Download 0974-8369-8-296 778.9 KB

Biology and Medicine
Open Access
Bio
l
e
cin
y and Medi
og
ISSN: 0974-8369
Biology and Medicine Journal being a broad discipline in the Medical research field offers the best platform
to publish innovative ideas and researches. It is an indexed bimonthly journal that aims to showcase outstanding
research articles from all areas of biology and medicine.
Biology and Medicine Journal is an International, Open- Access, Peer-reviewed, comprehensive journal,
publishing the most interesting and advanced research findings in the scientific community. The motto of the
journal is to publish original, genuine and relevant articles in the current research field.
The focus broadly covers Cellular biology, Developmental biology, Medical sciences, human biology, Medical
biology, Anatomy, Physiology, Disease research etc.
Biology and Medicine - Open Access uses online manuscript submission, review and tracking systems for quality
and quick review processing. Submit your manuscript at
www.editorialmanager.com/medicalsciences
Amina S Woods
Simon Kaja
National Institute of
Health, USA
University of Missouri
USA
Y Hasan Siddique
C Perry Chou
Aligarh Muslim
University, India
University of Waterloo
Canada
Suhel Parvez
Associate Professor
India
M Salah Khalil
Central of Agricultural
Pesticides Laboratory
Egypt
Jimmy Thomas
Efird
University of North
Carolina, USA
Kaiser Jamil
Jamal Zweit
Jagat R Kanwar
Virginia Commonwealth University
USA
Deakin University
Australia
N Pradhan
Ninoslav Djelic
Centre for
Biotechnology and
Bioinformatics, India
National Institute of University of Belgrade
Mental Health and
Serbia
Neurosciences, India
Tapasya Srivastava
VV Pillay
Anupam Bishayee Alejandro Giorgetti
University of Delhi
South Campus
India
Amrita Institute of
Medical Sciences &
Research, India
American University of
Health Sciences, USA
Haroon Khan
Jibing Yang
Amin A Fadl
Gandhara University University of Michigan University of WisconsinMadison, USA
Pakistan
USA
Tao Zhang
Yujing Li
Mohammad Afzal
Anita Mukherjee
The Research
Institute for Children
United States
Emory University
School of Medicine
USA
Professor Zoology
Aligarh
Professor University of
Calcutta, India
Qamar Rahman
Ramesh K Aggarwal
Alan Prem kumar
Sangeeta Shukla
Integral University
India
Deputy Director, Centre
for Cellular and Molecular Biology Hyderabad
India
University of Verona
Italy
Idress Hamad A
Zewei Miao
Omar El-Mukhtar
University, Libya
Agricultural Engineering Sciences Building
Urbana
Wei Li
Pierluigi Scalia
Jukka Hartikka
Azusa Pacific
University, California
San Diego, USA
Novartis Institutes for
BioMedical Research
China
University of North
Texas, USAff
Sangeeta Shukla
India
HS Abou-Auda
M Jahangir Alam
King Saud University
Saudi Arabia
University of Houston
College of Pharmacy
USA
David R Bachinsky Medani P BhandariMolecular Creativity
USA
OMICS International
5716 Corsa Ave, Suite 110, Westlake, Los Angeles, CA 91362-7354, USA, E-mail: [email protected].
Phone: +1-650-268-9744, Fax: +1-650-618-1414, Toll free: +1-800-216-6499
Syracuse University
New york
Bio
l
e
cin
y and Medi
og
Nezami et al., Biol Med (Aligarh) 2016, 8:4
http://dx.doi.org/10.4172/0974-8369.1000296
Biology and Medicine
ISSN: 0974-8369
Case Report
Open Access
The Role of Telomeres in Cancer Development and Progression, and the
Double Edge Sword Effect with Tamoxifen
Nezami MA1*, Hager S2 and Garner J1
1
2
Research Cancer Institute of America, Pacific Medical Center of Hope, Fresno, CA 93720, USA
Ccare, Fresno, CA, USA
Keywords: Tamoxifen; Cancer prevention; Telomeres
Introduction
The current practice regarding the use of estrogen receptor
antagonists in breast cancer, (such as Tamoxifen), has opened doors
for investigators to research these drugs for their use in the prevention
of breast cancer. Although this approach is suggested by the literature
to be an effective strategy, currently there are no established guidelines
applicable to the use of anti-estrogen receptor drugs or prevention in
the clinical setting [1,2].
We review the literature related to Tamoxifen therapy and
recommend expansion of the application of low dose Tamoxifen for
patients with positive estrogen receptor cancers to preventive oncology.
These applications include patients at risk for hormonally responsive
cancers, and expand beyond that to individuals who may not be even
at risk as defined by current risk stratification standards, such as
strong family history of breast cancer. In this article we also review an
opposing negative effect of Tamoxifen in patients with active cancer,
and discuss why we believe it should be “avoided” in the treatment of
solid tumors (except breast cancer), although it may be a meaningful
tool in prevention of cancer of all types.
Background
The double edge sword of Tamoxifen (favorable in prevention
and unfavorable in therapy), is based on our novel understanding of
telomeres and their role in carcinogenesis and cancer progression [36]. Further studies are warranted in application of low dose Tamoxifen
to prevent all solid tumors in unaffected individuals, in a safe and
efficacious manner. The theory of how Tamoxifen interacts with
telomeres also provides a basic understanding of possible unfavorable
mechanisms involved with Tamoxifen’s application and its resistance
in treated tumors.
Telomeres and Tamoxifen
Tamoxifen is shown in the literature to be a telomerase activator
[7]. The activation of telomeres is an important step in carcinogenesis
as it is secondary to what is known as a “telomere crisis” [3,8]. As we
age, the length of the telomeres shortens. Continuation of this process
over time is important, as it causes the cell DNA to be exposed to
genomic instability. This instability at a critical length of telomeres
promotes apoptosis, by activating the P53 and other onco-suppressor
genes in normal circumstances.
However, if this instability continues beyond a certain point, and/
or if the P53 system is impaired, or if the cell is exposed to a telomerase
activator (such as Tamoxifen), it can cause DNA damage and mutations
in both oncogene promotors as well as oncogene suppressors, which can
promote the cancer development at the first stages (carcinogenesis). It is
therefore postulated that the telomere crisis happens long before the DNA
mutations required for carcinogenesis. The unstable DNA shares the same
alterations identified in cancer. Finally, activation of telomerase can save
the cell from apoptosis, and death. This activation is uniform in almost all
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
cancer cells, with high proliferative index [4] shown by both tumor tissue
biopsy as well as liquid biopsies. Although it is suggested that telomerase
activity is not required for malignant transformation, and it merely an
index for highly proliferative cells, it is commonly used as a marker for
detection and monitoring the cancer cells, both in tissue biopsies as well as
circulating tumor cells or CTCs (Telomerase is an indicator for presence of
tumor epithelial cells in the blood) [9,10].
Studies have shown that by using tamoxifen in a cellular culture,
the ability of the cells to activate telomerase increases, and as the result
the cell will continue to stay young, with prolonged resistance to crisis
[7]. This can prevent the cell from an increased amount of genomic
instability and further carcinogenesis. However, the same mechanism
can explain the cancerous cell’s ability to survive longer in the presence
of Tamoxifen, as a telomerase activator [7]. The cancer cells exposed to
4-hydroxy Tamoxifen in culture are able to survive longer and infiltrate
distant organs in mice studies, explaining the increased invasion. The
critical question remains whether the application of Tamoxifen as early
as possible in individuals not known to have cancer may prevent the
telomere crisis, and if so, it can prevent carcinogenesis long before it is
clinically diagnosed.
Tamoxifen therapy also may have unintended effects on gene
expression. This theory is presented in the following two cases studies,
both patients with breast cancer who had positive circulating tumor
DNA for Neurofibromatosis-I gene post tamoxifen therapy.
Case Studies
Breast cancer with positive NF-1
70 year old female with history of left breast ductal carcinoma
diagnosed in 2001 status post lumpectomy and hormonal therapy.
Hormonal therapy consisted of Femara for 3 years and Arimidex
for 4 years. She was also treated with radiation, and was status-post
recurrence of the tumor in same side documented in September
2013, through core biopsy and referral for surgery (mastectomy), and
chemotherapies. The extent of disease was documented to involve the
skin and required neoadjuvant chemotherapies. Her left breast had a
5 cm mass. She was seen and evaluated for complimentary medicine,
and immediately started on IV epigenetic therapies after initial labs.
*Corresponding author: Nezami MA, Research Cancer Institute of America,
Pacific Medical Center of Hope, Fresno, CA 93720, USA, Tel: (559) 475 4300;
E-mail: [email protected]
Received: February 23, 2016; Accepted March 18, 2016; Published March 21,
2016
Citation: Nezami MA, Hager S, Garner J (2016) The Role of Telomeres in Cancer
Development and Progression, and the Double Edge Sword Effect with Tamoxifen.
Biol Med (Aligarh) 8: 296. doi: 10.4172/0974-8369.1000296
Copyright: © 2016 Nezami MA, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Volume 8 • Issue 4 • 1000296
Citation: Nezami MA, Hager S, Garner J (2016) The Role of Telomeres in Cancer Development and Progression, and the Double Edge Sword Effect
with Tamoxifen. Biol Med (Aligarh) 8: 296. doi: 10.4172/0974-8369.1000296
Page 2 of 4
Her initial labs showed extensively elevated angiogenic markers, including
Interleukin 8 (both in serum and plasma). Her Interleukin 8 was 103.3
in plasma (normal less than 34) and 136 in serum (normal less than 66),
measured on 6/3/14. Treatment was given every day in first two weeks, five
days a week, and twice a week after. She was started on Tamoxifen at a dose
of 5 mg daily. Her labs were repeated on 6/17/14 and 8/29/14. She reported
improved QOL while receiving therapies and no side effects experienced.
Her labs showed marked reduction in both markers. Her IL-8 in serum
dropped down to 89 and in her plasma down to 16.8. Further this dropped
down to normal range. Her Interleukin 8 normalized both in serum as well
as plasma (50 in serum and 27 in plasma), on 10/8/2014.
She subsequently underwent surgery on 12/14, and currently
is in remission. She received Firmagon injection, as well as Cytoxan
(metronomic dose) along with our therapy, and her VEGF dropped
down to less than 9, on 5/28/15. Her circulatory tumor DNA (ctDNA)
was studied through Guardant 360 Lab, on 6/25/15, which showed
positive NF-1, and APC, likely due to the exposure to anti-estrogen
therapy. Following further treatments with MTET (Multi-targeted
Epigenetic therapy), her Guardant 360 was repeated and showed no
ctDNA (Figure 1).
This anti-angiogenetic response to the therapies in a novel approach
Test Number 3 Status : CORRECTED
DOB
Reporting
Patient
Biopsy-FreeTMTumor Sequencing
Physician
MRN
ORIGINAL REPORT DATE
NAME
GENDER
CORRECTED DATE
ACCOUNT
JAN-08-2016
Female
MAR-15-2016
CLINICAL DIAGNOSIS
RECEIPT DATE
Breast Carcinoma
Mohammed Amin Nezami
Pacific Medical Centre of Hope
1680 E Herndon Ave ste 102, Fresno, CA 93720
DEC-30-2015
PHONE
(559) 439-5393
COLLECTION DATE
DEC-29-2015
FAX
(559) 439-5828
ADDITIONAL RECIPENT
SPECIMEN
Blood
Guardant360 Tumor Response Map
The Guardant360 Tumor Response Map illustrates the relative changes of observed cfDNA at different samples submission time points. The “somatic Alteration Burden” value
below refers to the maximum % cfDNA detected at each time point . Amplifications are not plotted and only the first and last four test dates are plotted. please see the
physician portal for the Tumor Response Mao with all test dates.
somatic Alteration Burden 0.5%
0.4%
0.4%
3 Total Alteration(s) Detected
0 with Associated Therapy
0 Associated with Lack of Response
No Clinical Drug Trial Available
JUN-04-15
AUG-05-15
DEC-29-15
Summary of Alterations & Associated Treatment Options
The percantage, or allele frequency, of altered cell-free DNA (% cfDNA) circulating in blood is related to the unique tumor biology of this patient. Factors that may affect the
amount/ percentage of detected genomic alterations in circualting cell-free DNA in blood include tumor growth, turn-over, size,heterogeneity, vascularization, disease
progression, or treatment
Mutation Trend
Alteration
EGFR
E967K
100
50
5
% cfDNA
0.4
ND
MET
CDK4
R1005Q
/136/#
5
5
0.1
0.5
ALK
R1120W
5
Clinical Drug Trials
established. The releavance of the therapists targeting this alterartion is uncertain. similar to
other alteration in circulatring cfDNA, the monitoring of this variant may be reflective of
disease progression or treatment: clinical correlation is advised.
established. The releavance of the therapists targeting this alterartion is uncertain. similar to
other alteration in circulatring cfDNA, the monitoring of this variant may be reflective of
disease progression or treatment: clinical correlation is advised.
There is no change in the amino acid at this position and it is not likely to be a
therapeutiuc target. similar to other alteration in circulating cfDNA, the monitoring of
the variant may be reflective of disease progression or treatment; clinical correlation is
advised.
ND
100
50
Available for use in
other indications
The functional consequences and clinical significance of this gene variant are not
0.2
0.5
ND
100
50
FDA Approved in
indication
The functional consequences and clinical significance of this gene variant are not
0.5
100
50
cf DNA Amplification
ND
0.5
ND
NF1
A1224A
100
50
5
ND
0.5
ND
BRCA2
Q407E
100
50
5
ND
0.5
ND
GUARDANT HEALTH
Arthur Baca, MD phd Labaratory Director CLIA ID: 05D2070300 505 Penobscot Drive, Redwood city, CA 94063
T:855-698-8887 [email protected] https://portal.guardanthealth.com TST-PRT-001 V13.0 PG 1 OF 6
Figure 1: Report showing the case study of case 1.
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
Volume 8 • Issue 4 • 1000296
Citation: Nezami MA, Hager S, Garner J (2016) The Role of Telomeres in Cancer Development and Progression, and the Double Edge Sword Effect
with Tamoxifen. Biol Med (Aligarh) 8: 296. doi: 10.4172/0974-8369.1000296
Page 3 of 4
when she was diagnosed first. None of the therapies was effective, and
in fact her cancer grew to 4 cm, and she opted for bilateral mastectomy
and axial lymph node resection in November 2012, which was positive
for 2 LN invasions. Upon her arrival at our clinic, she had recurrence
of her tumor, with two large palpable sites in the chest on skin. She
was complaining of a new onset consistent and dry cough, and was
concerning for lung metastasis. Upon evaluation, we ordered a PET
scan, which showed multiple pulmonary metastasis bilaterally, which
were too numerous to count, with an SUV max of 4.8. She had multiple
needs to be investigated further in clinical trials to reduce the risk of
recurrence and improve response to conventional treatments.
Breast cancer with positive NF-1
43 year old female with history of breast ductal carcinoma, 100
percent ER and PR positive, and a Her-2 negative. Her Ki67 was 80
percent; SBR on biopsy was determined to be 8/9.
She had exhausted many alternative cancer therapies since 5/2012,
Test Number 2
DOB:
Patient
MRN
REPORT DATE
09/19/2015
GENDER
RECEIPT DATE
09/09/2015
Female
CLINICAL DIAGNOSIS
NAME
Mohammed Amin Nezami
ACCOUNT
Pacific Medical Centre of Hope
1680 E Herndon Ave Ste 102, Fresno, CA 93720
COLLECTION DATE
09/08/2015
Breast Carcinoma
Biopsy-FreeTMTumor Sequencing
Physician
Reporting
FAX
PHONE
(559) 439-5393
SPECIMEN
Blood
(559) 439-5828
ADDITIONAL RECIPENT
Guardant360 Tumor Response Map
The Guardant360 Tumor Response Map illustrates the relative changes of observed cfDNA at different sample submission time points. The “somatic Alteration Burden” value
below refers to the maximum % cfDNA dtected at each time point. Amplifications are not plotted.
Somatic Alteration Burden0.1%
ND
0 Total Alterations(s) Detected
06.24.15
09.08.15
Genomic Alterations: Not Detected (ND). Genomic alterations may be present that are below the limit of detection of this test. Certain sample or variant characterstics may
result in reduced anaytic sensitivity , such as poor sample quality or improper collection. Genomic alterations in a tumor may be present, but are not detected in circulating cellfrre DNA from this blood specimen with this test
Summary of Alterations & Associated Treatment Options
The percenatage , or allele frequency, of altered cell -free DNA (% of DNA) circulating in blood is related to unique tumor biology of this patient. Factors that may effect the
amount/ percentages of detected genomic alterations in circulating cell-free DNA in blood include tumor growth, turn -over, size, heterogeneity , vascularization, disease
progression, or treatment.
Alteration
Mutation Trend
NF1
R1362Q
APC
S2632L
100
50
5
0.5
% cfDNA
cf DNA Amplification FDA Approved in
indication
Available for use in
other indications
clinical Drug Trials
ND
100
50
5
0.5
NO
ND
For a more detailec Guardant360 patient Report, log onto: http://portal.guardanthealth.com
To set up an account, contact CI ent Services: 855.698.8887
The chart above annotates the percentage or allele frequency , of altered circulating cell free-DNA (% cfDNA ) detected in this patient. The detected genomic alterations are listed in descending order by % by gene.
The “FDA Approved in indication ”and “ Available for use in other indications” columns describe drugs associated with specific fenomic alterations. It based on publicly
available information as described in the “ Detailed Therapy Results” and “clincial Relevance of Detected Alterations” sections of the report
Definitions
None.
GUARDANT HEALTH
Arthur Baca, MD phd Laboratory Director/2686 Middlefield Rd, Sube C, D, E. Redwood city, CA 94063
T: 855-698-887 [email protected] https://portal.guardanthealth.com Report Version 4.1 TST-PRT-001 V12.0 pg 1 of 4
Figure 2: Report showing the case study of case 2.
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
Volume 8 • Issue 4 • 1000296
Citation: Nezami MA, Hager S, Garner J (2016) The Role of Telomeres in Cancer Development and Progression, and the Double Edge Sword Effect
with Tamoxifen. Biol Med (Aligarh) 8: 296. doi: 10.4172/0974-8369.1000296
Page 4 of 4
masses in right breast with max SUV of 12.9, and multiple smaller
lesions with max SUV of 5.5, plus mediastinal and internal mammary
LNs in chest and supraclavicular LNs. In additional she had multiple
metastatic LNs in right axilla with SUV max of 2.9.
suggests further need to evaluate this novel combinational approach in
treating resistant and recurrent advanced breast cancer.
She had tumor markers all elevated in labs. Immediately she was
started on IV epigenetic therapies which she received on daily basis.
After 10 treatments, her labs were rechecked. The results showed
significant decreases in all her tumor markers. Her cough improved,
and she maintained her treatments at our clinic. She did not change
her diet, nor did she start any chemotherapy. At this time, she was
not on any hormonal blockade, confirming the independent response
to epigenetic therapy. In November 2014, she had a restaging PET
scan, showing marked reduction of the activities in mediastinal and
internal mammary LNs, with improved diffuse pulmonary metastasis.
The PET scan was performed and compared with PRE treatment scan
after 6 weeks of therapy. The following PET scan done on 1/12/15,
demonstrated complete resolution of all pulmonary metastasis and
axillary/supraclavicular lymph nodes. There was minimal residual
disease reported in the mediastinal lymph nodes, with SUV activity
decreased to 5 from 10.6, and to 3 from 7. At this time, the tumor
markers were substantially reduced and most returned to normal
limits. CA 15.3 was at 31, previously 37, 52, and 56 (respective dates:
4/7/15, 1/16/15, 11/21/14, 10/19/14). CA 27.29 was 33, previously 44,
47, 55.6, and 65 (respective dates 11/21/14, 10/9/14, 9/11/14, 8/8/14).
CA 125 was 18.6, previously 19.5 and 39.8 (respective dates 4/7/15, 1/16/15
and 10/9/14). At this time she was receiving combination epigenetic
therapies with hormonal blockade, consisting of GnRH blockade (Lupron)
as well as Tamoxifen at 5 mg every other day (1/8 normal dose of 20 mg per
day). She was restaged again with a PET/CT on 4/15/2015, which showed
progression of the local disease in surgical incision, but only minimal
residual disease and faint FDG activity (SUV activity of 1.5 compared to
4.8 pre-treatment) in her mediastinal pulmonary lesions, with complete
resolution of liver findings. Due to the fact that she was down staged from
a Stage IV disease to a local disease in the breast, it was justified to remove
the breast tissue and treat her locally with surgery.
Tamoxifen has been proven to prevent invasive and noninvasive
breast cancer [1,2]. Retrospective studies also indicate an effect on
incidence of endometrial and ovarian cancer [11,12]. We also recommend
large scale studies using Tamoxifen for prevention of cancer. Perhaps the
most important question that remains to be answered is the timing of
Tamoxifen administration in the prevention of cancer.
Following her surgery, her circulatory tumor DNA was evaluated
through Guardant 360, which revealed positive EGFR. Subsequently the
patient was started on Tarceva, and the Guardant 360 test was repeated.
Although the EGFR mutation allele fraction (MAF) decreased with
therapy, the second test showed NF-1, ALK, EGFR and cMET (Figure
2). The presence of NF-1 confirmed the mutated oncosuppressor gene,
likely due to the exposure to anti-estrogen therapy, an example of
induced heterogeneity. The presence of other alterations, confirmed the
induction of heterogeneity by Tarceva. The presence of NF-1 and other
alterations, although considered poor prognostic markers, did not
change this patient’s outcome, or her disease free survival. We believe
that this success was due to the combination of epigenetic therapies.
This case suggests an independent, as well as synergistic method
of epigenetic therapies combined with hormonal blockade, which
was able to treat non-operable Stage IV breast cancer, and down stage
the patient successfully to treat the local disease. This quick response
Citation: Nezami MA, Hager S, Garner J (2016) The Role of Telomeres in
Cancer Development and Progression, and the Double Edge Sword Effect with
Tamoxifen. Biol Med (Aligarh) 8: 296. doi: 10.4172/0974-8369.1000296
Conclusion
References
1. Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M (2007) Twenty-Year Followup of the Royal Marsden Randomized, Double-Blinded Tamoxifen Breast
Cancer Prevention Trial. J Natl Cancer Inst 99: 283-290.
2. Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, et al. (2007) Long-term
results of tamoxifen prophylaxis for breast cancer--96-month follow-up of the
randomized IBIS-I trial. J Natl Cancer Inst 99: 272-282.
3. Blackburn EH (2005) Telomerase and Cancer: Kirk A. Landon--AACR prize for
basic cancer research lecture. Mol Cancer Res 3: 477-482.
4. Belair CD, Yeager TR, Lopez PM, Reznikoff CA (1997) Telomerase activity: a
biomarker of cell proliferation, not malignant transformation. Proc Natl Acad Sci
USA 94: 13677-13682.
5. Lu L, Zhang C, Zhu G, Irwin M, Risch H, et al. (2011) Telomerase expression
and telomere length in breast cancer and their associations with adjuvant
treatment and disease outcome. Breast Cancer Res 13: R56.
6. Wang Z, Kyo S, Maida Y, Takakura M, Tanaka M, et al. (2002) Tamoxifen
regulates human telomerase reverse transcriptase (hTERT) gene expression
differently in breast and endometrial cancer cells. Oncogene 21: 3517-3524.
7. Henson JD, Neumann AA, Yeager TR, Reddel RR (2002) Alternative
lengthening of telomeres in mammalian cells. Oncogene 21: 598-610.
8. Blocking Telomerase Kills Cancer Cells but Provokes Resistance, Progression
(2012) Drug Week.
9. Xu T, Lu B, Tai Y, Goldkorn A (2010) A Cancer Detection Platform Which
Measures Telomerase Activity from Live Circulating Tumor Cells Captured on
a Microfilter. Cancer Research 70: 6420-6426.
10.Fizazi K, Morat L, Chauveinc L, Prapotnich D, De Crevoisier R, et al. (2007)
High detection rate of circulating tumor cells in blood of patients with prostate
cancer using telomerase activity. Ann Oncol 18: 518-521.
11.Vrscaj MU, Kovacic J, Bebar S, Djurisic A, Fras P, et al. (2001) Endometrial
and other primary cancers after tamoxifen treatment of breast cancer — results
of retrospective cohort study. Eur J Obstet Gynecol Reprod Biol 95: 105-110.
12.Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, et al. (1998)
Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical
Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388.
OMICS International: Publication Benefits & Features
Unique features:
•
•
•
Increased global visibility of articles through worldwide distribution and indexing
Showcasing recent research output in a timely and updated manner
Special issues on the current trends of scientific research
Special features:
•
•
•
•
•
•
•
•
700+ Open Access Journals
50,000+ Editorial team
Rapid review process
Quality and quick editorial, review and publication processing
Indexing at major indexing services
Sharing Option: Social Networking Enabled
Authors, Reviewers and Editors rewarded with online Scientific Credits
Better discount for your subsequent articles
Submit your manuscript at: www.omicsonline.org/submission/
Biol Med (Aligarh)
ISSN: 0974-8369 BLM, an open access journal
Volume 8 • Issue 4 • 1000296