text:
AstraZeneca: Lynparza granted Priority Review in the US for BRCA-mutated HER2-negative high-risk early breast cancer
AstraZeneca's supplemental New Drug Application (sNDA) for Lynparza (olaparib) has been accepted and granted Priority Review in the US for the adjuvant treatment of patients with BRCA-mutated (BRCAm) HER2-negative high-risk early breast cancer who have already been treated with chemotherapy either before or after surgery.
Lynparza is being jointly developed and commercialised by AstraZeneca and MSD.
The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that offer significant advantages over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance.[1] The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is during the first quarter of 2022.
Breast cancer is now the most diagnosed cancer worldwide with an estimated 2.3 million patients diagnosed in 2020.[2 ]Nearly 91% of all breast cancer patients are diagnosed at an early stage of disease and BRCA mutations are found in approximately 5% of patients.[3,4,5 ]
The sNDA was based on results from the OlympiA Phase III trial presented (https://www.astrazeneca.com/media-centre/press-releases/2021/lynparza-reduced-the-risk-of-cancer-recurrence-by-42-in-the-adjuvant-treatment-of-patients-with-germline-brca-mutated-high-risk-early-breast-cancer-in-olympia-phase-iii-trial.html#:~:text=Phase%20III%20trial-,Lynparza%20reduced%20the%20risk%20of%20cancer%20recurrence%20by%2042%25%20in,in%20OlympiA%20Phase%20III%20trial) during the 2021 American Society of Clinical Oncology Annual Meeting and simultaneously published in The New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2105215).
These results showed Lynparza demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS), reducing the risk of invasive breast cancer recurrence, second cancers or death by 42% versus placebo (based on a hazard ratio of 0.58; 99.5% confidence interval 0.41-0.82; p<0.0001). The safety and tolerability profile of Lynparza in this trial was in line with that observed in prior clinical trials.
Lynparza is approved in the US (https://www.astrazeneca.com/media-centre/press-releases/2018/lynparza-approved-by-us-fda-in-germline-brca-mutated-metastatic-breast-cancer-12012018.html), EU, Japan (https://www.astrazeneca.com/media-centre/press-releases/2018/lynparza-approved-in-japan-for-brca-mutated-metastatic-breast-cancer-02072018.html) and several other countries for the treatment of patients with germline BRCAm, HER2-negative, metastatic breast cancer previously treated with chemotherapy based on results from the OlympiAD Phase III trial. In the EU, this indication also includes patients with locally advanced breast cancer.
Early breast cancer
Early breast cancer is defined as disease confined to the breast with or without regional lymph node involvement, and the absence of distant metastatic disease.[6] The 5-year survival rate is 99% for localised breast cancer (only found in the breast area) and 86% for regional breast cancer (cancer that has spread outside the breast to nearby structures or lymph nodes).[3 ]Despite advancements in the treatment of early breast cancer, up to 30% of patients with high-risk clinical and/or pathologic features, such as BRCA mutations, recur within the first few years.[7,8]
Breast cancer is one of the most biologically diverse tumour types with various factors fuelling its development and progression.[9] The discovery of biomarkers in the development of breast cancer has greatly impacted scientific understanding of the disease.[10]
OlympiA is a Phase III, double-blind, parallel group, placebo-controlled, multicentre trial testing the efficacy and safety of Lynparza tablets versus placebo as adjuvant treatment in patients with germline BRCAm high-risk HER2-negative early breast cancer, who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy.[11]
The primary endpoint of the trial is iDFS defined as time from randomisation to date of first loco-regional or distant recurrence or new cancer or death from any cause.[11]
The OlympiA Phase III trial is led by the Breast International Group (BIG) in partnership with the Frontier Science & Technology Research Foundation (FSTRF), NRG Oncology, AstraZeneca and MSD.[11]
BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells.[11]
When either of these genes is mutated or altered such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer and confer sensitivity to PARP inhibitors including Lynparza.[1][2-15]
Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as new hormonal agents).
Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.
Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy.
It is also approved in the US, EU and Japan as a 1st-line maintenance treatment with bevacizumab for patients with HRD-positive advanced ovarian cancer (BRCAm and/or genomic instability).
Lynparza is approved in the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer.
It is also approved in the US, the EU, Japan and several other countries for the treatment of germline BRCAm metastatic pancreatic cancer.
Lynparza is approved in the US for HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm and other HRR gene mutations) and in the EU and Japan for BRCAm metastatic castration-resistant prostate cancer.
Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers. Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 40,000 patients worldwide.
Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types.
Lynparza is the foundation of AstraZeneca's industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.
The AstraZeneca and MSD strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US (known as MSD outside the US and Canada) announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world's first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types.
Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.
AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need - with the bold ambition to one day eliminate breast cancer as a cause of death.
AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment.
AstraZeneca aims to continue to transform outcomes for HR-positive breast cancer with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and the next-generation selective estrogen receptor degraders (SERD) and potential new medicine camizestrant (formerly known as AZD9833).
Lynparza is a targeted treatment option for metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD continue to research Lynparza in early and metastatic breast cancer patients with a BRCA mutation.
Building on the first approval of Enhertu (trastuzumab deruxtecan), a HER2-directed antibody-drug conjugate (ADC), in previously treated HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are exploring its potential in earlier lines of treatment and in new breast cancer settings. Results from the DESTINY-Breast03 Phase III trial showed that Enhertu significantly improved progression-free survival in patients with HER2-positive metastatic breast cancer.
To bring much needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in combination with other oncology medicines, including Lynparza and Enhertu, assessing the potential of AKT kinase inhibitor, capivasertib, in combination with chemotherapy, and collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan.
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com (http://www.astrazeneca.com/) and follow the Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca).
For details on how to contact the Investor Relations Team, please click here (https://www.astrazeneca.com/investor-relations.html#Contacts). For Media contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html).
1. US Food and Drug Administration. Priority Review. Available at: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review. Accessed November 2021.
2. GLOBOCAN. Breast Cancer. Available at https://gco.iarc.fr/today/data/factsheets/cancers/20-Breast-fact-sheet.pdf. Accessed November 2021.
3. Cancer.org. Survival rates for breast cancer. Available at https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html. Accessed November 2021.
4. De Talhouet S, et al. Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes. Scientific Reports. 2020;10:7073.
5. Cancer.gov. Early-stage breast cancer. Available at https://www.cancer.gov/publications/dictionaries/cancer-terms/def/early-stage-breast-cancer. Accessed November 2021.
6. WHO. Early stage breast cancer. Available at https://www.who.int/selection_medicines/committees/expert/20/applications/EarlyStageBreast.pdf?ua=1. Accessed November 2021.
7. Johnston S, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998.
8. Smith KL, Isaacs C. BRCA mutation testing in determining breast cancer therapy. Cancer J. 2011;17(6):492-499. doi:10.1097/PPO.0b013e318238f579
9. Yersal O, and Barutca S. Biological Subtypes of Breast Cancer: Prognostic and therapeutic implications. World J Clin Oncol. 2014;5(3):412-424.
10. Rivenbark A, et al. Molecular and Cellular Heterogeneity in Breast Cancer: Challenges for Personalized Medicine. Am J Pathol. 2013;183(4):1113-1124.
11. ClinicalTrials.gov. Olaparib as Adjuvant Treatment in Patients with Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer (OlympiA). Available at https://clinicaltrials.gov/ct2/show/NCT02032823. Accessed November 2021.
12. Roy R, et al. BRCA1 and BRCA2: Different Roles in a Common Pathway of Genome Protection. Nat Rev Cancer. 12(1):68-78.
13. Wu J, et al. The Role of BRCA1 in DNA Damage Response. Protein Cell. 2010;1(2):117-123.
14. Gorodetska I, et al. BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance. J Cancer. 2019;10(9):2109-2127.
15. Li H, et al. PARP Inhibitor Resistance: The Underlying Mechanisms and Clinical Implications. Mol Cancer. 2020;19:107.
Cision


text:
Q: Unable to copy audio disc with Brasero It seems it creates the image correctly. After I insert the blank cd I get:
Checking session consistency (brasero_burn_check_session_consistency brasero-burn.c:1739)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao getting varg
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao called brasero_job_set_output_size_for_current_track
BraseroCdrdao got varg:
BraseroCdrdao stopping
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_session_output_size
BraseroCdrdao output set (IMAGE) image = /tmp/brasero_tmp_OSAF0X.bin toc = /tmp/brasero_tmp_OSAF0X.toc
BraseroCdrdao called brasero_job_get_session_output_size
BraseroCdrdao getting varg
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao called brasero_job_get_output_type
BraseroCdrdao called brasero_job_get_image_output
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_set_use_average_rate
BraseroCdrdao got varg:
    cdrdao
    read-cd
    --device
    /dev/sr0
    --read-raw
    --datafile
    /tmp/brasero_tmp_OSAF0X.bin
    -v
    2
    /tmp/brasero_tmp_OSAF0X.toc
BraseroCdrdao Launching command
BraseroCdrdao called brasero_job_get_fd_in
BraseroCdrdao called brasero_job_get_fd_out
BraseroCdrdao stderr: WARNING: Environment variable 'HOME' not defined- cannot read .cdrdao.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Cdrdao version 1.2.3 - (C) Andreas Mueller <andreas@daneb.de>
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: /dev/sr0: HL-DT-ST DVD+-RW GU70N  Rev: A102
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Using driver: Generic SCSI-3/MMC - Version 2.0 (options 0x0000)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:
BraseroCdrdao stderr: Reading toc and track data...
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:
BraseroCdrdao stderr: Track   Mode    Flags  Start                Length
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: ------------------------------------------------------------
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:  1      AUDIO   0      00:00:00(     0)     03:54:30( 17580)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:  2      AUDIO   0      03:54:30( 17580)     03:18:17( 14867)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:  3      AUDIO   0      07:12:47( 32447)     04:33:01( 20476)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:  4      AUDIO   0      11:45:48( 52923)     03:00:23( 13523)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:  5      AUDIO   0      14:45:71( 66446)     03:46:36( 16986)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:  6      AUDIO   0      18:32:32( 83432)     02:27:71( 11096)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:  7      AUDIO   0      21:00:28( 94528)     02:30:53( 11303)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:  8      AUDIO   0      23:31:06(105831)     03:31:68( 15893)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:  9      AUDIO   0      27:02:74(121724)     03:21:26( 15101)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 10      AUDIO   0      30:24:25(136825)     03:43:35( 16760)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 11      AUDIO   0      34:07:60(153585)     02:48:62( 12662)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 12      AUDIO   0      36:56:47(166247)     02:38:16( 11866)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 13      AUDIO   0      39:34:63(178113)     03:20:38( 15038)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 14      AUDIO   0      42:55:26(193151)     04:13:38( 19013)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 15      AUDIO   0      47:08:64(212164)     03:38:45( 16395)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 16      AUDIO   0      50:47:34(228559)     03:33:54( 16029)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 17      AUDIO   0      54:21:13(244588)     03:31:65( 15890)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Leadout AUDIO   0      57:53:03(260478)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr:
BraseroCdrdao stderr: PQ sub-channel reading (audio track) is supported, data format is BCD.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Raw P-W sub-channel reading (audio track) is supported.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Cooked R-W sub-channel reading (audio track) is supported.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Copying audio tracks 1-17: start 00:00:00, length 57:53:03 to "/tmp/brasero_tmp_OSAF0X.bin"...
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_set_current_action
BraseroCdrdao stderr: Track 1...
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 00:00:00
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Found ISRC code.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 00:01:00
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 00:02:00
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 57:51:00
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: 57:52:00
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Found 552 Q sub-channels with CRC errors.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Found CD-TEXT data.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Found disk catalogue number.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: Reading of toc and track data finished successfully.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao stderr: HUP
BraseroCdrdao process finished with status 0
BraseroCdrdao Finished successfully session
BraseroCdrdao stopping
BraseroCdrdao called brasero_job_get_done_tracks
BraseroCdrdao called brasero_job_get_fd_out
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_output_type
BraseroCdrdao Automatically adding track
BraseroCdrdao called brasero_job_get_image_output
BraseroCdrdao called brasero_job_get_session_output_size
BraseroCdrdao called brasero_job_add_track
BraseroCdrdao called brasero_job_get_action
Checking session consistency (brasero_burn_check_session_consistency brasero-burn.c:1739)
BraseroBurnURI called brasero_job_get_action
BraseroBurnURI called brasero_job_get_action
BraseroBurnURI called brasero_job_set_output_size_for_current_track
BraseroBurnURI stopping
BraseroBurnURI called brasero_job_get_action
BraseroBurnURI called brasero_job_get_session_output_size
BraseroBurnURI output set (IMAGE) image = /tmp/brasero_tmp_Z6XR0X.bin toc = /tmp/brasero_tmp_Z6XR0X.toc
BraseroBurnURI called brasero_job_get_session_output_size
BraseroBurnURI called brasero_job_get_action
BraseroBurnURI called brasero_job_get_current_track
BraseroBurnURI no burn:// URI found
BraseroBurnURI stopping
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao getting varg
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao got varg:
BraseroCdrdao deactivating
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao getting varg
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_input_type
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao called brasero_job_get_bus_target_lun
BraseroCdrdao called brasero_job_get_flags
BraseroCdrdao called brasero_job_get_flags
BraseroCdrdao called brasero_job_get_speed
BraseroCdrdao called brasero_job_set_use_average_rate
BraseroCdrdao called brasero_job_set_current_action
BraseroCdrdao got varg:
    cdrdao
    write
    --device
    /dev/sr0
    -n
    -v
    2
    --simulate
    --speed
    24
    /tmp/brasero_tmp_OSAF0X.toc
BraseroCdrdao Launching command
BraseroCdrdao called brasero_job_get_fd_in
BraseroCdrdao called brasero_job_get_fd_out
BraseroCdrdao stderr: WARNING: Environment variable 'HOME' not defined- cannot read .cdrdao.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: Cdrdao version 1.2.3 - (C) Andreas Mueller <andreas@daneb.de>
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: /dev/sr0: HL-DT-ST DVD+-RW GU70N  Rev: A102
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: Using driver: Generic SCSI-3/MMC - Version 2.0 (options 0x0000)
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr:
BraseroCdrdao stderr: Starting write simulation at speed 24...
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: Process can be aborted with QUIT signal (usually CTRL-\).
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: WARNING: No super user permission to setup real time scheduling.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: Turning BURN-Proof on
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: Enabling JustLink.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: Info fld=-11634, Current
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: SCSI command failed: sense key: 0x03: Medium Error
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: Additional sense indicates: Write error
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: Raw sense data: 0xf0 0x00 0x03 0xff 0xff 0xd2 0x8e 0x0a 0x00 0x00
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: 0x00 0x00 0x0c 0x00 0x00 0x00
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: ERROR: Write data failed.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: ERROR: Simulation failed.
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_action
BraseroCdrdao called brasero_job_get_current_track
BraseroCdrdao stderr: HUP
BraseroCdrdao process finished with status 1
BraseroCdrdao called brasero_job_error
BraseroCdrdao finished with an error
BraseroCdrdao asked to stop because of an error
    error       = 0
    message = "no message"
BraseroCdrdao stopping
Session error : unknown (brasero_burn_record brasero-burn.c:2859)

A: Try this:
Open a terminal,Press Ctrl+Alt+T
Run it:
sudo -i
apt-get update
apt-get install --reinstall brasero brasero-cdrkit brasero-common cdrdao cdparanoia cue2toc dvdauthor dvd+rw-tools genisoimage wodim

If the error persists, I suggest change to k3b

redpajama_set_name: RedPajamaStackExchange


text:
The Knicks Took a Big Swing by Trading Away Kristaps Porzingis. Will It Be Worth It?
The Knicks trading away Kristaps Porzingis shook the NBA world Thursday but no one should overreact before we see what happens this summer.
By Chris Mannix
Before you wind up for a big swing at the Knicks, before you rail that Steve Mills isn't qualified to run an NBA franchise and groan how Scott Perry has not brought a promised sense of order, understand this: It could all work out. It's a big, Aaron Judge-like swing for the fences, but New York's decision to send Kristaps Porzingis to Dallas for a package headlined by Dennis Smith, draft picks and expiring contracts comes with a path to success—a realistic one.
The Knicks interrupted everyone's Anthony Davis trade machine-ing Thursday to drop this bomb, and the reactions were predictable. Knicks fans—jilted by decades of ineptitude matched by an almost equal level of front office incompetence—angrily took to social media. And it's understandable—Porzingis is a budding star. Last season's ACL tear has scuttled this season, but the lack of urgency in bringing Porzingis back has more to do with New York's indifference to winning as Porzingis's recovery. No one in New York is concerned about the long-term health of Porzingis's knee (Dallas certainly isn't) and no one would have blinked at extending Porzingis a max-level offer sheet this summer, when he becomes a restricted free agent.
If anything, Porzingis's interest in being a Knick—which was addressed in a meeting with team officials Thursday—played a meaningful role.
NADKARNI: The Kristaps Porzingis Trade Is All About Kevin Durant for the Knicks
"As is standard for this time of year, we were exploring various options on potential trades," said Perry. "Considering the uncertainty regarding Kristaps's free agent status and his request today to be traded, we made a trade that we are confident improves the franchise."
Keeping Porzingis, continuing to bottom out, hoping the lottery balls bounce your way and crossing your fingers that all that, plus max cap space, would net you a superstar is the safe play.
The Knicks are choosing not to play it safe.
Who knows what the Knicks know about the 2019 free-agent class. The NBA huffs and puffs about tampering, but its willingness—and ability—to investigate is limited. Yet in trading Porzingis the Knicks are sending an unmistakable message: We're getting Kevin Durant. And if Durant does take his talents to 33rd street, they are coming for Kyrie Irving next.
It's a dangerous game—and one the Knicks have played before. In 2010, the Knicks entered a star-studded free agency summer with double max cap space. They wooed LeBron James. They wined and dined Dwyane Wade. They courted Chris Bosh. They signed Amar'e Stoudemire. Later, Wade would say that the market was appealing—it was the organization that didn't seem prepared.
But it could work. Is anyone betting on Durant re-upping in Golden State after this season? The Knicks will not be Durant's only option—the Clippers and Lakers, among other teams, will come a calling—but there likely will be some appeal in Durant 3.0 starting anew in New York, where he can attempt to breathe life into one of the NBA's flagship franchises—what's leading a team to a championship in New York worth to a player?—while growing his brand in the marketing capital of the universe.
And Irving? Irving's repeated statements that he intends to re-sign in Boston this summer give the Celtics confidence that he'll be back, but Boston has long understood the magnetic pull New York has on the West Orange, N.J.-raised Irving. It's why the possibility New York could get in the mix for Davis—a close friend of Irving's—made the Celtics brass anxious. Durant, along with the possible No. 1 pick, could cause comparable consternation.
WOO: Kristaps Porzingis Trade Grade: Knicks Deal Potential Star for Promise of Cap Space
That's right, the pick, the Knicks reward for being catastrophically bad this season. The NBA's attempts to level the playing field in the lottery means the 10-40, worst-record-in-the-NBA Knicks aren't guaranteed No. 1, but if they do nab it, presumed top pick Zion Williamson is another carrot to dangle in a free agent's direction. Don't underestimate the value of a pair of Dallas first-round picks—unprotected in 2021, top ten protected in 2023, per a source familiar with the deal, in fleshing out the roster with talent or for a future trade, either.
It's a long way until July though, and the Knicks just threw down a gauntlet. Boston—which should have a clock hanging in TD Garden, is counting down the hours until the Feb. 7 trade deadline, hoping it comes and goes without a Davis deal—will undoubtedly become even more desperate to land Davis. Irving and Davis are tight, and there is a strong belief internally that if they land Davis, Irving will re-sign and the Celtics will have a pair of All-NBA players and enough young pieces left over to chase championships well into the next decade.
Before, they wanted Davis. They may need him now.
The Knicks went all-in on free agency Thursday, and make no mistake—if they strike out, everyone is fired. Mills is gone, Perry too and polarizing owner James Dolan won't be able to buy a hot dog without checking it for spit. The methodical rebuild the Knicks pledged allegiance to has been replaced by a big-market franchise going big game hunting once again.
kristaps porzingis
nba trade
porzingis trade
knicks trade
kristaps porzingis trade

redpajama_set_name: RedPajamaCommonCrawl


text:
News Sports Entertainment Lifestyle Food USA TODAY Obituaries eNewspaper Legals
Judge OKs Hernandez trial delay in 2012 killings
BOSTON (AP) - A judge has agreed to delay the trial of former New England Patriots player Aaron Hernandez in the 2012 slaying of two Boston men.
The Providence Journal
Hernandez is charged with murder in the fatal shootings of Daniel de Abreu and Safiro Furtado after a chance encounter at a nightclub. His trial was scheduled to begin in May.
But during a court hearing Tuesday, Hernandez's lawyer asked a judge to delay the trial by six months, citing a separate murder trial Hernandez faces in the 2013 killing of semi-professional football player Odin Lloyd.
The judge agreed to delay the Boston trial, but said he wants to see how long the trial in Lloyd's murder takes before setting a new date.
Jury selection in the Lloyd case is set to begin Jan. 5
© 2023 www.providencejournal.com. All rights reserved.


Next week our editorial team will be taking a small break for one week, starting on Monday the 10th of April. We will be joining our families and loved ones in celebration of the Easter holidays. We will be back with more street photography news, posts and videos on the 18th of April 2017.
During the time we will be on a break, we will not be posting anything on our blog, or our Social Media channels. However if you want to get in touch with us, you can do so using Facebook messenger or our email. We will have irregular access to our means of communication we will get back to you.
Now that we will not be filling your timeline with posts for a week, we invite you to take this opportunity and go outside and shoot more! Just grab your cameras, go outside and lose yourselves in street photography!
Press Release: MOPP'S "The Wall"
Hey, enjoy this break and Stay Sharp & Keep Shooting 2!


text:
newsday.co.zw
Court shoots down Chiwenga directive
By newsday.co.zw
VICE-PRESIDENT Constantino Chiwenga and Health and Child Care minister has suffered a crashing legal defeat after the High Court barred him from forcing nurses to return to full-time shift work.
Nurses in public hospitals and clinics early this month approached the High Court through the Zimbabwe Nurses Association (Zina) seeking an interdict against Chiwenga's directive for the removal of their flexible working hours, commonly referred to as flexitime.
Flexitime was introduced as a result of a collective bargaining agreement in January 2019 to allow nurses and doctors to report for duty two or three times per week in view of their low remuneration, but Chiwenga, upon assuming the position of Health minister, scrapped the arrangement, prompting the nurses to seek legal recourse.
High Court judge Justice Martin Mafusire yesterday agreed that the nurses had raised valid concerns relating to incapacitation and lack of personal protective equipment for COVID-19.
The judge hit out at Chiwenga saying he acted against the spirit of fair negotiation by unilaterally ordering an end to flexitime.
Justice Mafusire, however, said the ruling did not serve as a final solution to the impasse and stressed that dialogue was the way to go.
In arriving at the ruling, Justice Mafusire noted that government had not made any significant improvements in the working conditions of nurses to warrant the removal of flexitime.
Flexitime would have ordinarily lapsed in April 2019 had government reviewed upwardly the nurses' salaries.
"It is common cause that no review of remuneration was carried out in April 2019 as had been envisioned or at any time thereafter," part of Justice Mafusire's ruling read.
"Instead, in August 2019, government made a cost of living adjustment on nurses' basic salaries and an allowance of between 50% and 76% on a sliding scale effective August 1, 2019. There was another BNP [Bipartite Negotiating Panel] agreement 28 August 2019. On flexitime, the agreement was inconclusive."
After these developments, the court noted that there were two other attempts by government to end flexitime which ended in deadlocks, only for Chiwenga to thereafter issue a unilateral order bringing an end to the arrangement.
In the court's eyes, this was unfair.
"The next development (after the two deadlocked attempts) was a directive by the third respondent (Chiwenga).
"It is one development that sparked the legal confrontation. The spirit of negotiation and compromise only seemed broken by the third respondent's directive on October 19 2020.
"That directive seemed incongruous to what had prevailed before. The applicant (Zina) cannot be accused of inaction. It called for dialogue. That seemed quite in line with precedent.
"It was in line with the spirit and letter of the law. Only after a deadlock or an impasse had manifested did the applicant come to court. Any reasonable person can see that it was time to act," the judge noted, adding that after assessing the merits of the case, he was left with no choice but to grant the applicants the relief they sought.
"In casu, respondents undoubtedly find themselves between a hard place and a rock. They are in an invidious position.
"Having analysed the BNP agreements at length, as I have done above, I come to the conclusion that applicant's main case is not without merit. The application succeeds. An order is hereby granted in in terms of the draft," Justice Mafusire ruled.
He, however, urged the disputants to go back to the drawing board and solve their problems through dialogue.
"An urgent chamber application is generally an unsatisfactory method of solving disputes. It is disruptive," the judge said.
@NewsDayZimbabwe
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Sunday we will reach the middle of our vision-minded series "These Three Things." In case you missed it, we began by asking just what we want FBC to be known for in greater St. Petersburg. We have staked a claim on meaningful worship, impacting young adults and families and loving, and serving St. Pete. This trio of noble pursuits is worthy of our or best and most focused efforts. Furthermore, they align well with our gifts and the specific needs of the community where God has placed us.
The next three things answer the question what do we want each of us to be doing? Our first button on that three-piece suit is to "Grow." In the oft-overlooked epistle of Second Peter, the most impetuous apostle himself implores fellow Jesus followers to show the evidence of change for the better. In a list that rings of Paul and the Fruits of the Spirit Peter lays out the scorecard for such imitation. For him faith, received through the acceptance of grace has seven add-ons; goodness, knowledge, self control, perseverance, godliness, brotherly kindness, and love.
According to Peter, it is our faith that makes the embodiment of these virtues possible. However, that alone does not have the ability to make it inevitable. That comes when we value these Christian markers and own the responsibility to foster them in our own heart and life. Unfortunately, we seem live in a world where it has become easier, acceptable and even admirable to abandon these traits in favor of their shadow sides. Lord, help us. Yes Lord, help us grow.
Sunday, we unpack a second invitation; "Belong." Even that word will have a three-fold ring to it. Baptism and Deacon commissioning will give rise to that. And both in and immediately after the service you will be given three distinct ways where you can become more deeply imbedded in the fellowship of the church on Gandy. You see, we won't stop at only talking about what we ought to do. We will focus on why and show ways to do it. I look forward to looking out and seeing you then.


text:
using Microsoft.Xaml.Interactivity;
using System;
using System.Collections.Generic;
using System.Globalization;
using System.Linq;
using System.Text;
using System.Text.RegularExpressions;
using System.Threading.Tasks;
using Windows.System;
using Windows.UI.Xaml;
using Windows.UI.Xaml.Controls;
using Windows.UI.Xaml.Input;

namespace Naylah.Toolkit.UWP.Behaviors
{
    public class NumericTextBoxBehavior : DependencyObject, IBehavior
    {

        public enum NumericTextBoxBehaviorType
        {
            Integer,
            Double,
        }

        public string NumericFormat
        {
            get { return (string)GetValue(NumericFormatProperty); }
            set { SetValue(NumericFormatProperty, value); }
        }

        public static readonly DependencyProperty NumericFormatProperty =
            DependencyProperty.Register("NumericFormat", typeof(string), typeof(NumericTextBoxBehavior), new PropertyMetadata("N", NumericValueChangedCallback));

        public double NumericValue
        {
            get { return (double)GetValue(NumericDecimalValueProperty); }
            set { SetValue(NumericDecimalValueProperty, value); }
        }

        public static readonly DependencyProperty NumericDecimalValueProperty =
            DependencyProperty.Register("NumericValue", typeof(double), typeof(NumericTextBoxBehavior), new PropertyMetadata(default(double), NumericValueChangedCallback));

        private static void NumericValueChangedCallback(DependencyObject d, DependencyPropertyChangedEventArgs e)
        {
            var behavior = (NumericTextBoxBehavior)d;
            behavior.SetTexts(behavior.GetNumericNumberFormated());

        }

        public void SetTexts(string text)
        {
            try
            {
                AssociatedObjectAsTextBox.Text = text;
                AssociatedObjectAsTextBox.SelectionStart = AssociatedObjectAsTextBox.Text.Length;
            }
            catch (Exception)
            {
            }
            finally
            {
            }

        }

        private string GetNumericNumberFormated()
        {
            if (Type == NumericTextBoxBehaviorType.Double)
            {
                return NumericValue.ToString(NumericFormat);
            }
            else
            {
                return ((int)NumericValue).ToString(NumericFormat);
            }

        }

        public NumericTextBoxBehaviorType Type
        {
            get { return (NumericTextBoxBehaviorType)GetValue(TypeProperty); }
            set { SetValue(TypeProperty, value); }
        }

        public static readonly DependencyProperty TypeProperty =
            DependencyProperty.Register("Type", typeof(NumericTextBoxBehaviorType), typeof(NumericTextBoxBehavior), new PropertyMetadata(NumericTextBoxBehaviorType.Integer, TypeChangedCallback));

        private static void TypeChangedCallback(DependencyObject d, DependencyPropertyChangedEventArgs e)
        {
            var behavior = d as NumericTextBoxBehavior;
            behavior.SetTexts(behavior.GetNumericNumberFormated());
        }

        private void AssociatedObjectAsTextBox_TextChanged(object sender, TextChangedEventArgs e)
        {
            if (AssociatedObjectAsTextBox == null)
            {
                return;
            }

            try
            {
                AssociatedObjectAsTextBox.TextChanged -= AssociatedObjectAsTextBox_TextChanged;

                if (string.IsNullOrEmpty(AssociatedObjectAsTextBox.Text))
                {
                    NumericValue = 0;
                }

                if (GetNumericNumberFormated() != AssociatedObjectAsTextBox.Text)
                {
                    SetTexts(GetNumericNumberFormated());
                }
            }
            catch (Exception)
            {
                SetTexts(GetNumericNumberFormated());
            }
            finally
            {
                AssociatedObjectAsTextBox.TextChanged += AssociatedObjectAsTextBox_TextChanged;
            }

        }

        private void AssociatedObjectAsTextBox_KeyDown(object sender, KeyRoutedEventArgs e)
        {
            if (AssociatedObjectAsTextBox == null)
            {
                return;
            }

            var num = GetDigitBykey(e.Key);

            if (num != null)
            {
                AddNumberStack(num.Value);
            }
            else
            {
                if (e.Key == VirtualKey.Back)
                {
                    var asii = AssociatedObjectAsTextBox.SelectionLength;
                    RemoveNumberStack();
                }
            }

            e.Handled = !(e.Key == VirtualKey.Tab);

        }

        private void AddNumberStack(int num)
        {
            var nv = GetCleanNumberStack();

            if (Double.Parse(nv) == 0)
            {
                if (nv.Length > 0)
                {
                    nv = nv.Remove(nv.Length - 1);
                }
            }

            nv += num.ToString();

            SetStackNumberToNumeric(nv);

        }

        private void SetStackNumberToNumeric(string nv)
        {

            if (Type == NumericTextBoxBehaviorType.Double)
            {
                nv = nv.Insert(nv.Length - CultureInfo.CurrentCulture.NumberFormat.CurrencyDecimalDigits, CultureInfo.CurrentCulture.NumberFormat.CurrencyDecimalSeparator);
                NumericValue = Double.Parse(nv);
            }
            else
            {
                NumericValue = Int64.Parse(nv);
            }

            SetTexts(GetNumericNumberFormated());

        }

        public string GetCleanNumberStack()
        {

            string r = string.Empty;

            var nv = GetNumericNumberFormated();

            if (Type == NumericTextBoxBehaviorType.Integer)
            {
                nv = nv.Split(CultureInfo.CurrentCulture.NumberFormat.CurrencyDecimalSeparator[0])[0];
            }

            for (int i = 0; i < nv.Length; i++)
            {
                if (Char.IsDigit(nv[i]))
                    r += nv[i];
            }

            return r;
        }

        private void RemoveNumberStack()
        {
            try
            {
                var nv = GetCleanNumberStack();

                if (nv.Length > 0)
                {
                    nv = nv.Remove(nv.Length - 1);
                }

                if (string.IsNullOrEmpty(nv)) { nv = "0"; }

                SetStackNumberToNumeric(nv);

            }
            catch (Exception)
            {
            }

        }

        private int? GetDigitBykey(VirtualKey key)
        {
            switch (key)
            {
                case VirtualKey.NumberPad0:
                case VirtualKey.Number0:
                    return 0;

                case VirtualKey.NumberPad1:
                case VirtualKey.Number1:
                    return 1;

                case VirtualKey.NumberPad2:
                case VirtualKey.Number2:
                    return 2;

                case VirtualKey.NumberPad3:
                case VirtualKey.Number3:
                    return 3;

                case VirtualKey.NumberPad4:
                case VirtualKey.Number4:
                    return 4;

                case VirtualKey.NumberPad5:
                case VirtualKey.Number5:
                    return 5;

                case VirtualKey.NumberPad6:
                case VirtualKey.Number6:
                    return 6;

                case VirtualKey.NumberPad7:
                case VirtualKey.Number7:
                    return 7;

                case VirtualKey.NumberPad8:
                case VirtualKey.Number8:
                    return 8;

                case VirtualKey.NumberPad9:
                case VirtualKey.Number9:
                    return 9;

            }

            return null;
        }

        public void Attach(DependencyObject associatedObject)
        {
            AssociatedObjectAsTextBox = associatedObject as TextBox;

            if (AssociatedObjectAsTextBox == null)
            {
                throw new ArgumentException("NumericTextBoxBehavior can only be used with a TextBox.");
            }

            AssociatedObjectAsTextBox.KeyDown += AssociatedObjectAsTextBox_KeyDown;
            AssociatedObjectAsTextBox.TextChanged += AssociatedObjectAsTextBox_TextChanged;

            if (AssociatedObjectAsTextBox.InputScope == null)
            {
                var inputScope = new InputScope();
                inputScope.Names.Add(new InputScopeName(InputScopeNameValue.Number));
                AssociatedObjectAsTextBox.InputScope = inputScope;
            }

            AssociatedObjectAsTextBox.Loaded += (s, e) => { AssociatedObjectAsTextBox_TextChanged(s, null); };

        }

        public void Detach()
        {
            if (AssociatedObjectAsTextBox != null)
            {
                AssociatedObjectAsTextBox.TextChanged -= AssociatedObjectAsTextBox_TextChanged;
            }
        }

        public DependencyObject AssociatedObject { get; private set; }
        public TextBox AssociatedObjectAsTextBox { get; private set; }
    }
}

redpajama_set_name: RedPajamaGithub


As part of the Mathematical Sciences Collaborative Diversity Initiatives, six mathematics institutes are pleased to host their annual SACNAS pre-conference event, the 2019 Modern Math Workshop (MMW). The Modern Math Workshop is designed to encourage undergraduates from underrepresented minority groups to pursue careers in the mathematical sciences, and to build research and networking opportunities amoung undergraduates, graduate students and recent PhDs.
The workshop includes two mini-courses aimed at undergraduates, research sessions aimed at graduate students and recent PhDs, a panel addressing professional issues of interest to both, a reception open to all participants, and a Q&A with NSF Math Institute representatives.
The MMW is part of the SACNAS National Conference and begins with registration at noon on Wednesday, October 30 and ends at noon on Thursday, October 31.
Recipients of SACNAS travel scholarships will be eligible to receive one additional night of lodging support through the Mondern Math Workshop. Those who do not receive funding from SACNAS are eligible to receive full support for travel and lodging (double-occupancy) and partial reimbursement of SACNAS registration fees. The deadline to apply for funding through the MMW is July 8, 2019.


text:
Adyar Pamphlets No. 209
BUDDHA AND HIS MESSAGE
by C. JINARAJADASA
as published by the Theosophical Publishing House, Adyar, Chennai [Madras], 600 020, India
AMONG all the great personalities who stand out as revealing the genius of Asia, Buddha is the foremost. The spirit of Asia, when Asia is at her noblest, is the spirit of Buddha. Above all other teachers of India, above Confucius and Lao-Tse of China, this great Teacher of India dominates Asia. The peoples of Asia, from the Tartars of Russia and Turkestan in the West to the Chinese and Japanese peoples in the far East, from the Mongolians in the North to the Annamites, Siamese, Cambodians, Burmans and Sinhalese in the South, all alike reverence him as their guide and teacher. Tens of thousands of temples have been built in his honour, to express the gratitude which millions feel to this Teacher whose spirit of compassion and tenderness has modified the harshnesses in human nature and taught men to tread the way of peace. [Page 2]
For two thousand five hundred years, Asia has grown under the peace-making and refining influences of Buddhism. And now, that same influence is being felt in Europe also. There are Buddhist Societies in France, England and Germany; several magazines, dedicated to Buddhism in European languages, show that the interest in Buddha's teachings is steadily growing: Why has Asia come under the sway of the Buddha's teachings, and why are thousands in Europe and America today moulding their lives as if they were born in Buddhist lands and not Christian?
Not one writer but a thousand are needed to explain the significance of the Buddha's message. I can narrate only one aspect of his great work. To me, the most significant fact in his teachings is that he appeals to man, and not to God. Let me explain what I mean.
BUDDHA'S TEACHING
We know that Christianity, Hinduism, Islam, Zoroastrianism, Judaism, base their teachings on the idea of God. These religions say that till a man believes in God, he cannot [Page 3] begin to live a truly righteous or useful life. We know that millions in these religions do live lives of charity, purity and holiness because they worship their God and obey His commandments. But the strange fact is that lives of charity, purity and holiness are also lived by thousands who follow Buddha who never asked men to worship any God as the first step towards their salvation. Buddha taught men to rely upon themselves in order to achieve their own salvation, and not to look to any external saviour. He never assumes the role of a saviour; he never says: "Believe in me; give me your trust; and I will free you from your sins and save you". On the contrary, Buddha proclaims that he is not a saviour but a teacher, that he is not one who carries you on his shoulder over the obstacles in your path to salvation, but rather one who has trodden that path in advance of you and so can show you your way.
SUMMED UP IN "DHARMA"
All the teachings of Buddha can be summed up in one word: Dharma. Dharma is the [Page 4] Sanskrit form; in the language of Pali which Buddha spoke, it is softened to Dhamma. But Dharma, the Sanskrit form, is better known. What is Dharma on which all Buddhist teachings are based?
Let me first tell you what Dharma means in Hinduism. Buddha was born a Hindu; all his disciples were Hindus. He spoke to Hindu audiences. He used words and phrases of Hinduism. Yet he did not teach Hinduism, for he revealed new meanings in the old Hindu ideas. Now, all Hinduism is based on Dharma. In Hinduism, Dharma means Duty. It is the duty which is imposed on you by the will of God. It is God, says Hinduism, who weighs your good and evil, and sends you to be born in this or that race or religion, and as a man or as a woman. This is your Karma, the result of your good or evil in a previous life, which God gives you as your reward or punishment when you are born again. When you are born according to your Karma, God imposes upon you your Dharma or duty. If you are born in the Brahmin or priestly class, your Dharma or duty is to teach and to perform ceremonies of worship; [Page 5] if you are born into the fighter's caste, as a Kshattriya, your duty is to fight for your King and to protect the people. If you are born a Vaishya, in the merchant caste, your Dharma is to engage in trade, and to spend much in charity. If you are a Sudra, in the servant's class, your duty is to be the servant of the other three castes and loyally do the work for which you are paid. Each man and woman, says Hinduism, has certain Dharmas or duties, allocated to him or her by God.
DHARMA IS LAW
Now, when Buddha made Dharma the central theme of all his teachings, he never said that Dharma was the will of God. He never mentioned God. On the contrary, he proclaimed that Dharma exists in a man's own heart and mind. Dharma is law, said Hinduism, the law of God. Dharma is law, said Buddha, the law which is at the heart of a man's conscience. Buddha appeals to man to be noble, to be pure, to be charitable, to be tender, not in order to please any [Page 6] God, but in order to be true to the highest in him, in order to be at peace with himself.
As Buddha proclaimed Dharma, this inner principle of goodness and holiness, which resides in a man's inmost self, he proclaimed that Dharma exists in the universe also. All the universe is an embodiment or revelation of Dharma. The laws of nature which modern science has discovered are revelations of Dharma. If the sun rises and sets, it is because of Dharma; for Dharma is that law inherent in the universe which makes matter act in the ways studied in physics, chemistry, zoology, botany and astronomy. Dharma is inherent in the universe, just as Dharma is inherent in the heart and mind of man. Dharma is the principle of righteousness, the basis of the highest morality. If a man will live by Dharma, he will escape misery and come to salvation.
A RELIGION OF CONDUCT
How shall a man discover Dharma, which will lead him to salvation? Is it by accepting [Page 7] Buddha as a saviour; is it by praying to him; or worshipping him at his temples? This is not the way. On this, we have very clear teachings from Buddha himself. Buddha never puts himself forward as a mediator between you and your final salvation. He cannot help you, unless you help yourself: He can tell you what to do, because he has done it himself, and so knows the way; but unless you yourself act, Buddha cannot take you to your goal. Though you may "take refuge in Buddha", as is the Buddhist phrase, in the simple ceremony of pledging yourself to live a righteous life, it must not be with any blind belief that he can save you. He can point out the way; he can tell you of its difficulties and of the beauties which you will find as you tread the way; but he cannot tread it for you. You must tread the way yourself.
It is not by any kind of prayer, by any ceremonies in temples, or by any appeal to invisible agencies like Devas, that a man will discover Dharma. He will discover it only in one way — by developing his own character. I do not mean by developing his character the [Page 8] practice of Yoga or magic to acquire occult powers. The development which is necessary is a control of the mind and a purification of the emotions. Until a man stills the storm in his heart, until he radiates from him the spirit of goodwill to all, he will not find the first step of the way to salvation.
Buddhism is essentially a religion of conduct. It is by the life which a man lives that he determines for himself whether he is proceeding on the right road or the wrong. It is therefore necessary that a man should first understand himself; for how shall he proceed rightly until he knows what is his baggage, his equipment of good and bad thoughts, or good and bad feelings? Like as a traveller up a difficult mountain path must rearrange his baggage, and discard much that will be merely a hindrance as he climbs to the higher levels where the air is rare, so must the traveller on the road to salvation examine his character and decide what he must discard from it. He must understand himself, so as to be prepared for the obstacles on his path. What are these obstacles? [Page 9]
BLINDED BY DESIRE
They are certain evil elements in our own character. Buddha says that three great currents of force are sweeping each one of us on the road to misery, just as the swift current of a river will carry with it all the helpless logs which have fallen into it. Of these three currents, the first is Rãga or desire. Rãga means desire in all forms. The sensuality of the body whether coarse like that of a mere animal, or more refined in ways that our social conventions permit, this sensuality is Rãga. It makes us selfish, so that we think only of our own need for gratification; and it makes us unscrupulous, if not cruel to others. And this Rãga when once gratified is never satisfied; it clamours for further gratification. It carries us on like helpless logs on a stream. What happens to us when desire sways us is well described in a Japanese proverb, referring to drunkenness. No man who begins drinking a little wine or a little arrack or whiskey dreams of becoming a drunkard; he would be horrified if he saw that that was to be his future. [Page 10]
Nevertheless it is true, as says the Japanese proverb:
First the man takes a drink;
Then the drink takes a drink;
Then the drink takes the man.
There are forms of Rãga that are not the lusts of the body, but the more refined lusts of the emotions. We want to be praised; and are hurt if we are not properly appreciated. Or we are jealous; if someone whose admiration we desire gives that admiration to another and no longer to us. All this is Rãga or desire. This Rãga is like a thick mist such as we meet when climbing mountains. Then we cannot see which way the path goes. Sometimes at sea, when ships enter a territory of fog, and nobody can see what lies ahead, two ships will collide, and perhaps both sink. When men are blinded by desire; they are carried away by a powerful current; and they do not realize whither they are going. If many are blinded by desire, and they desire the same things, there is jealousy and rivalry. As they act to satisfy their desires, they hurt each other. This is our life of competition, our social life [Page 11] of wanting pleasures, amusements, wealth and rank; each thinks only for himself. The end of it is suffering.
THE FOG OF ANGER
Rãga or desire is one current which carries us along to misery. But there is a second current which equally leads us to misery., It is called Dosa. The word means ill-will or hatred. It is that instinct in us which resents any action of another which challenges our right to what we desire. Our natural instinct is to dominate over others; we want them to obey our will. We want our servants to obey us instantly; we want our children to be obedient to us, that is to say, to suppress their wills in order to carry out ours. In all sorts of ways, we feel sure of our individuality, of our uniqueness as egos; only when no one opposes us.
But when someone opposes his will against our will, then our action is like that of a dog with a bone when another dog approaches. There is instant resentment. In a hundred ways, we are irritated by our inferiors, equals [Page 12] or superiors. Our irritation may be slight, or it may burst out in a fury of anger. Sometimes we may suppress all outward manifestation of our anger, because it is dangerous to express it. Then we go on feeding our anger day by day, till it grows into a deep hatred. The anger in a man leads to crimes; we say that an angry man is "beside himself". That is absolutely true; he is being swept along by a torrent of hatred, one part of which is his own anger, but another part of it is like an invisible storage battery of anger which exists in the world.
If Rãga or desire envelops a man in a fog so that he does not see clearly, a thicker fog which surrounds him is the fog of Dosa. Many are its gradations; first there is in us a mild irritation; then it becomes a resentment. If we do not get out of the stream which is carrying us on, the stream gathers speed, and our resentment turns to anger, and later to hatred. All of us are surrounded by a fog of Dosa or hatred; with some of us the fog is light, and with a little struggle we manage to look through it; but with others the fog is so thick that they see nothing [Page 13] beyond, and are aware only of their hatred, which eats into them like an acid.
THE MAGIC OF DELUSION
There is yet a third current which carries us to misery. It is called Moha or delusion. This is far more subtle, and even the cleverest of us become hypnotized by it. Moha is that instinct which makes us want to feed our individuality. We want the whole world to turn to us; we want to become the world's centre. We feel we are nothing unless we have our own possessions. Our "I" is precious and without it we lose our sense of individuality. So a man thinks and says: My money, my house, my property; my child; my rights, my country. He draws a circle round himself, and then says: "These things are mine. Those things are not mine".
Under the subtle magic of Moha, a man plans continually, with the thought: "My happiness, my future, my immortality". Year after year, he feeds his ambitions for personal happiness, for personal knowledge, for personal growth. It is impossible for him to understand [Page 14] that his "I" is like a malignant growth or cancer which ever grows as he dwells more and more upon himself. Then, one day he finds that all men have turned against him, that the world does not want him any longer; he may be powerful, but he is feared and not loved. And as he grows old, he is alone. He blames others; he does not know that in himself is the poison which has made a healthy world around him into a diseased world. He does not know that as he fed the fire of his ego with his ambitions, with his refusals to look beyond his own needs, he has been wrapt in a deep fog of delusion.
It is these raging torrents of Rãga, Dosa, Moha — of desire, hatred, and delusion — which bar our way, as we try to find peace and happiness. We long for peace, and yet we blunder and create confusion; we long for happiness, and yet unhappiness is what we obtain. Our intentions are good, and yet we fail. Why? Because, says Buddha, we are like logs carried along helplessly in the streams of desire, anger and delusion; or, to use the other simile, because we are continually surrounded by a fog created by these [Page 15] defects in our character. If we are to find happiness, we must step outside the stream, we must dissolve the fog. And how?
It is here that the technique of salvation which is characteristic of Buddhism is so different from that of all other religions. They say: "Turn to God; pray to Him; give yourself utterly to Him; become one with Him." The Buddhist technique is to still the raging torrents of desire, anger and delusion, not by prayer to any God but by a careful self-culture. "Save thyself by thyself", "Rouse thyself by thyself", are phrases of Buddha. He sounds a trumpet-call, as it were; giving us an order to act. Our action must be carefully planned; it must be as scientific as the methods of a physician to cure a malady. The method very briefly is as follows.
AN END OF MISERY
If we are to escape from Moha or delusion; we must remove our ego from ourselves; we must substitute the world for our ego. We must become aware that others are like [Page 16] ourselves, seeking happiness and finding sorrow. We must develop in ourselves the sense of affection and pity. We must develop one attribute in us, sympathy. Somewhere in us, in all of us, in even the most brutal of men, there is the capacity for sympathy. It may be sympathy for a man or woman or child, or even only for a dog. We must nourish that little flame with thoughts of kindness for others. Little by little, the fog of delusion thins; we begin to find how interesting are other people, other nations, the whole world. We discover a new and friendly world.
How shall there be an ending to anger? By understanding that there is no injustice, and that the universe is one of law. If a man is opposed to me; if he injures me, I am but reaping the unhappy harvest of a selfish and careless sowing. Understanding the law of Karma, that as a man sows, so does he reap, I shall not be resentful, but feel patient. And I shall try to learn from the lesson set before me. That lesson tells me that the ill-will of others which I resent is only my ill-will of the past which returns to me. My enemy is only my own evil self in a past life which is [Page 17] returning to me. For if another hates me, and I hate him in return, he is showing me to myself, as in a mirror. If there is no hatred in me; I shall not mind how many thousands hate me; I shall be serene and send them thoughts of pity for their ignorance and delusion. If I am always truthful, do I get angry if I am called a liar? No; smile and remain unmoved. But if I get angry, it is only because there is still somewhere in me a part that likes to tell lies. It may not be telling lies to others, but only to myself, about my: self. All this is Karma, and when a man knows that justice rules his life, the fog of hatred dissipates little by little.
And lastly, there is the ending of desire: Desire is in all of us like a raging thirst, which cries: "Water ! Water !" We cry: "I want; I must have; I cannot do without." The things which we want are for ourselves. There is no evil in wanting happiness, knowledge, peace or even power. Misery enters only when in what we desire there is no place for others. Let us desire such things as we can share with others, and then our desires become wiser, more unselfish. Let us desire [Page 18] wealth, but only in order to do works of mercy and charity; let us desire happiness, but only in order to create a world of happiness around us. Slowly the fog created by desire begins to dissipate, and at last we begin to see clearly into the meaning of life for the first time.
In this manner, as we control Rãga, Dosa and Moha, we discover in ourselves the great principle of Dharma. Dharma is Wisdom; it is Power; it is Peace. We discover that we do not need wealth in order to be happy; we have a new wealth of our own in our thoughts of love and pity, in our thoughts of courage and tenderness. Then a little flower is as rich in wealth to us as a handful of gold. A tender heart becomes a nobler object of ambition than wealth or land or titles. As problems of life come before us, we discover in ourselves the wisdom which will tell us how to act rightly. We then know the joy of forgetting our little ego in the delight of seeing the beauty of mankind and the world.
It is Dharma which will guide us so to live that our little ego will be like a mirror of [Page 19] the World Ego, till our ego contains the Universal Ego.
It is when the three streams of Desire, .Anger and Delusion have died down and ended in a man's heart and mind, that he has an intuition of that wonderful state called Nirvana. Nirvana is not a state of annihilation or nothingness; what is annihilated, like the light of a lamp that dies down because the oil is ended, is the inner turmoil in a man caused by the turbulency of the three streams. So wonderful is the state called Nirvana that it cannot be described in words; its nature cannot be understood by any process of mind. It must be experienced by each directly and for himself. It is a state where all the limitations of the individual self have dropped away; perfect wisdom gives insight into every problem; and the individual merges all that is purest, highest and noblest in him with all that is highest and noblest in his fellowmen in one immense wave of tenderness and compassion. [Page 20]
EVERY MAN HIS OWN SAVIOUR
The very especial characteristic of Buddha's gospel is the emphasis which he lays on the idea that each individual must, to use his phrase, " work out his salvation with diligence:" Each man must himself quieten the storm of the passions and the ambitions which are ever creating a turmoil within him. This result is to be achieved not by prayer to any deity, nor by the aid of rites and ceremonies conducted by priests; there is only one way, which is by a life of the highest morality: Buddha has summed up for us his whole gospel in one verse of four lines. The verse is:
Sabba pãpassa akdranam,
Kusalassa upasampadã;
Sachittapariyodapanam;
Etam Buddhanasdsanam.
" Not to do evil,
To increase good,
To purify the mind;
This is the teaching of the Buddhas." [Page 21]
I ask you to note the last line: "This is the teaching of the Buddhas", that is to say, Buddha declares that it is not only his teaching but that of all the Buddhas who have preceded him. To come to salvation by producing in the heart and the mind purity, peace and love, says Buddha, is the eternal law.
A PLAN OF LIFE
In order to help his listeners to live in such a manner that they may feel even now something of the wonder to come; Nirvana that is their goal, Buddha has carefully mapped out the moral life which must be lived. Like an engineer who constructs a pathway up a difficult mountain, so Buddha has constructed a code of morality. First come the Five Precepts, as they are called. These are:
1. Not to kill.
2. Not to steal:
3. Not to commit adultery.
4. Not to lie.
5. Not to take intoxicating liquors or drugs. [Page 22]
These are not Buddha's commandments, the breaking of which entails sin. They represent the preliminary ideals of a virtuous life which a man is to accept wholeheartedly, if he is to call himself a Buddhist. He does not promise to Buddha not to break the precepts; he gives the promise to himself. For the phrase is: "I accept the precept to refrain from taking life," and so on with the other precepts. Each man, as he repeats the precepts, puts himself upon his own honour to do his best not to break them.
And if he breaks them? Then the only repentance, which is constructive, is to make the pledge to himself again, indeed, as many times as necessary, day after day, month after month, year after year, till he wins in the struggle against his lower nature. A man must win the goal of purity and nobility by himself. Not Buddha, nor all the Devas, can bring a man to salvation.
Upon this groundwork of harmlessness, self-control and purity, the individual is to build a perfect life. Buddha carefully tabulates the duties which surround us men and women of the workaday world, and he [Page 23] explains how we should perform them. He considers one by one the mutual relations which exist between (1) parent and child, (2) teacher and pupil, (3) friend and friend, (4) the Buddhist monk and layman, (5) husband and wife, (6) master and servant. What are the duties of a man towards his wife, of a wife towards her husband, of a master towards his servant, and of a servant towards his master, and so on, are all tabulated, so that men may live a life of kindliness and helpfulness, supporting each other in joy and sorrow.
GREAT IDEALS
I have said that a man must "work out his salvation with diligence", and that he must not look to another to do his work for him. Yet he is not left alone and unaided at this difficult task. His help will come to him not from any vicarious saviour, but by contemplating and uniting himself with three great ideals. These three ideals are Buddha, Dhamma and Sangha. A Buddhist repeats the phrases: " I go to Buddha for refuge, [Page 24] I go to Dhamma for refuge, I go to Sangha for refuge. "Now," going for refuge to Buddha" does not mean that Buddha is waiting as a saviour to save his devotee. Buddhist tradition is positive that Buddha has "passed into Nirvana", and is beyond the reach of any suppliant. What, then, does it mean to " take refuge in Buddha"? It is not going for aid to a particular Buddha, but rather going for inspiration to a natural fact that; always, from the beginning of time to its end, Buddhas have appeared and will appear. Each Buddha toils during hundreds of lives to discover the Truth so as to reveal it to man�kind; each reveals the same fundamental morality, the same laws of human relations. Each when he discovers the Truth, "attains Buddhahood" as is the phrase, appears to show men that the road to Nirvana is open, and that no man who struggles for Liberation is alone. For Buddhas appear not only on this earth, but in all the planets and stars; there are Buddhas always somewhere in the universe, even if at any given epoch no Buddha moves on this earth. It is this invisible mystical fellowship with all Buddhas, [Page 25] who have triumphed, which the earnest man is to remember as he fights his way to his Iiberation.
When he says, "I take refuge in Dhamma," once more he contemplates an ideal and takes refuge in it. It is the ideal of universal law; the law which orders the invisible electrons and protons within an atom to move according to mathematical laws, which orders planets to circle round their suns according to law, and which orders the smaller suns to circle round larger suns. It is this same Dhamma or Law which is Karma, and declares that as a man sows, so he shall reap; it is Dhamma dwelling in a man's heart which states that "hatred never ceases by hatred, hatred ceases only by love". All the noblest and loveliest virtues of pity, charity and renunciation are within a man's heart, for Dhamma is a creative power within him. The Dhamma or doctrine which Buddha stated is only a revelation or reflection of what dwells in every man; in saluting Buddha's Dhamma, in "going to refuge" to his Dhamma, a man goes as to a refuge to the highest which is within him. [Page 26]
THE NOBLE ONES
The Sangha is that band of noble souls who are striving to become Buddhas, so that they may lead mankind some day from misery to happiness, from darkness to light. They form a Brotherhood of the Saints or Noble Ones, and each is a centre of compassion and wisdom. The yellow robed Buddhist monks were, in Buddha's days, all pledged to this work of helping the world, and each was a leader and guide: Today, the monks are that in name; they do not know by direct experience the way to Nirvana. When a Buddhist says: "I take refuge in Sangha", he is recollecting that there is still, somewhere;, if not in Buddhist lands today; the true Sangha, or the Noble Brothers who live as the Buddha trained them to live. He contemplates the inspiring fact that their eyes, dwell on him in compassion, and that they share their strength with him.
So, while no Buddhist is to look outside himself for aid, yet he is invisibly encouraged by the power of certain ideals to which he has given his trust — Buddha, Dhamma, Sangha. [Page 27]
VITAL SAYINGS
There are three sayings of Buddha which I desire to quote, as they express more than anything else I know, in Buddha's own words, the spirit of his teaching and the message of his life. They both tell us how the true Buddhist must live, always with thoughts of love. In Metta Sutta, the Discourse on Compassion, he says:
"As a mother, even at the risk of her own life, protects her son; her only son, so let him cultivate goodwill without measure among all beings. Let him cultivate goodwill without measure toward the whole world, above, below, around, unstinted, unmixed with any feeling of differing or opposing interests. Let a man remain steadfastly in this state of mind all the while he is awake, whether he be standing, sitting or lying down. This state of heart is the best in the world."
In another sermon he says:
"And he lets his mind pervade one quarter of the world with thoughts of love, and so the second, and so the third, and so [Page 28] the fourth. And thus the whole wide world, above, below, around and everywhere, does he continue to pervade with heart of love, far reaching, grown great and beyond measure."
The third saying is:
"All the means in this life, ye monks, to acquire religious merit have not the value of a sixteenth part of love, the liberation of the mind."
BUDDHA'S GREATNESS
It is because Buddha taught these truths that all Asia has bowed in reverence before his greatness. He never claimed to be divine; he never asserted that he was different from other men, except that he had won his victory, while they are still in the middle of the battle; and he insisted that all men could become like him. Though he descended to our level and stated that he was as we are, yet the intuition of Asia has sensed his greatness — a greatness beyond all the Gods of her Scriptures. To his name tens of thousands of temples have been erected during the last [Page 29] two thousand five hundred years. Yet the power of Buddha is not in his temples but in the hearts of the men and women who look to him and say: "I take refuge in Buddha". And to take refuge in him is not by repeating formulas and by offering flowers; it is: By not doing evil; By developing the good; and By purifying our thoughts.
I am a Buddhist by birth; but I am a Theosophist first and a Buddhist after. For to be a Theosophist is to realize that all religions are like the seven colours of the solar spectrum, into which the blinding white ray of the sun is separated by a glass prism. Who shall say that in the solar spectrum the colour blue is better than the green, the yellow better than the red? My love and reverence for Buddha do not make me feel that I am holier and nearer to salvation than the Christian or Mohammedan or Hindu. Yet I know this: that help comes to me as I contemplate the ideals represented by Buddha, Dhamma and Sangha. It is the help which I have received which I would share with you. I hope I have given to those of you who are already Buddhists more light on your faith. [Page 30]
I hope that when you repeat: "Namo Tassa Bhagavato Arahato Samma-sambuddhassa", �Praise be to the Lord, the Holy One Perfect in Wisdom", you will have a more definite idea of him and of his greatness. I hope that in those who are not Buddhists I have roused some interest to know more of a teacher who has truly been called "The Light of Asia".
THE BUDDHA'S ENLIGHTENMENT
Yea! and so holy was the influence
Of that high Dawn which came with victory
That, far and near, in homes of men there spread
An unknown peace. The slayer hid his knife;
The robber laid his plunder back; the shroff
Counted full tale of coins; all evil hearts
Grew gentle, kind hearts gentler, as the balm
Of that divinest Daybreak lightened Earth.
The Spirit of our Lord
Lay potent upon man and bird and beast,
Even while he mused under that Bodhi-tree,
Glorified with the Conquest gained for all,
And lightened by a Light greater than Day's.
The Light of Asia


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Fact A Look Back At «Harry Potter»
Harry Potter merchandise are on display at the Scholastic Store November 16, 2001 in New York, NY. (Photo by Justin Sullivan/Getty Images)
A child looks at a Harry Potter product December 13, 2002 in London, England. Harry Potter merchandise to be one of the best-selling gifts for the 2002 Christmas season. (Photo by Scott Barbour/Getty Images)
Actors Emma Watson, Daniel Radcliff and Rupert Grint attend a photocall for the movie "Harry Potter and the Chamber of Secrets" at the Guildhall October 25, 2002 in London, United Kingdom. (Photo by Dave Hogan/Getty Images)
Eight year old Mason Hoppe waits for his chance to purchase a copy of the new "Harry Potter and the Order of the Phoenix" book by J.K. Rowling at Barnes and Noble bookstore on June 21, 2003 in Schaumburg, Illinois. (Photo by Scott Olson/Getty Images)
Actors Emma Watson, Rupert Grint and Daniel Radcliffe attend a photocall to present the new cast of the Harry Potter Films, London, August 23, 2000. (Photo by Dave Hogan/Getty Images)
Harry Potter author JK Rowling arrives at Edinburgh Castle where she will read passages from the sixth magical children's title "Harry Potter And The Half-Blood Prince", on July 15, 2005 in Edinburgh, Scotland. (Photo by Christopher Furlong/Getty Images)
(L to R) Actors Rupert Grint, Emma Watson and Daniel Radcliffe arrive at the World Premiere of "Harry Potter And The Goblet Of Fire" at the Odeon Leicester Square on November 6, 2005 in London, England. (Photo by Dave Hogan/Getty Images)
(L-R) Actors Daniel Radcliffe and Ralph Fiennes attend the premiere of "Harry Potter and the Goblet of Fire" on November 12, 2005 in New York City. (Photo by Peter Kramer/Getty Images)
Actors Daniel Radcliffe and Emma Watson arrive at the Sony Ericsson Empire Film Awards 2006, the annual awards show voted for by the public, at the Hilton London Metropole on March 13, 2006 in London, England. (Photo by Dave Hogan/Getty Images)
Actor Rupert Grint meets fans at the european premiere of "Harry Potter And The Order Of The Phoenix" at Odeon Leicester Square on July 3, 2007 in London, England. (Photo by Dave Hogan/Getty Images)
A Borders books customer walks by a sign advertising the new Harry Potter book at a Borders store July 19, 2007 in San Francisco, California. (Photo by Justin Sullivan/Getty Images)
Harry Potter fan Hanna Polasky looks on in the Union Square Barnes and Noble before the final book goes on sale tonight at midnight July 20, 2007 in New York City. (Photo by Mario Tama/Getty Images)
A Harry Potter fan begins to read the final novel by author J.K. Rowling, "Harry Potter and the Deathly Hallows", at the much anticipated launch on July 21, 2007 at the Carriage Works in Sydney Australia. (Photo by Lisa Maree Williams/Getty Images)
(L-R) Daniel Radcliffe, Emma Watson, J K Rowling and Rupert Grint attend the World Premiere of "Harry Potter And The Deathly Hallows: Part 1" held at The Odeon Leicester Square on November 11, 2010 in London, England. (Photo by Dave Hogan/Getty Images)
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The painting "The Denizens of the River" (1926) (L) by artist Rene Magritte is displayed during the private...
The painting "The Denizens of the River" by artist Rene Magritte is displayed during the private opening...
The painting "The Denizens of the River" (1926) (L) by artist Rene Magritte is displayed during the private opening of the exhibition "Magritte: The Mystery of the Ordinary" at The Museum of Modern Art in New York September 17, 2013. Belgian painter Magritte's work, featuring men in bowler hats, mysterious landscapes and bright blue skies, may be familiar to many art lovers, but the new exhibition, which opens on September 28 and runs through January 12, focuses attention on the artist's surrealist pieces. REUTERS/Joshua Lott (FRANCE - Tags: SOCIETY)
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Joshua Lott


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Brentuximab Vedotin with Re-induction Chemotherapy Effective, Well Tolerated in AML
Kevin Wright
Acute Myeloid Leukemia, Leukemia and Lymphoma
Combination treatment of brentuximab vedotin (BV; Adcetris) with a standard chemotherapy regimen of mitoxantrone, etoposide, and cytarabine (MEC) in patients with relapsed/refractory acute myeloid leukemia (AML) was found to be safe and well tolerated, according to a study published in Cancer.1
In this phase I, dose escalation clinical trial, 22 patients with CD30-expressing relapsed/refractory AML were given 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) on day 1 of a 7-day cycle, followed by the MEC chemotherapy on days 3 through 7. Preliminary efficacy measures showed a composite response rate (CRR) of 36%, with a response rate of 42% among those patients who received the highest dose of BV. Median overall survival (OS) was 9.5 months, with a median disease-free survival of 6.8 months observed among responders.
Febrile neutropenia (64%) was the most common adverse event (AE) noted across all grades, with anorexia (59%) and oral mucositis (55%) also commonly reported. AEs higher than grade 3 included thrombocytopenia (45%) and anemia (32%), with no new toxicities attributable to the study treatment combination of BV and MEC.
"Overall, the results of the current phase I study identified a well-tolerated dose of BV given during reinduction therapy with MEC for patients with CD30- expressing (relapsed/refractory) AML, with a toxicity profile that generally was similar to that of MEC alone," noted the authors.
The study enrolled 22 patients between May 2013 and April 2018, with a median age of 58 years (range, 23-72 years). Fifteen (68%) were male and 20 (91%) were white. Upon enrollment, 4 patients (18%) had primary refractory disease and 18 patients (82%) had relapsed disease, with 21 (95%) having received prior cytotoxic induction chemotherapy combining an anthracycline with cytarabine as initial induction therapy. One patient (5%) had received high-dose cytarabine.
Due to the smaller sample size, the authors were unable to detect a predictive cytogenetic or molecular pattern for response, but they noted that responses were observed in "patients with adverse risk cytogenetics and unfavorable molecular features." There was no observed response in patients with primary refractory disease however, which the authors believe suggests the difficulty in overcoming chemoresistance.
"The current study highlighted the challenges of treating patients with (relapsed/refractory) AML," wrote the authors. "Although several intensive and non-intensive chemotherapy re-induction options currently are available, to the best of our knowledge there has not been a clear preferred option."
The authors called for additional research and larger studies to confirm the results shown in this phase I study, citing the need to more comprehensively assess the efficacy and toxicity of CD30-targeted therapy in patients with AML.
Narayan R, Blonquist TM, Emadi A, et al. A Phase 1 Study of the Antibody-Drug Conjugate Brentuximab Vedotin with Re-Induction Chemotherapy in Patients with CD30-Expressing Relapsed/Refractory Acute Myeloid Leukemia. Cancer. doi:10.1002/cncr.32657.


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Microsoft TechSpark expands to Texas, Virginia, Washington and Wyoming
Mar 16, 2018 | Brad Smith - President
Images from Microsoft TechSpark regions in North Dakota, Texas, Virginia, Washington and Wyoming.
In October, we announced Microsoft TechSpark, a national civic program to introduce initiatives designed to foster greater economic opportunity and job creation in six communities in the United States. Today, we're announcing four TechSpark regions: El Paso, Texas; Southern Virginia; North Central Basin of Washington, around Quincy; and, Cheyenne, Wyoming. Microsoft is focusing its efforts in these regions along with previously announced Fargo, North Dakota and Northeast Wisconsin.
Technology is rapidly changing our economy, including how we communicate, learn, work and access health care and other essential services, creating opportunities as well as challenges. Regions outside of major metropolitan areas sometimes have been affected by the challenges even more than the country's largest cities. We aim to bring educators, business, governments, nonprofits and other civic organizations together to turn these challenges into opportunities. By partnering closely with communities on the ground, we aim to learn more about regional challenges and how technology can help local economic growth and create jobs, with a plan to share our learnings more broadly.
The TechSpark initiative focuses on five program areas: digital transformation, digital skills and computer science education, career pathways, rural broadband, and support for nonprofits. In each region we will have a signature project which will be a major investment that we hope will help accelerate a community's transformation. We announced our first signature project late last year and will announce projects in other TechSpark regions in the coming months.
We've been building the foundation for TechSpark more than a year, including recruiting and hiring employees to work with the local community and with the different groups inside Microsoft that will help deliver these programs. I'm pleased to introduce the community managers for the four regions we're announcing today: JJ Childress in El Paso will manage TechSpark Texas, Dennis Ellis in Cheyenne will manage TechSpark Wyoming, Lisa Karstetter in Quincy will manage TechSpark Washington, and Jeremy Satterfield in Boydton will manage TechSpark Virginia. In addition to dedicated community managers, we will create new opportunities for Microsoft employees to volunteer and engage in projects, including for many, lending a hand in the communities where they grew up.
Our hope is that TechSpark will help communities and businesses work better together to address critical economic challenges at the local level. We believe this model of a deep, long-term community partnership can help communities address their unique needs and create a future-ready workforce and be a catalyst for economic investment and opportunity for all Americans.
Tags: Brad Smith, education, Microsoft TechSpark
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