 59.2 ± 9.2% (N=41). These results demonstrate that tandem transplantation in the cooperative group setting is feasible and support a randomized comparison of single vs tandem myeloablative consolidation with PBSC support for high-risk neuroblastoma.

Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children's Oncology Group Report.

Optimal therapy for posttransplant lymphoproliferative disease (PTLD) remains problematic. A phase II trial adding rituximab to a low-dose cyclophosphamide and prednisone regimen was conducted for pediatric patients with Epstein-Barr virus (EBV) (+), CD20 (+) PTLD. Fifty-five patients were enrolled. Toxicity was similar for cycles of therapy containing rituximab versus those without. The complete remission (CR) rate was 69% (95% confidence interval (CI); 57%-84%). Of 12 patients with radiographic evidence of persistent disease at the end of therapy, eight were in CR 28 weeks later without further PTLD therapy. There were 10 deaths, 3 due to infections while receiving therapy and 7 from PTLD. The 2-year event-free survival (alive with functioning original allograft and no PTLD) was 71% (95% CI: 57%-82%) and overall survival was 83% (95% CI: 69%-91%) with median follow-up of 4.8 years. Due to small numbers, we were unable to determine significance of tumor histology, stage of disease, allograft type or early response to treatment on outcome. These data suggest rituximab combined with low-dose chemotherapy is safe and effective in treating pediatric with EBV (+) PTLD following solid-organ transplantation.

Assessing the environmental performance of English arable and livestock holdings using data from the Farm Accountancy Data Network (FADN).

Agri-environment schemes (AESs) have been implemented across EU member states in an attempt to reconcile agricultural production methods with protection of the environment and maintenance of the countryside. To determine the extent to which such policy objectives are being fulfilled, participating countries are obliged to monitor and evaluate the environmental, agricultural and socio-economic impacts of their AESs. However, few evaluations measure precise environmental outcomes and critically, there are no agreed methodologies to evaluate the benefits of particular agri-environmental measures, or to track the environmental consequences of changing agricultural practices. In response to these issues, the Agri-Environmental Footprint project developed a common methodology for assessing the environmental impact of European AES. The Agri-Environmental Footprint Index (AFI) is a farm-level, adaptable methodology that aggregates measurements of agri-environmental indicators based on Multi-Criteria Analysis (MCA) techniques. The method was developed specifically to allow assessment of differences in the environmental performance of farms according to participation in agri-environment schemes. The AFI methodology is constructed so that high values represent good environmental performance. This paper explores the use of the AFI methodology in combination with Farm Business Survey data collected in England for the Farm Accountancy Data Network (FADN), to test whether its use could be extended for the routine surveillance of environmental performance of farming systems using established data sources. Overall, the aim was to measure the environmental impact of three different types of agriculture (arable, lowland livestock and upland livestock) in England and to identify differences in AFI due to participation in agri-environment schemes. However, because farm size, farmer age, level of education and region are also likely to influence the environmental performance of a holding, these factors were also considered. Application of the methodology revealed that only arable holdings participating in agri-environment schemes had a greater environmental performance, although responses differed between regions. Of the other explanatory variables explored, the key factors determining the environmental performance for lowland livestock holdings were farm size, farmer age and level of education. In contrast, the AFI value of upland livestock holdings differed only between regions. The paper demonstrates that the AFI methodology can be used readily with English FADN data and therefore has the potential to be applied more widely to similar data sources routinely collected across the EU-27 in a standardised manner.

DNER modulates adipogenesis of human adipose tissue-derived mesenchymal stem cells via regulation of cell proliferation.

OBJECTIVES: In recent years, obesity has become a global epidemic, highlighting the necessity for basic research into mechanisms underlying growth of adipose tissue and differentiation of stem cells into adipocytes, in humans. For better understanding of cell signalling in adipogenesis, the role of DNER (delta/Notch-like EGF-related receptor) in adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells (hAMSC) was investigated. MATERIALS AND METHODS: To assess the role of DNER in hAMSC adipogenesis, hAMSCs were transfected with DNER small interfering RNA (siDNER). Real-time quantitative reverse transcriptase polymerase chain reactions to assess expression levels of adipogenesis-related genes regulated by siDNER, cell cycle and immunoblot analyses were performed. RESULTS: First, it was determined that DNER mRNA was profoundly expressed in hAMSCs and reduced during adipogenic differentiation. Knockdown of DNER altered cell morphology, inhibited proliferation and increased frequency and efficiency of adipogenesis in hAMSC. Expression of CCAAT/enhancer-binding protein delta increased and proportion of cells in S phase decreased by knockdown of DNER, using specific siRNA. Moreover, adipocyte-specific genes including peroxisome proliferator-activated receptor gamma, fatty acid binding protein 4 and perilipin were up-regulated in siDNER compared to the siControl group during adipogenesis in hAMSC. CONCLUSIONS: These results indicate that DNER knockdown in hAMSC accelerated onset of adipogenic differentiation by bypassing mitotic clonal expansion during the early stages of adipogenesis.

Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells.

OBJECTIVES: Histone deacetylase (HDAC) is an important therapeutic target in cancer. Two of the main anticancer mechanisms of HDAC inhibitors are induction of terminal differentiation and inhibition of cell proliferation. To investigate the role of HDAC in maintenance of self-renewal and cell proliferation, we treated mesenchymal stem cells (MSCs) that originated from adipose tissue or umbilical cord blood with valproic acid (VPA) and sodium butyrate (NaBu). MATERIALS AND METHODS: Human MSCs were isolated from mammary fat tissue and cord blood. We performed MTT assay and flow cytometry-based cell cycle analysis to assess self-renewal of MSCs. In vitro differentiation assays into osteogenic, adipogenic, neurogenic and chondrogenic lineages were conducted to investigate MSC multipotency. Immunocytochemistry, Western blot and reverse transcription-polymerase chain reaction were used to interrogate molecular pathways. RESULTS: VPA and NaBu flattened the morphology of MSCs and inhibited their growth. VPA and NaBu activated the transcription of p21(CIP1/WAF1) by increasing the acetylation of histone H3 and H4 and eventually blocked the cell cycle at G2/M phase. The expression level of p16(INK4A), a cdk inhibitor that is closely related to cellular senescence, was not changed by HDAC inhibitor treatment. We performed controlled differentiation into bone, fat, cartilage and nervous tissue to elucidate the role of HDAC in the pluripotency of MSC to differentiate into functional tissues. VPA and NaBu decreased the efficiency of adipogenic, chondrogenic, and neurogenic differentiation as visualized by specific staining and reverse transcription-polymerase chain reaction. In contrast, osteogenic differentiation was elevated by HDAC inhibitor treatment. CONCLUSION: HDAC activity is essential for maintaining the self-renewal and pluripotency of MSCs.

The roles of Wnt antagonists Dkk1 and sFRP4 during adipogenesis of human adipose tissue-derived mesenchymal stem cells.

OBJECTIVES: The canonical Wnt signalling pathway performs an important function in the control of adipogenesis. However, the mechanisms and mediators underlying these interactions have yet to be defined in detail. Thus, this study was performed in order to elucidate the roles of the Wnt family during adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells (hAMSCs). MATERIALS AND METHODS: We assessed several members of the Frizzled (FZD) family, the receptors of Wnts, inhibitors including the secreted frizzled-related protein (sFRP) family and Dickkopfs (Dkks), and the downstream factor, beta-catenin. Expressional levels of adipogenic markers regulated by the small interfering RNA of Dkk1 (siDkk1) and sFRP4 (sisFRP4) were assessed using real-time quantitative PCR and Western blot analysis. RESULTS: The mRNA level of Dkk1 was expressed abundantly in the early stages of adipogenesis and decreased rapidly during the late stages of adipogenesis. However, sFRP4 mRNA was up-regulated gradually during adipogenic differentiation in hAMSCs. Expression of FZD1, FZD7 and beta-catenin were reduced during adipogenic differentiation. Transfection of hAMSCs with siDkk1 or sisFRP4 partially inhibited differentiation of hAMSCs into adipocytes and restored levels of beta-catenin. CONCLUSIONS: We determined that Dkk1 was up-regulated transiently in the early stages of adipogenesis, and that sFRP4 levels increased gradually during adipogeneis via inhibition of Wnt signalling. Collectively, these results show that Dkk1 and sFRP4 perform an important function in adipogenesis in hAMSCs.

Determination of environmental factors influencing methane oxidation in a sandy landfill cover soil.

It is advantageous to use coarse soils as landfill cover because they allow better aeration of the biologically active zone. In this study, therefore, patterns of methane oxidation were investigated under various environmental conditions including soil moisture content, temperature, and the addition of NH4+ in a sandy landfill cover soil. The kinetics of CH4 oxidation was also studied at different moisture contents and temperatures. Soil moisture content of 10% (wt/wt) resulted in the maximum CH4 oxidation rate (19.2-22.4 nmol gsoil DW(-1) min(-1)). A Vmax value was not significantly different when the moisture content was more than 10%, but a Km value increased from 5.23 to 75.24 microM as the moisture content increased. The ratio of Vmax to Km was the highest at 10% moisture content. The CH4 oxidation rate increased as the incubation temperature increased, and Q10 values and optimum temperature were determined to be 2.57-2.69 and 30 degrees C, respectively. Both Vmax and Km values decreased at the temperatures below and above 30 degrees C. The addition of various levels of NH4+ resulted in increased or decreased CH4 oxidation rates, however, the initiation of appreciable CH4 oxidation was delayed with increasing amounts of NH4+ application in all samples tested. Among the environmental variables tested, moisture content control seems to be the most important and an efficient means of managing methane oxidation when sandy soils are used in landfill cover.

Deep soft tissue infections in the neutropenic pediatric oncology patient.

PURPOSE: Necrotizing fasciitis and myonecrosis can be rapidly fatal without prompt and aggressive medical and surgical therapy. We reviewed our experience with necrotizing fasciitis and myonecrosis in neutropenic pediatric oncology patients to describe associated clinical characteristics and outline therapeutic interventions. PATIENTS AND METHODS: A retrospective chart review was performed for all cases of deep soft tissue infection found in neutropenic pediatric oncology patients during an 11-year period. RESULTS: Seven cases of necrotizing fasciitis and/or myonecrosis associated with chemotherapy-induced neutropenia were diagnosed during the study period. Deep soft tissue infection was diagnosed a median of 14 days after the initiation of chemotherapy. All of the patients presented with fever and pain, generally out of proportion to associated physical findings. Most patients (86%) also had tachycardia and subtle induration at the site of soft tissue infection. The pathogenic organism in four of seven patients originated in the gastrointestinal tract. Patients were treated with antibiotics, surgical debridements, granulocyte colony-stimulating factor, and hyperbaric oxygen. Granulocyte transfusions were administered if there were no signs of neutrophil recovery. Five patients survived their deep soft tissue infection. CONCLUSIONS: The diagnosis of necrotizing fasciitis and/or myonecrosis should be considered in any neutropenic patient with fever, tachycardia, and localized pain out of proportion to the physical findings. Appropriate therapy includes broad-spectrum intravenous antibiotics and urgent surgical intervention. Granulocyte colony-stimulating factor should be administered to all patients to enhance neutrophil recovery. Granulocyte transfusions should be considered if a prolonged period of neutropenia is anticipated.

Phase I topotecan preparative regimen for high-risk neuroblastoma, high-grade glioma, and refractory/recurrent pediatric solid tumors.

We evaluated the toxicity and maximum tolerated dose of topotecan in a novel myeloablative regimen as treatment for high-risk pediatric tumors. Patients received an assigned topotecan dosage in combination with fixed doses of carboplatin and thiotepa, followed by autologous hematopoietic stem cells infusion. Topotecan dose was escalated in cohorts of four patients until the maximum tolerated dose of topotecan was defined or until accrual of 30 patients. Pharmacokinetics of topotecan were examined, and event-free survival was estimated. We describe preliminary results following treatment of 25 pediatric patients with high-risk solid tumors.

Foot screening technique in a diabetic population.

Foot complications are a well known factor which contribute to the morbidity of diabetes and increases the chance of amputation. A total of 126 consecutive diabetic patients were evaluated by diabetic foot screening. Forty-one patients showed an impaired protective sense when tested with Semmes-Weinstein monofilament 5.07 (10 g), and 92% of them showed peripheral polyneuropathy in nerve conduction study (NCS). The mean vibration score of the Rydel-Seiffer graduated tuning fork in patients with peripheral polyneuropathy in nerve conduction (NCV) study was 5.38+/-2.0, which was significantly different from that of patients without polyneuropathy in NCS. Among the deformities identified on examination, callus, corn, and hallux valgus were the greatest. While checking the ankle/ brachial index (ABI), we also evaluated the integrity of vasculature in the lower extremities. After extensive evaluation, we classified the patients into eight groups (category 0,1,2,3,4A,4B,5,6). The result of this study suggested that the Semmes-Weinstein monofilament test, Rydel-Seiffer graduated tuning fork test, and checking the ankle/brachial index were simple techniques for evaluating pathologic change in the diabetic foot by office screening, and that this screening based on treatment-oriented classification helps to reduce pedal complications in a diabetic population.

Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors.

Myelokathexis is a congenital disorder that causes severe chronic leukopenia and neutropenia. Characteristic findings include degenerative changes and hypersegmentation of mature neutrophils and hyperplasia of bone marrow myeloid cells. The associated neutropenia can be partially corrected by treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These features led us to propose that accelerated apoptosis of neutrophil precursors might account for the neutropenic phenotype. Blood and bone marrow aspirates were obtained from 4 patients (2 unrelated families) with myelokathexis before G-CSF therapy and from 2 of the affected persons after G-CSF therapy (1 microg/kg per day subcutaneously for 3 weeks). Bone marrow was fractionated using immunomagnetic bead cell sorting into CD34(+), CD33(+)/CD34(-), and CD15(+)/CD34(-)/CD33(- )cell populations. Examination of these cells by flow cytometry and electron microscopy revealed abundant apoptosis in the CD15(+) neutrophil precursor population, characterized by enhanced annexin-V binding, extensive membrane blebbing, condensation of heterochromatin, and cell fragmentation. Colony-forming assays demonstrated significant reduction in a proportion of bone marrow myeloid-committed progenitor cells. Immunohistochemical analysis revealed a selective decrease in bcl-x, but not bcl-2, expression in the CD15(+)/CD34(-)/CD33(-)cell population compared with similar subpopulations of control bone marrow-derived myeloid precursors. After G-CSF therapy, apoptotic features of patients' bone marrow cells were substantially reduced, and the absolute neutrophil counts (ANC) and expression of bcl-x in CD15(+)/CD34(-)/CD33(-)cells increased. The authors concluded that myelokathexis is a disease characterized by the accelerated apoptosis of granulocytes and the depressed expression of bcl-x in bone marrow-derived granulocyte precursor cells. These abnormalities are partially corrected by the in vivo administration of G-CSF. (Blood. 2000;95:320-327)

Unidirectional single-mode Nd:YAG laser with a planar semimonolithic ring cavity.

Unidirectional single-mode operation of a diode-pumped Nd:YAG laser with a planar semimonolithic ring cavity has been demonstrated at 1064 nm. The semimonolithic cavity consists of a laser active medium placed in a magnetic field, a crystal quartz plate, and an output coupling mirror, which form an optical diode by acting as a Faraday rotator, a reciprocal polarization rotator, and a partial polarizer, respectively. A single-mode output power of 155 mW and a slope efficiency of 17% were obtained with a 1.2-W diode laser at 809 nm. A laser linewidth of less than 100 kHz is inferred from a beat note frequency spectrum between two identical laser systems and continuous tuning to greater than 2 GHz was observed.

Down-regulation of apurinic/apyrimidinic endonuclease expression is associated with the induction of apoptosis in differentiating myeloid leukemia cells.

The human DNA repair enzyme apurinic/apyrimidinic endonuclease (APE/ref-1) is a multifunctional protein in the DNA base excision repair (BER) pathway that is responsible for repair of apurinic/apyrimidinic (AP) sites in DNA. DNA repair and programmed cell death both function using different mechanisms to protect the organism from the consequences of extensive cellular damage; however, little is known about the relationship of the DNA BER repair pathway to apoptosis. We have determined the relationship of a BER DNA repair enzyme, APE, to apoptosis using the myeloid leukemia cell line HL-60, which can be induced to differentiate down the granulocytic or monocytic/ macrophage pathway. Treatment of HL-60 cells with retinoic acid/DMSO (granulocytic) or phorbol 12-myristate 13-acetate (monocytic) results in apoptosis and in down-regulation of APE expression at both the RNA and protein levels. Moreover, double-labeling experiments using APE immunohistochemistry and the terminal deoxyribonucleotidyl transferase-mediated dUTP-fluorescein nick end labeling assay for apoptosis demonstrate that individual cells undergoing apoptosis lose expression of APE regardless of their state of differentiation. Blocking apoptosis by overexpression of the bcl-2 proto-oncogene in HL-60 cells or by a bcr-abl-related mechanism in K562 cells and subsequent differentiation results in morphological differentiation but no loss of APE expression. These studies establish that down-regulation of APE expression is associated with programmed cell death in cells of the myeloid lineage.

Preresection chemotherapy improves survival for children with Askin tumors.

OBJECTIVE: To test whether patients with Askin tumor treated with aggressive neoadjuvant chemotherapy have a better clinical outcome. DESIGN: Retrospective case series. SETTING: Pediatric referral center. PATIENTS: All children diagnosed with malignant small-cell tumors of the chest wall (Askin tumor) and treated from 1975 to September 1987 (phase 1, n = 6) and from September 1987 to the present (phase 2, n = 9). MAIN OUTCOME MEASURES: Survival as a function of extent of disease and response to therapy as measured by tumor volume, survival, and recurrence. RESULTS: All phase 2 patients had significant reduction of tumor volume and improved survival by Kaplan-Meier estimates compared with phase 1 patients. No phase 1 patients are still alive. CONCLUSION: Patients with Askin tumor treated with aggressive preresection chemotherapy have smaller tumors to resect and improved survival.