Imaging Findings in Children Presenting with CNS Nelarabine Toxicity.

Nelarabine is a nucleoside analog critical for the treatment of patients with T-cell acute lymphoblastic leukemia/lymphoma. However, clinical peripheral and central neurologic adverse events associated with nelarabine administration have been reported. Neuroimaging of brain neurotoxicity has only been described in very few reports in pediatric patients so far. Six children with diagnosed T-cell acute lymphoblastic leukemia who clinically experienced possible, probable, or definite nelarabine-induced toxicity and underwent spine and/or brain MR imaging were reviewed. Neuroimaging findings showed a mixture of patterns including features of acute toxic leukoencephalopathy (seen in 6 cases), posterior reversible encephalopathy syndrome (2 cases), involvement of deep gray structures (1 case) and brainstem (2 cases), cranial and spinal neuropathy (2 cases each), and myelopathy (2 cases). Even though neuroimaging findings are nonspecific, the goal of this article was to alert the pediatric neuroradiologists, radiologists, and clinicians about the possibility of nelarabine-induced neurotoxicity and its broad neuroimaging spectrum.

Perception of a modular 3D print model in undergraduate endodontic education.

AIM: To evaluate a modular 3D print training dental model with embedded human teeth and electronic working length determination for undergraduate endodontic education. METHODOLOGY: Cone-beam volume tomography data of a human skull were transferred into stereolithographic (STL) data, and a customizable modular 3D print model with individually removable sextants and teeth was generated for the use in commercially available phantom heads. Each of sixty-eight students performed a complete root canal treatment on an extracted human tooth. Working lengths were determined with electronic apex locators (EAL) and verified radiographically. Subsequently, an evaluation was carried out with regard to the difficulty of the working steps access cavity preparation, working length determination, root canal preparation/irrigation and canal filling, and these steps were compared to commonly used benchtop models. Additionally, the agreement of electronic and radiographic working length determination was assessed and analysed statistically with the chi-square test. RESULTS: A total of 68 teeth (20 incisors, 26 premolars and 22 molars) with 127 root canals were treated. In total, 87% of the students considered the modular 3D print model considerably more demanding than the conventional benchtop model. Overall, 96% felt better prepared for the clinical situation, 92% felt markedly reduced stress levels during endodontic practice in the subsequent clinical courses, and 93% of the students suggested the model should be used in future preclinical endodontic training. The preradiographic use of EAL resulted in 85% of the cases having radiographically acceptable working length determination within 0-2 mm from the radiographic apex. Readings more than 2 mm from the apex or beyond were significantly more common in molars than in premolars and incisors (P < 0.05). CONCLUSIONS: The vast majority of students rated the modular 3D print training model positively despite it being more demanding. They also recommended its use in preclinical teaching and training. The model allowed a more realistic simulation of the clinical situation with a simultaneous use of EALs and led to reduced stress levels in endodontic treatment in the subsequent clinical courses.

Physico-chemical investigation of endodontic sealers exposed to simulated intracanal heat application: epoxy resins and zinc oxide-eugenols.

AIM: To gain information in a laboratory setting about the effect of thermal treatment of epoxy resin-based and zinc oxide-eugenol-based sealers. METHODOLOGY: AH Plus and Pulp Canal Sealer (PCS) were exposed to thermal treatment at 37, 47, 57, 67, 77, 87 and 97 °C for 30 s. According to clinically relevant considerations, intracanal sealer temperature is likely not to exceed 60 °C during warm vertical root canal filling. Heat application is recommended for less than 30 s during continuous wave technique, but might exceed this threshold in complex cases. Furthermore, heat treatment at 97 °C was performed for 60 and 180 s to simulate inappropriate implementation of warm vertical filling techniques. Specimens were heated inside 2-mL plastic tubes in a thermo-controlled water bath until the temperatures were reached and kept at this temperature for the determined period of time. Afterwards, specimens were cooled to body temperature and physical properties (setting time, flow, film thickness according to ISO 6876) were assessed. Chemical properties (Fourier transformed infrared spectroscopy) were assessed after complete setting of the specimens in an incubator at 37 °C and 100% humidity. Statistical analysis of physical properties was performed using Kruskal-Wallis test (P = 0.05). RESULTS: The setting time of AH Plus and PCS decreased when temperature and duration of heat application increased. Whilst the setting time of AH Plus decreased from 622 min at 20 °C (for 30 s) to 381 min at 97 °C (for 180 s; P < 0.05), heat treatment of PCS at 97 °C for 180 s led to an immediate setting of the material. From 20 °C (for 30 s) to 97 °C (for 30 s), the setting time of PCS decreased from 80.1 to 41.0 h (P < 0.05). Film thickness and flow were not relevantly influenced by thermal treatment except for PCS at 97 °C for 180 s. FT-IR spectroscopy did not reveal any chemical changes of either sealer after thermal treatment. CONCLUSIONS: Thermal treatment simulating clinically relevant temperature levels and heating times did not lead to any substantial physical or chemical changes at all temperature levels when heating did not exceed 60 s. AH Plus and Pulp Canal Sealer can be considered suitable for warm root filling techniques.

A critical appraisal of studies on cyclic fatigue resistance of engine-driven endodontic instruments.

The endodontic literature contains a plethora of studies on static and dynamic cyclic fatigue resistance tests performed on a large array of rotary or reciprocating nickel-titanium endodontic instruments. It was the aim of this review to summarize the currently available evidence to point out the different outcomes from static versus dynamic tests and to assess whether cyclic fatigue tests provide useful data and information for clinical practice. An electronic literature research in the database PubMed was performed using appropriate search terms, and the titles and abstract were screened for relevance. Language was restricted to English. The review reveals marked differences between the results obtained in static and dynamic tests, and also, the results for the same instruments assessed either under static or dynamic experimental conditions are widely inconsistent. Between the lowest and the highest value for one and the same pathfinding instrument was a factor of about 123 when cyclic fatigue was assessed either under static or dynamic experimental conditions. Moreover, standard deviations of up to 30% have been reported. Environmental temperature has a 500% impact on the lifetime of instruments. In conclusion, fatigue resistance tests conducted under room temperature should be regarded as having little meaning and the scientific and clinical benefits of fatigue resistance tests are very limited. These data should be provided by the manufacturer of the instruments.

Real-time dynamic torque values and axial forces during preparation of straight root canals using three different endodontic motors and hand preparation.

AIM: To assess the real-time dynamic torque values and axial forces during preparation of straight root canals using three different endodontic motors and hand preparation. METHODOLOGY: Sixty maxillary incisors were divided into four homogeneous groups (n = 15). After glide path establishment (size 20) the root canals were prepared to an apical size 40 using the rotary NiTi system F6 SkyTaper. Motors (DentaPort ZX OTR, EndoPilot and VDW.silver) were set to 'auto-torque-reverse' mode and DentaPort ZX was set to its specific OTR mode (optimum torque reverse). One group served as a control using manual balanced-force canal preparation with K-Flexofiles. Teeth were embedded in resin and fixed in a multi-component sensor measuring axial and torsional load during active instrumentation with 50 Hz. Preparation time was also recorded. Data were statistically analysed using the Kruskal-Wallis test. RESULTS: The maximum axial forces (peak) and both peaks of dynamic clockwise and counter-clockwise torque did not differ significantly when using the three different motors despite different gear ratios and pre-settings. Only the VDW.silver motor exceeded the torque values during the use of 30 instruments (3.3%). The Morita OTR motor exceeded the maximum intrinsic torque set at 1.0 Ncm in approximately 53% of cases. The larger tapered F6 SkyTaper instruments (size 20, .06 taper and size 30, .06 taper) created significantly higher torque values (P < 0.0001). Manual instrumentation created significantly lower torque levels and higher axial values compared to rotary instrumentation (P < 0.0001) and was significantly more time consuming (P < 0.0001). CONCLUSIONS: Manual preparation was associated with significantly lower torque peaks compared to rotary instrumentation. The three motors remained well within the safety torque values of the instruments.

New thermomechanically treated NiTi alloys - a review.

In the past 10 years, several proprietary processing procedures for nickel titanium (NiTi) alloy were developed to improve the mechanical properties of NiTi endodontic instruments. Beside specific thermal and mechanical treatments, manufacturers introduced several machining procedures (e.g. twisting, electrical discharge machining), as well as techniques for final surface finishing. NiTi alloys used for endodontic instruments can be subdivided into instruments that mainly contain the austenite phase (austenitic: conventional NiTi, M-Wire, R-Phase) and those mainly containing the martensite phase (martensitic: CM Wire, Gold and Blue heat-treated NiTi). Thermomechanically treated NiTi alloys have been reported to be more flexible with improved cyclic fatigue resistance and greater angle of deflection at failure when compared to conventional NiTi. These enhanced properties may be attributed to a modified phase composition containing varying amounts of R-phase and martensite. Endodontic instruments made of austenitic alloys possess superelastic properties because of stress-induced martensite transformation and consequently tend to spring-back to their original form after deformation. In contrast, the martensitic instruments can easily be deformed due to the reorientation of the martensite variants and show a shape memory effect when heated. The use of martensitic alloy results in more flexible instruments, with an increased cyclic fatigue resistance compared with austenitic alloy.

Effects of pituitary adenylate cyclase activating polypeptide on small intestinal INT 407 cells.

Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide having a widespread distribution both in the nervous system and peripheral organs including the gastrointestinal tract. It has been shown to exert actions on intestinal functions, mainly affecting glandular secretion and motility. PACAP has several different effects on cell survival depending on the cell type and the applied stimulus. Its influences on small intestinal epithelial cells are not yet elucidated, therefore the aim of the present study was to investigate the effects of PACAP on intestinal epithelial cells having high turnover (INT 407) against different harmful stimuli, such as oxidative stress, in vitro hypoxia and gamma radiation. We tested the effect of PACAP on proliferation and cell survival using MTT assay. Moreover, various cancer-related factors were evaluated by oncology array. PACAP did not influence the proliferation rate of INT 407 cells. Its cell survival-enhancing effect could be detected against oxidative stress, but not against in vitro hypoxia or gamma irradiation. Clonogenic survival assay was performed to analyze the effect of PACAP on clonogenic potential of cells exposed to gamma radiation. Surprisingly, PACAP enhanced the clone-forming ability decrease induced by irradiation. Western blot analysis of ERK1/2 phosphorylation was performed in order to obtain further information on the molecular background. Our data showed phospho-ERK1/2 suppression of PACAP in irradiated cells. Furthermore, the role of endogenous PACAP against oxidative stress was also investigated performing ADCYAP1 small interfering RNA transfection. We found significant difference in the cell vulnerability between cells undergoing silencing and cells without transfection suggesting the protective role of the endogenously present PACAP against oxidative stress in INT 407 cells. In summary, PACAP seems to be able to exert contradictory effects in INT 407 cells depending on the applied stressor, suggesting its regulatory role in the cellular household.

Apical transportation and canal straightening with different continuously tapered rotary file systems in severely curved root canals: F6 SkyTaper and OneShape versus Mtwo.

AIM: To compare apical transportation and canal straightening when using three continuous tapered rotary NiTi systems [F6 SkyTaper (Komet/Brasseler, Lemgo, Germany), Mtwo (VDW, Munich, Germany) and OneShape (Micro Méga, Besançon, France)] in severely curved root canals. METHODOLOGY: A total of 60 root canals in extracted human teeth with angles of curvatures ranging between 25° and 35° and radii ranging between 4 and 9 mm were divided into three groups (n = 20). Based on radiographs taken prior to instrumentation, the groups were balanced with respect to the angle and the radius of canal curvature (P = 1.0 and P = 0.994, respectively). All canals were prepared to an apical size 30 according to the manufacturer's instructions. Pre- and post-instrumentation radiographs were superimposed and apical transportation and canal straightening were analysed using a computer imaging program. Preparation time and instrument failure were also recorded. Data were analysed statistically using anova and Student-Newman-Keuls test. RESULTS: During preparation, no file fractured. All instruments maintained the original canal curvature well with no significant differences between the instruments (P = 0.542). Concerning apical transportation, no significant differences were obtained (P = 0.414). Regarding preparation time, no significant differences were obtained between F6 SkyTaper and OneShape (P > 0.05), but both were significantly faster than Mtwo (P < 0.05). CONCLUSION: Under the conditions of this study, all instruments respected the original canal curvature well and apical transportation was negligible. Instruments were safe to use. Preparation with F6 SkyTaper and OneShape was faster than with Mtwo.

Incidence of dentinal defects after preparation of severely curved root canals using the Reciproc single-file system with and without prior creation of a glide path.

AIM: To investigate the incidence of dentinal defects after preparation of severely curved root canals using the Reciproc single-file system with and without prior creation of a glide path. METHODOLOGY: Mesial roots from extracted mandibular first molars were collected and scanned with CBCT to assess the morphology of the root canal systems. Three groups of 20 anatomically comparable specimens were generated. The control group was left unprepared, whilst the experimental groups were prepared with Reciproc R25 with and without a glide path (groups RG and R, respectively). Roots were then sectioned perpendicular to the long axis at 2, 4, 6, 8 and 10 mm from the apex, and coloured photographs of the sections at 40× were obtained. Two blinded examiners registered the presence of dentinal defects twice at 2-week interval. Data were statistically analysed using the Fisher exact and Cochran's Q tests. RESULTS: No defects were observed in the control group. The overall incidence of dentinal defects was 26% in group R and 24% in group RG, with no significant differences between them (P > 0.05). Dentinal defects occurred significantly more often in the middle and coronal thirds compared to the apical third of the canals (P < 0.05). CONCLUSIONS: Prior preparation of a glide path had no impact on the incidence of dentinal defects when using Reciproc files.

Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

Shaping ability of ProTaper NEXT and BT-RaCe nickel-titanium instruments in severely curved root canals.

AIM: To compare the shaping ability of four different nickel-titanium rotary instruments during the preparation of curved root canals in extracted teeth. METHODOLOGY: A total of 80 root canals with curvatures ranging between 25° and 39° were divided into four groups of 20 canals. Based on radiographs taken prior to instrumentation, the groups were balanced with respect to the angle and the radius of canal curvature. Canals were prepared to a final apical size of 40 using Mtwo, ProTaper Universal, ProTaper NEXT and BT-RaCe. Using pre- and post-instrumentation radiographs, straightening of the canal curvatures and canal transportation were determined with a computer image analysis programme. Preparation time and instrument failures were also recorded. The data were analysed statistically using anova and Student-Newman-Keuls test. RESULTS: The use of BT-RaCe files resulted in significantly more straightening during instrumentation compared to Mtwo (P < 0.05), whilst the differences between all other instruments were not significant (P > 0.05). No significant differences were obtained between all four instruments regarding canal transportation (P = 0.429). Instrumentation with ProTaper NEXT files was significantly faster than with all other instruments (P < 0.05). During the preparation of the curved canals, one BT2 instrument fractured, whilst no fracture occurred when using the other instruments (P > 0.05). CONCLUSIONS: Within the parameters of this study, all instruments maintained root canal curvature well and were safe. However, care should be taken when using the BT2 instrument due to its unique cylindrical design.

Comparative evaluation of the shaping ability of WaveOne, Reciproc and OneShape single-file systems in severely curved root canals of extracted teeth.

AIM: To compare the shaping ability of WaveOne, Reciproc and OneShape single-file systems in severely curved root canals in extracted human molar teeth. METHODOLOGY: Sixty mandibular molars with mesio-buccal canals with curvatures ranging between 25° and 35° and radii of curvature ranging between 4 and 9 mm were divided into three groups of 20 teeth each: group W (WaveOne), group R (Reciproc) and group O (OneShape). Using standardized pre- and post-instrumentation radiographs, straightening of canal curvatures was determined using the NIH Image J software. A double-digital standardized radiographic technique was used to determine apical transportation at 0.5 mm from the working length (1.5 mm coronal to the major foramen). Preparation time and instrument failures were also recorded. Data were analysed using one-way analysis of variance (anova) and post-hoc Tukey-test. RESULTS: During root canal preparation, no instruments fractured but all OneShape instruments were deformed after preparation of four canals. The use of OneShape resulted in significantly greater canal straightening and apical transportation than WaveOne and Reciproc (P < 0.05), with no significant differences between WaveOne and Reciproc (P > 0.05). Instrumentation with OneShape was significantly faster than with WaveOne and Reciproc (P < 0.05), whilst Reciproc was significantly faster than WaveOne (P < 0.05). CONCLUSIONS: All instruments were safe to use. Reciproc and WaveOne instruments respected the original canal curvature better than OneShape files. The use of OneShape instruments required less time to prepare the curved canals compared with Reciproc and WaveOne.

Comparative evaluation of the shaping ability of ProTaper Next, iRaCe and Hyflex CM rotary NiTi files in severely curved root canals.

AIM: To compare the shaping ability of ProTaper Next, iRaCe and Hyflex CM rotary NiTi files during the preparation of severely curved root canals in extracted human molar teeth. METHODOLOGY: Sixty mandibular molars with mesio-buccal canals having angles of curvature ranging from 25° to 35° were divided according to the instrument used into three groups of 20 teeth each: group PTN (ProTaper Next), group IR (iRaCe) and group HF (Hyflex CM). Using standardized pre- and post-instrumentation radiographs, straightening of canal curvature was determined using image analysis software. A double-digital standardized radiographic technique was used to determine apical transportation 0.5 mm from the working length (1.5-mm coronal of the major foramen). Preparation time and instrument failures were also recorded. Data were analysed using one-way analysis of variance (anova) and post hoc Tukey's test, and significance was set at P < 0.05. RESULTS: During root canal preparation, no instruments fractured. The use of PTN resulted in significantly greater canal straightening than IR and HF (P < 0.05), with no significant differences between IR and HF (P > 0.05). There were no significant differences between the three groups with respect to apical transportation (P > 0.05). IR and HF were significantly faster than PTN (P < 0.05), with no significant differences between IR and HF (P > 0.05). CONCLUSIONS: Under the conditions of this study, PTN, IR and HF respected original canal curvature well and were safe to use.

Quantitative evaluation of apically extruded debris with different single-file systems: Reciproc, F360 and OneShape versus Mtwo.

AIM: To assess in a laboratory setting the amount of apically extruded debris associated with different single-file nickel-titanium instrumentation systems compared to one multiple-file rotary system. METHODOLOGY: Eighty human mandibular central incisors were randomly assigned to four groups (n = 20 teeth per group). The root canals were instrumented according to the manufacturers' instructions using the reciprocating single-file system Reciproc, the single-file rotary systems F360 and OneShape and the multiple-file rotary Mtwo instruments. The apically extruded debris was collected and dried in pre-weighed glass vials. The amount of debris was assessed with a micro balance and statistically analysed using anova and post hoc Student-Newman-Keuls test. The time required to prepare the canals with the different instruments was also recorded. RESULTS: Reciproc produced significantly more debris compared to all other systems (P < 0.05). No significant difference was noted between the two single-file rotary systems and the multiple-file rotary system (P > 0.05). Instrumentation with the three single-file systems was significantly faster than with Mtwo (P < 0.05). CONCLUSIONS: Under the condition of this study, all systems caused apical debris extrusion. Rotary instrumentation was associated with less debris extrusion compared to reciprocal instrumentation.

Comparison of preparation of curved root canals with Hyflex CM and Revo-S rotary nickel-titanium instruments.

AIM: To compare the shaping ability of three different nickel-titanium rotary instruments during the preparation of curved root canals in extracted teeth. METHODOLOGY: A total of 60 root canals with curvatures ranging between 25° and 35° were divided into three groups of 20 canals. Based on radiographs taken prior to instrumentation, the groups were balanced with respect to the angle and the radius of canal curvature. Canals were prepared to a final apical size of 35 using Mtwo, Hyflex CM, and Revo-S. Using pre- and post-instrumentation radiographs, straightening of the canal curvatures was determined with a computer image analysis program. Preparation time, changes of working length and instrument failures were also recorded. These data were analysed statistically using anova and Student-Newman-Keuls test. RESULTS: During preparation, no file fractured. Mtwo and Hyflex CM maintained the original canal curvature significantly better than Revo-S (P < 0.05). Instrumentation with Mtwo and Hyflex CM was significantly faster than with Revo-S and resulted in less loss of working length (P < 0.05), whilst no significant differences were obtained between Mtwo and Hyflex CM (P > 0.05). CONCLUSIONS: Under the conditions of this study, Mtwo and Hyflex CM respected the original canal curvature well and were safe to use. The use of Revo-S instruments required more time to prepare the curved canals and resulted in more pronounced canal straightening compared with Mtwo and Hyflex CM.

Shaping ability of different single-file systems in severely curved root canals of extracted teeth.

AIM: To compare the shaping ability of three different single-file systems with Mtwo rotary instruments during the preparation of curved root canals in extracted teeth. METHODOLOGY: A total of 80 root canals with curvatures ranging between 25° and 35° were divided into four groups of 20 canals. Based on radiographs taken prior to instrumentation, the groups were balanced with respect to the angle and the radius of canal curvature. Canals were prepared to the following apical sizes: Mtwo: size 30 using the single-length technique; Reciproc, F360, and OneShape: size 25. Using pre- and post-instrumentation radiographs, straightening of the canal curvatures was determined with a computer image analysis programme. Preparation time, changes in working length, and instrument failures were also recorded. These data were analysed statistically using anova and Student-Newman-Keuls test. RESULTS: During preparation, no file fractured. All instruments maintained the original canal curvature well with no significant differences between the instrument systems (P = 0.792). Instrumentation with Reciproc and OneShape was significantly faster than with F360 and Mtwo (P < 0.05), while F360 was significantly faster than Mtwo (P < 0.05). No significant differences were obtained regarding changes in working length during instrumentation with the different instruments (P = 0.784). CONCLUSIONS: Under the conditions of this study, all instruments respected the original canal curvature well and were safe to use. The use of Reciproc and OneShape instruments required less time to prepare the curved canals compared with Mtwo and F360.

Quality-of-care for leg ulcers in the metropolitan area of Hamburg--a community-based study.

BACKGROUND: Diagnosis and therapy of chronic wounds constitute an interdisciplinary challenge and should be oriented on the guideline standards. Although no data on the quality-of-care are available for Germany, it can be concluded from qualitative estimates and expert reports that the majority of patients are not receiving adequate treatment. OBJECTIVES: Evaluation of the quality-of-care for leg ulcers in the metropolitan area of Hamburg by means of newly developed guideline-based indicators. METHODS: Leg ulcer patients of any aetiology were consecutively included. The spectrum of 220 health-care providers ranged from wound clinics, office-based practices, nursing homes to home-care services and doss houses. The survey included a clinical examination and the completion of questionnaires covering quality of life, experiences with treatment and quality of health care. RESULTS: A total of 520 patients with leg ulcers were included. Among these patients, 63% were of venous, 23% of mixed, 2% of vasculitic and 12% of other origin; 78.6% of the patients were treated with moist wound dressings. Pain therapy was performed in 54.1%, compression therapy in 53.5%. Shortcomings were noted in the diagnostic work-up and in concomitant wound care such as physiotherapy. Around 70% displayed marked to profound impairment in quality of life. The quality-of-care index showed that 64% of the indicators were met by the actual care; 61.8% of the patients exhibiting a sufficient quality-of-care, regardless of age, social status, place of abode or insurance status. CONCLUSIONS: Although the majority of patients received adequate therapy, many patients are not being treated properly in accordance with the guidelines.

PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling.

Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK MAPK pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified p21-activated kinase 1 (PAK1) as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 30--33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation.