Maa ke Bidaai! (Farewell Ma)

Maar Aagomon

Maa aesheche shonge niye shoroter shishir baatash..
Dhaaker aawaz, aanonder jowaar, meghe bhoraa aakash..
Shiuli phooler gondho aar jhiri jhiri brishti..
Shob diche janaan je Maa aasche shiggiri…
(Missing the pujo atmosphere at home) Shubho Mahalaya all my dear friends..!!!
-Anindita Roy

Kiss of The FeyKiss of The Fey by Charlotte Cyprus
My rating: 3 of 5 stars

Set in a mystical world full of magic, kings, queens and balls, this book describes the story of an illegitimate princess and a much-feared king- both of them unloved by everyone and joined by their cursed fate. But is it really a curse or a blessing in disguise? Cyprus takes a formulaic story of doomed love of the Beauty and the Beast and magics it into a twisted tale filled with interesting characters and heart-melting love. However, the writer’s main fallacy is that she gave up on the story much before she should have. The characters should have been much more fleshed out-they had so much potential. Xenos is an interesting character but nothing is ever said how he got his horrid nickname. Johara is better sketched out but her sorrows get over before I could even begin sympathizing with her. The warlock and the fairy are a nice touch but the other characters seemed to have been added just to give an animated illusion. Nothing ever comes of Cecilia’s wrong doings. This and many other fallacies leave the characters only a shadow of what they could have been. And then the bad editing and jumpy narration kept on stopping me from enjoying the good points in the story. Also, Cyprus could have researched more before writing the book.

Even then I like the story, not because of what it is, but because of what it could have been. I will surely be keeping an eye out for your next publications. I want to thank Cyprus for asking me to review the book.

Cheers,
Annie

View all my reviews

The Books which influenced me the most!

I believe every book you read affects you and helps you in forming your character-some more than the others. Here is the list of the books that helped me the most. Not all of them are excellently written but they were read by me at defining moments of my life and had characters which affected me the most.

  • Who will cry when you die? – Robin Sharma

The only book I carry with me wherever I go. It always offers me salvation during my times of conflict. Also, it was gifted to me by my best friend during high school, Priyanka Singh (it is the only thing I have to remember her by).

  • Harry Potter series- J. K. Rowling

Though I started reading the books after seeing the first two films, this book series remains my all-time favorite even after multiple reading. Harry Potter will remain my childhood hero. He has always inspired me for his ability to battle his darkness, accept his demons and rise above it and his pure love for his friends despite their fallacies. Harry, Ron and Hermione’s bond is the ultimate definition of friendship for me.

  • Pride and Prejudice- Jane Austen

The first novel I ever read and still my favorite classic. Elizabeth showed me my own independent spirit and the book basically started my passion for reading. And Mr. Darcy remains the man-of-my-dreams.

  • Angels and Demons, and Da Vinci Code – Dan Brown

Dan Brown is my favorite writer and these two are actually my favorite thrillers. The way Dan Brown writes his books are a treat to my mind. I wish more people researched more like him before writing.

  • Short stories by Guy de Maupassant and Saki.

I was around 10 when I read my first short stories by both Saki and Maupassant and I was so struck by Saki’s witty writing and Maupassant’s treatment of human characters that I had to read more. Maupassant’s dramatic writing revealed to me the multiple shades of human nature that I had never even thought about growing up in my sheltered life and Saki’s satirical writing just changed the way I looked upon any situation.

  • Uncle Tom’s Cabin- Harriet Beecher Stowe

I don’t even remember when I first read this book. Maybe the first time I read an excerpt from the book as a chapter in my Class I/II Gen. English book.  But just the memory of the story still bring me to tears. It was so touching and it infused me with the will to live and live independently without becoming slave to anything or anyone.

  • Sherlock Holmes – Sir Arthur Conan Doyle

My love for intelligently crafted detective stories obviously started with the wickedly smart, suave genius “Sherlock” (I am sure innumerable people will agree with me here). He is everyone’s favorite detective, especially after the extremely well-acted BBC drama “Sherlock”  where Benedict Cumberbatch plays the eponymous detective with a flair that just makes me go crazy with awe and Martin Freeman plays Dr. Watson with the much needed and well-deserved dignity and intelligence that Sherlock’s best friend and accomplice always deserved.

  • Nicholas Nickleby, David Copperfield, Great Expectations, Oliver Twist – Charles Dickens

I love most of the novels written by Dickens and all of them hold a special place in my heart. I also like the wonderful adaptations that have been made of these books.

  • Black Beauty – Anna Sewell

I love, love, love horses. They are so very proud and elegant creatures. I wished as a kid I was born into the previous generation of horse-drawn carriages. However, reading this novel gave me a completely different perspective to the world. Every child shoud be made to read this book just to show them how much an animal can feel.

  • If Tomorrow Comes and Rage of Angels- Sidney Sheldon

Two of the earliest novels I ever read and they are on the list not because of Sidney’s thrilling style of writing (which I still am a fan of) but because they had two of my most memorable female characters who intrigued and influenced me a lot during my trying teenage years. Tracy Whitney and Jennifer Parker both had to face such extreme conditions, yet they never stopped fighting and while Whitney eventually won over her fate, Parker got the most tragic ending ever. Anyway, these women instilled in me the spirit to fight to survive against every odd.

  • The Satan Bug – Alistair MacLean

I was 10-11 when I read it and this was the book that showed me the possibilities of biological research in a thrilling way. Also, it coincided with me seeing The Jurassic Park. So, I must say I owe a great deal to this book.

  • Coma – Robin Cook

The first Cook’s story I ever read and I still feel it was his best though I have read almost everything else he wrote. Still gives me nightmares when I have to visit a doctor. I read his books avidly during the last two of my high school years and in their own way they showed me how commercial the medical world has become. I know it’s a silly reason but these books gave me such creeps that it helped me decide against becoming a doctor myself (though there were several other more important reasons and anyway I wanted to become a biotech researcher more).

  • Chronicles of Narnia series- C. S. Lewis

Aslan! Another of my all-time favorite book and movie character. Te feeling that comes with this character is so.. complex! I love the innocence in the books, the pure morality that Aslan stands for and the sweetness that steeps from the pages. I loved almost all the books in this series though I liked the first movie the most. Makes me want to go in search of the hidden door in my wardrobe.

  • The Book Thief- Markus Zusak

I love this book. This narration by death left me feeling extremely raw and vulnerable. Though I read it just a few months back, it added a new dimension in my life (I have reviewed this book in another page).

  • Shiva Trilogy – Amish Tripathy

One of the few books written by modern Indian fiction writers that I truly loved. The way the writer mixed fiction with mythology left me marveled at how much I believe that the legends that our religion teaches us are more of fiction than based on truth. Shiva has been my favorite Indian God and I loved this story of his life and the main lesson the trilogy teaches us- there is both God and Devil in all of us (I have reviewed this book in another page).

  • Little Women – Louisa May Alcott

A wonderful classic. Maybe, it was like a sitcom story but I love these little women to bits and pieces. AndI would love to have a girl like you someday. Jo, dear Jo..I loved how independent, undeterred, feisty, tomboyish and strong you are.

  • Hercule Poirot and Miss Marple- Agatha Cristae

Another clever writer who made such memorable characters.

  • The Alchemist and Veronica Decides to Die- Paolo Coelho

I love the way Coelho treats the subject matter and the way he writes. These books made me introspect my life a lot. I am a fan of his writing.

  • Atlas Shrugged – Ayn Rand

I am not a follower of Ayn Rand’s philosophy of objectivism but I respect her for giving a new dimension to philosophy. I happen to believe in several of her tenets if not all. This book was too long and too cold to become my favorite but I still liked it a lot (I have an extensive review on this book before).

  • Ignited Minds and India 2020-A. P. J. Abdul Kalam

Kalam’s writings ignited in me the dreams I have for my future. I haven’t done much yet but I am yet to go a long way.

  • Life and Philosophy of Swami Vivekananda- G. S. Banhatti

Growing up in Bengali culture, I am bound to be influenced by Ramkrishna and Vivekananda. Though I knew about their philosophies my whole life and saw serials based on their lives, it was only recently that I actually read about them.

  • The Story of My Life- Helen Keller

Another wonderful story of a person who won over the most daunting challenges in life. Remembering Keller always humbles me.

Kadcyla: the advantages of the FDA-approved antibody-drug conjugate for breast cancer over the other available treatment approaches

(I will upload the accompanying pictures tomorrow. Please do not plagiarize this content. If you want to use some information from here, just cite my name Anindita Roy and the website.)

ABSTRACT:
Kadcyla (Trastuzamab Emtansine or T-DM1) is a new FDA-approved (February, 2013) antibody-drug conjugate (ADC) comprised of trastuzumab (Herceptin), a HER2 (Human Growth Receptor 2) receptor-binding monoclonal antibody approved by FDA for treating early stage HER2 positive breast cancer, linked via a non-reducible thioether bond to mertansine (DM1) which is a cytotoxic agent blocking polymerization of microtubules. This conjugate has been approved for metastatic breast cancer and late stage breast cancer. This paper will focus on the mechanism of action of both the individual therapeutics separately and the conjugate, why the antibody and drug was conjugated, the methods of combined therapy and chemical conjugation attempted and how the conjugate is better than other treatment options available.
INTRODUCTION:
Breast cancer is the most common cancer found in woman worldwide and about 28% of new cases in woman are breast cancer (1). About 20-25% of breast cancer cases have been found to have gene amplification or overexpression of HER2 receptor (2). HER2 (also called neu) is from the human growth receptor family of transmembrane receptor proteins known to play important roles in cancer growth and progression (3). HER2 overexpression is associated with a more adverse form of breast cancer with aggressive tumor growth, higher resistance to treatments and clinical therapies, higher risk of recurrence and minimal overall survival rate and remission (4). HER2 positive breast cancers are usually treated by the humanized HER2 receptor antibody: trastuzumab (Herceptin) which was approved by FDA in 1998 and dual HER2 receptor and tyrosine kinase inhibitor: lapatinib (Tykerb) which was approved by FDA in 2007 in combination with chemotherapy or hormone therapy (5). Even with advanced treatment approaches and combinational therapies, the patients develop resistance to these drugs and the cancer eventually progresses and metasizes and the patient either succumbs to the progressive cancer or to the cytotoxicity due to chemotherapy. Thus antibody-drug conjugates make a good choice for HER2 (+) breast cancer.
HISTORY:
Breast cancer is usually treated with a combination of chemotherapy and monoclonal antibodies. Chemotherapies are basically cytotoxic drugs like vinca alkaloids, doxorubicin, etc. which enter the cell and either stop it from proliferating by blocking the microtubulin polymerization, intercalating DNA, inhibiting protein synthesis, etc. or cause apoptosis. However, cytotoxic drugs are not selective for cancer cells and are highly toxic for even normal cells and hence are limited by low therapeutic index. They are major causes of co-morbidity. Even monoclonal antibodies, if not humanized, are known to elicit a host of adverse responses including the full range of hypersensitivities and patients have been shown to develop resistance to antibody therapy (6). Antibody drug conjugates are thus a much better approach as they have a chemotherapeutic conjugated with an antibody thus delivering the drug selectively to only specific cancer cells and increasing the therapeutic index. Though targeted drug delivery has been researched since a long time, it has met with limited success and only a few antibody-drug conjugates have been clinically successful. Mylotarg (gemtuzumab ozogamicin) was approved by FDA in 2000 for treatment of CD33-positive AML (Acute Myeloid Leukemia) but was withdrawn from use due to less efficacy in real life patients (7). Another ADC brentuximab vedotin was approved in 2011 for treating patients with Hodgkin lymphoma where other treatment approaches have failed (8). However, several other ADCs are currently in clinical development.
Trastuzumab is a humanized monoclonal antibody that accelerates HER2 receptor endocytosis and subsequent degradation and also inhibits cell cycle progression. Moreover, it also induces Ab-dependent cell-mediated cytotoxicity in HER2 expressing cancer cells. However, patients treated with trastuzumab still eventually progress to advanced stage after developing resistance to treatment. Hence, it is used as an adjuvant therapy with chemotherapy. Mertansine (DM1) is a much more potent drug than vincristine or doxorubicin. It is a maytansine derivative that is a microtubulin polymerization inhibitor but it is too cytotoxic to use directly on patients. In trastuzumab emtansine, this highly cytotoxic drug is delivered specifically to only HER2 overexpressing cancer cells and improves survival in trastuzumab-resistant cells as well as even metastatized cancers. It was highly successful in Phase I, II and II clinical trials and was much more effective than other antibody-drug conjugates attempted and was thus approved by FDA on February 22, 2013 for late stage and metastatic breast cancer (9).
MECHANISM OF ACTION OF TRASTUZAMAB AND DM1 SEPARATELY:
Trastuzumab (Herceptin) was approved for metastatic breast cancer in 1998 and as an adjuvant therapy for HER2 overexpressing cancer cells in 2006 has had several highly successful clinical trials (Phase I, II, III, IV). Several mechanisms of its action has been researched and documented (fig 1). It has been shown to down regulate HER2 expression in HER2 overexpressing cells by increasing receptor endocytosis and degradation (10). It also forms a p27/Cdk2 complex and thereby inhibits cell cycle (11). It has also been found to induce antibody-dependant apoptosis and is regulated by antibody receptors FcvRIII and FcvRIIB (12). It also interferes with signal transduction pathways, impairs of extracellular domain (ECD) cleavage, inhibits of DNA repair and decreases angiogenesis (13). Figure 2 shows the four domains of HER2 : Domains I (blue), II (green), III (yellow) and IV (red) and the complex of HER2 with the Fab. Trastuzumab is only effective in divalent form, the individual fragments being ineffective in creating the affinity or the overall cross-linking effect (14). Trastuzumab binds to the C-terminal portion of HER2’s domain IV (fig 2b black circle) thus effectively burying a large portion of the domain resulting in a very good binding. The close-up in Fig 2(b) shows the part of Her2 in the complex in red and the specific interacting residues in yellow while the Fab surface is shown in cyan along with the three interacting loops of HER2 and also the non-visible loop (blue circle). The first and third loop makes electrostatic contacts and the second loop makes hydrophobic interactions. The binding of the extracellular region of HER2 by trastuzumab crosslinks it thereby facilitating the endocytosis and also causes cleavage of the extracellular domains thereby blocking its interactions (14). Some of the causes of resistance trastuzumab are cross-talk between HER2 and insulin-like growth factor-1 receptor, (IGF-1R), truncation of the extracellular region of HER2 resulting in the loss of the Trastuzumab-binding pocket, deficiency of PTEN, and other kind of mutations affecting the binding or the internalization of HER2 (15).
On the other hand, mertansine (DM1) is a maytansine derivative that binds to microtubulin uring its polymerization at the same site as the vinca alkaloids thus blocking the cell cycle at G1/M phase and thereby leading to cell apoptosis. Maytansine was isolated from the plants of family Rhamnaceae and uphorbiaceae. Maytansine was one of the first cytotoxic compounds with IC50 values in picomolar range. Maytansine derivatives have been found to be 25 to 500 fold more effective than paclitaxel and 100-4000 times more potent than doxorubicin. However, after clinical trials, it was found ineffective on cancer cells in patients at normal doses and at higher doses, it caused several unrelated organ-related toxicities (16).
MECHANISM OF ACTION OF T-DM1:
A molecule of Trastuzumab emtansine consists of one to eight (3.5 on average) molecules of mentansine conjugated to a single trastuzumab molecule by SMCC. SMCC, or succinimidyltrans-4-(maleimidylmethyl)cyclohexane-1-carboxylate, is a heterobifunctional crosslinker containing two reactivefunctional groups, a succinimide ester and a maleimide. The trastuzumab contains lysine residues with free amino group with which the succinimide group of SMCC reacts and mertansine has a free sulfhydryl group with which the maleimide moiety of SMCC connects, thereby forming a covalent bond between the antibody and mertansine (4). The conjugate binds the HER2 receptor and gets internalized as an endosome. The endosome then undergoes lysosomal degradation resulting in the release of mertansine and its catabolites Maytansine binds to tubulin and disrupts the microtubule polymerization. Moreover, T-DM1 retains the mechanisms of Trastuzumab like blocking of signal transduction pathways, anitibody-dependent cellular apoptosis, etc. Thus, the conjugate combines two highly effective treatment approaches in a more targeted and specific way and has been shown to have a stronger effect with much less chance of resistance (17).
REASON OF SUCCESS OF T-DM1 OVER OTHER ANTIBODY-DRUG CONJUGATES:
After a series of failures in clinical inefficacy of a number of antibody-drug conjugates, it was carefully determined what were the issues leading to their failure. The major cause of the in vivo inefficacy was the lack of potency of the conjugate compared to the drug alone. Two major factors limiting efficient delivery of the chemotherapy in an ADC are: i) limited number of the cell surface antigens, ii) release of the drug upon antibody-antigen internalization may not be efficient (18. Thus, we need the drug to be highly effective even in small amounts. Maytansine was, thus, a better choice than other cytotoxic drugs like doxirubicin or vinca alkaloids due to its higher potency and IC50 values in picomolar range. Also, as discussed before trastuzumab has very good binding capacity with the HER2 receptor compared to other antibodies and easily internalizes inside the cell. Also the antibody and drug should be conjugated through a linker in a way such that the binding of the antibody with the receptor is not hampered and also the linker gets cleaved efficiently upon being internalized but not before. Antibody-DM1 conjugates were originally designed with a disulfide-based linker for release of active drug by intracellular reduction. However, during the oxidizing endocytic pathway, there is problem in the cleavage of the disulfide linker, SPP. Thus, different trastuzumab ADCs were constructed to investigate the effect of disulfide linker hindrance on the biological activity of these conjugates (Fig. 6). A trastuzumab-DM1 conjugate made with the SPDP linker contains no methyl substitutions adjacent to the disulfide bond and is therefore the least hindered disulfide-containing design. Trastuzumab ADCs composed of SPP-DM1, SSNPP-DM3, or SSNPP-DM4 contain one, two, or three methyl groups, respectively, around the disulfide bridge and show increasing resistance to cleavage via thiol-disulfide exchange reactions. DM3 and DM4 nomenclature reflects addition of methyl groups to the DM1 (drug) moiety (addition of one or two methyls, respectively). Trastuzumab conjugated to DM1 through the thioether SMCC linker displays better efficacy and pharmacokinetics and lower toxicity than conjugates with disulfide linkers. (6)
ADVANTAGES OF T-DM1 OVER TRASTUZUMAB AND DM1:
It has been shown that there is enhanced potency of trastuzumab-maytansinoid conjugates compared with trastuzumab in both cell lines and clinical trials (19). When comparing potency as molar DM1 equivalents, DM1 conjugated to trastuzumab is 5-fold more potent than free L-DM1. Nontargeted effects of trastuzumab-maytansinoid conjugates were assessed on breast cancer lines expressing normal levels or lacking expression of HER2. All ADCs tested showed minimal antiproliferative activity in both cell lines, whereas free DM1 showed potency equal to that observed on the HER2-amplified lines. (6)
CLINICAL EFFICACY:
T-DM1 has shown tremendous potential as a HER2 positive anticancer drug and is much more potent than other existing drugs including Trastuzumab. The table 1 shows a brief complilation of some of the successful clinical trials of the conjugate. In the Phase III EMILIA trial, T-DM1 decreased the risk of progression-free survival by 35% and mortality risk by 38% also the risk of serious side-effects was lesser by one-third when combined with capecitabine plus lapatinib. There are several more clinical trials still going on: The MARRIANNE study is trying to compare (taxane + trastuzumab) vs T-DM1 vs (T-DM1 + pertuzumab) as primary treatment for HER2 positive, unresectable, advanced stage/metastatic breast cancer patients. The THERESA study is trying to compare T-DM1 vs other treatments for people with HER2 positive breast cancer already treated with trastuzumab or lapatinib. Another phase III trial is going on to compare T-DM1 vs taxane for HER2 positive gastric cancer. All the trials carried out till now have shown excellent results for T-DM1 or its adjuvant therapy and very limited cases of resistance have been found till now (20, 25).
OTHER ANTIBODY-DRUG CONJUGATES IN CLINICAL TRIALS:
The success of T-DM1 and Brentuximab vedotin has accelerated the research for other antibody-drug conjugates ssome of which are in clinical trials II and III as well (table 2)
A COST ESTIMATE:
Genentech which is distributing T-DM1 under the brand name Kadcyla estimated a cost of about $9800 per month or about $94000 on an average time-plan of treatment. This is higher than trastuzumab (Herceptin) alone which is also produced by Genentech. However, T-DM1 price is comparable to the other new cancer drugs in market now and since it is still given after trastuzumab resistance, the cost is not supposed to be that high especially keeping in perspective it has been found to increase the survival by 6 months for advanced stage breast cancer patients compared to other treatments options in clinical trials (1).
CONCLUSION:
Targeted drug delivery was originally attempted for a more selective treatment approach to treat different cancers in order to decrease the unrelated cytotoxicity of chemotherapy in other parts of the body and related side-effects. Though a lot of research has been directed in this area in the last three decades with many drugs going to clinical trials but most of them have been unsuccessful with FDA approved Mylotarg (gemtuzumab ozogamicin) being a classical failure. However, the persistent researchers have worked on all the separate reasons of the various failed conjugates and have strived to come up with the best solutions to improve every aspect of the conjugation process. The conjugates attempted now have humanized antibodies decreasing the chances of immunogenicity and use only antibodies having very good binding capacities and capable of getting internalized easily. The chemotherapeutic drugs used in the conjugates are much more potent than the ones used before and which could never be used as separate treatments before due to their high toxicity. The linkers are designed in a way not to disrupt the binding or internalization of the antibody and so that they stay stable during circulation in the body but dissociates effectively only when internalized in the cell so that the drugs are effectively released from the endosomes. Trastuzumab emtansine, being one of the first such conjugates to be approved by FDA and highly successful in several phase II and III clinical trials, has efficiently paved the way for other such selective conjugate treatment options. It has been met with raving reviews by the medical population in general due to its high survival rate increase while having lesser side-effects than other existing treatments for the aggressive HER2+ breast cancer.
ACKNOWLEDGEMENT:
This paper has been written as a part of the Medicinal Chemistry Course and I would like to acknowledge everyone who helped review it.
REFERENCES:
1) Jemal A, et al. (2010). Cancer statistics, CA Cancer J Clin ;60:277–300.
2) Dawood S, e al. (2010), Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol ;28:92–8
3) Girish S, et al. (2012). “Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer”. Cancer Chemother. Pharmacol.69 (5): 1229–40
4) Slamon DJ, et al (1987), Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science; 235:177–82
5) Phillips G. D. et al. (2008). Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate, Cancer Res. 68 (22): 9280–90
6) Baldo A. B., (2014), IgE and Drug Allergy: Antibody Recognition of ‘Small’ Molecules of Widely Varying Structures and Activities, Antibodies, 3(1), 56-91
7) Bross P. F. et al. (2001), Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia, Clin Cancer Res, 7(6):1490-6.
8) Gopal A. K. (2012), Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation, Blood, 120 (3): 560-568
9) Pollack A (2013), F.D.A. Approves a New Drug for Advanced Breast Cancer, The New York Times
10) Molina M. A. et al (2001). Trastuzumab (Herceptin), A humanized Anti-HER2 Receptor Monoclonal Antibody, inhibits basal and activated HER2 Ectodomain Cleavage in Breast cancer cells, Cancer Res June 15, 2001 61; 4744
11) Sliwkowski M. X., et al (1999). Nonclinical studies addressing the mechanism of action of Trastuzumab (Herceptin).Semin. Oncol., 26 (12): 60-70
12) Clynes R. A. et al (2000), Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med., 6: 443-446
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14) Hyun-Soo C. et al (2003), Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab, Nature 421, 756-760
15) Roger Y et al (2011), Lapatinib, a Dual-Targeted small Molecule Inhibitor of egfr and Her2, in Her2-Amplified Breast Cancer: From Bench to Bedside, Clinical Medicine Insights: Therapeutics, 3: 1–13
16) Lopus M. et al. (2010), Maytansine and Cellular Metabolites of Antibody-Maytansinoid Conjugates Strongly Suppress Microtubule Dynamics by Binding to Microtubules, Mol Cancer Ther , 9;2689
17) LoRusso P. M. et al, (2011), Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2–Positive Cancer, Clin Cancer Res, 17; 6437
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19) Barginear M. F. et al. (3013), Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer. Mol Med, 22;18:1473-9
20) Baron J. M. et al (2014), Ado-trastuzumab emtansine (T-DM1): a novel antibody-drug conjugate for the treatment of HER2-positive metastatic breast cancer, J Oncol Pharm Pract
21) Burris HA et al (2011), Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011; 29: 398–405.
22) Krop I. E., et al (2012), A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol ; 30:3234–3241.
23) Hurvitz SA, et al (2013), Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol ;31: 1157–1163.
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25) Trastuzumab Emtansine, Wikipedia (http://en.wikipedia.org/wiki/Trastuzumab_emtansine)

 

Review of Markus Zusak’s fiction “The Book Thief”

The Book ThiefThe Book Thief by Markus Zusak

My rating: 5 of 5 stars

A vivid narration by Death Himself, this book chronicles the life story of a German girl (the eponymous Book Thief) during the WWII..yes, the Nazi era. Each book she steals depicts an important point in her life in her own history, an important lesson learned, a challenge overcome by her or an important person in her life. This is not a story of a revolution caused by some great name, but a simple story of a child who shakes the simple lives around her with her simple words in a tremendous way. The perspective of the story is to highlight the suffering of the poorest sections of the Nazi society through the eyes of Death with the clear focus being this child who happens to be a book thief. But this thief is remarkable- from her struggle to let go of the grim dreams seeded from her brother’s death and mother’s abandonment to her growing love for her foster parents, from her gradual victory over the words that were once her enemy to her beautiful friendship with Rudy and Max. She grows so much throughout the book and survives so much that slowly you start suffering everything with her, with Death. Whatever I write in the review cannot justify the way the narration touches you. Just go and read it, you will understand what I mean.
On an end note, Death, you are some narrator!

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Review on Gillian Flynn’s psychological thriller “Gone Girl”

Gone GirlGone Girl by Gillian Flynn

My rating: 4 of 5 stars

CREEEEPYY!! (shudder)..not scary but chillingly creepy-both the characters as well as the way long-term relationships are portrayed. The story is about a couple-two very sick-minded persons- both narrating alternately.(Spoiler alert) The woman, Amy Elliot Dunne, is a classic sociopath-extremely manipulative, grandiose sense of self-worth, thinks whatever she does is correct (one of the cases whose moral compass changes as she deems fit!)- while the guy, Lance Nicholas Dunne, is a tremendous dickhead (for want of a more proper adjective). Both of them are hateful characters to the extreme. The main similarity between them-they both are PATHOLOGICAL LIARS! You end up feeling they both deserve each other completely and they do end up with each other. Non-poetic justice! However, Nick at least was a flawed human and though he was pathetic in every sense, I still pitied him at times. But Amy, she was purely crazy. I had the bad luck to be friends with a real sociopath recently until I realized she had every textbook symptom of Antisocial-Personality Disorder and then started distancing myself without much luck. (She still doesn’t want to let go of me as a friend even though she hates me thoroughly and has tried to harm me several times…she actually is like the younger version of Amy.) So yeah, the character of Amy really stroke a chilling chord with me. However, the creepiest part was how the book portrayed long-term relationships-the initial excitement and feeling of being the best with your loved one, the subsiding interest after sometime, growing discontent and boredom and resentment, increased half-lies, lies by omission, white lies and then manipulations, love eventually turning to hate. Yes, this was a highly unusual couple, but don’t most long-term relationships reflect most of these phases? Makes one realize just how much of Amy and Nick are there in every person. That under similar circumstances, we might also try to manipulate people, tell such pathetic lies, make such gross errors of judgement and then get stuck in such a quagmire of our own selfish mistakes, woven lies and manipulations. (SHUDDER)!!!

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Suddenly in mood of painting again!!

So yesterday I went into the campus store for some work and came upon the painting and skydiving section. I couldn’t keep myself from buying new acrylic colors and brushes and canvas papers… So here are my first paintings after coming to the states…:) 🙂 🙂
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My first Introduction

I am about to change my homepage so I just wanted to post the details of my previous info..….
Heyya…everybody!!!

I’m Anindita Roy. My friends usually call me Donna as my name seems to be a bit mouthful to some. I’m a B.E. Biotechnology student and presently am in the senior or final year of my college, Birla Institute of Technology, Mesra, Ranchi, India. Here’s everything there is to know about me…

I was born at Agartala, Tripura and was brought up at Silchar, Assam which is my small n simple hometown. I have a lovely family which includes the most supportive parents in the world and my charming, younger brother. I studied at Holy Child High School, Silchar till my 10th and was the school topper throughout. I studied my +2 at Ramanuj Gupta Junior College with PCMB. Doing research in biotechnology was my dream since class 11. It materialized when I got the opportunity to study at BIT, Mesra, India’s premier engineering college, after clearing AIEEE. I took my engineering major in biotechnology which is quite an unconventional major. Here, I made some really superb friends, participated in a variety of activities, had loads of fun n masti n also studied a bit. I have been involved in several research projects since the start of my my 2nd year and have done two summer internships.

I am very much interested in biochemical research and hope to study more in my field and be a brilliant researcher someday. I am a complete book-worm, in fact, I’m also an ebook-worm (I just need something readable, though I always prefer quality over quantity). You can go through my reading list which mainly consists of suspense, thrillers, fantasy and romances, and maybe some course books. I love listening to music and have ears for a really wide variety. I’ll add my playlist later on. I am passionate about dancing, painting and since recently, writing. I also like making handicrafts. I love hanging out with my best friends (who doesn’t). (I’ll add more things later).

This blog is mainly about me and the topics that interests me in life. Go through them if you like to…

With love and cheer,
Anindita (aka Donna)

Review of “Immortals of Meluha-Shiva Trilogy 1” & “Secret of the Nagas-Shiva Trilogy 2”

Review of “Till the Last Breath”

Biofuels, Biodiversity Conservation and Climate Change: A Perspective

Endophytic Fungi: New Hopes for Plant Secondary Metabolites

Efficient Genetic Transformation System for Lathyrus sativus (Grasspea): Agrobacterium-Mediated Transformation

Lathyrus sativus or Grass pea is the poor man’s pulse but it is banned in many places owing to its causing Neurolathyrism-a paralytic disease- on prolonged intake. Genetic Transformation aims to remove this major drawback of this otherwise high potential plant. I did this project in University of Calcutta as a recipient of Summer Undergraduate Research Fellowship(SURF)-2011 of Indian Academy of Sciences (IASc), India, under the guidance of Dr. Karabi Datta. The following is the abstract of my work and some photographs of my work. The work and photographs are copyrights of Anindita Roy. To use them, cite my name and source or contact me at anindita1302.09@bitmesra.ac.in .

ABSTRACT:

 Lathyrus sativus or commonly called grass pea is a leguminous crop plant cultivated extensively in various parts of the world especially the food-deficit countries due to its qualities of being a very cheap source of diet protein and fodder plant along with its excellent N2-fixation properties and high resistance to agricultural stresses like floods, drought, salinity, low soil fertility, and pathogen-infestation of soil. In spite of its many advantages, Lathyrus has not been exploited to its full potential due to the presence of a neurotoxic amino acid β-N-oxalyl-l-α,β-diaminopropionic acid (β-ODAP) in the grain protein that causes neurolathyrism in humans on prolonged consumption. This long-ignored controversial legume with its long list of advantages and some removable disadvantages has, in recent times, drawn attention to itself as a subject for genetic transformation and breeding experiments. Various theories have been proposed to input detoxification causing genes into the plant genome as well as to boost expression of essential amino acids. However, first of all, a standardized transformation method has to be prepared before desired genetic manipulation. The Agrobacterium tumefaciens strain LBA 4404 containing the plasmid pCAMBIA 1301 with a hygromycin phosphotransferase II gene (hptII), a neomycin phosphotransferase II gene (nptII) and the β-glucouronidase (gus) gene was studied as vector system to genetically transform the explants obtained from the seed PRATEEK. The best transformation rate was obtained for an OD600 of nearly 0.6 of the final infiltration media made from the Agrobacterium culture grown in LB media with rifampicin and kanamycin. Four kinds of explants were used for the experiment- (i)leaf and (ii)internode explants were obtained from the Lathyrus sativus plants grown in test tubes containing seed germination (MSO) media under sterile conditions and (iii)epicotyl and (iv)cotyledonary node (CN) explants obtained from the germinating seeds grown in petriplates containing germination media. Different concentrations of different growth regulators (IAA, NAA, BAP) were added to different sets of pre-cultivation media, co-cultivation media, selection media and regeneration media used for the explants in order to find a standard media composition. Also, different concentrations of hygromycin were used in the SM and the RM. The internode explants and CN explants showed better survival in SM and regeneration/callusing in RM and also gave positive results to GUS histochemical assay.

Keywords:

Lathyrus sativus (grasspea), internode explants, epicotyl explants, cotyledonary node explants, Agrobacterium tumefaciens

Abbreviations:

β-ODAP      β-N-oxalyl-l-α,β-diaminopropionic acid

BAP            6-Benzylaminopurine

hpt II           Hygromycin phosphotransferase II

IAA             Indole-3-acetic acid

LB               Luria Bertani

ACKNOWLEDGEMENT

Submitted Thesis and Presented Work as part of the Summer Undergraduate Research Fellowship (SURF)-2011 awarded under the Combined Support of IASc, INSa and NASI. Worked in the Plant Molecular Biology and Biotechnology Lab of Dept. of Botany, University of Calcutta, India, under the guidance of Dr. Karabi Datta.

REFERENCES

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3)      Akbulut M, Yucel M, Oktem HA (2008); Analysis and organization of DNA delivery into chickpea (Cicer arietinum L.) seedlings by Agrobacterium tumefaciens; African Journal of Biotechnology 7: 1011-1017.

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20)  Malik, KA, Ali-Khan ST & Saxena PK (1993); High frequency organogenesis from direct seed culture in Lathyrus; Annals of Botany 72: 629–637.

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31)  Rahman QN, Akhtar N and Chowdhury AM (1974); Proximate composition of food-stuffs in Bangladesh; Part 1. Cereals and Pulses; Journal of Scientific and Industrial Research 9: 129-133.

32)  Rotter RG, Marquardt RR and Campbell CG(1991); The nutritional value of low lathyrogenic Lathyrus (Lathyrus sativus) for growing chicks; British Poultry Science 32: 1055-1067.

33)  Roy PK, Singh B, Mehta SL, Barat GK, Gupta N, Kirti PB and Chopra VL(1991); Plant regeneration from leaf discs of Lathyrus sativus; Indian Journal of Experimental Biology 29: 327–330.

34)  Sambrook J David W.Russel (2001); Molecular Cloning A Laboratory Manual- Third edition, Cold Spring Harbor Laboratory Press, New York.

35)  Sanyal I, Singh AK, Kaushik M, Amla DV (2005); Agrobacterium-mediated transformation of chickpea (Cicer arietinum L.) with Bacillus thuringiensis cry1Ac gene for resistance against pod borer insect Helicoverpa armigera; Plant Science 168: 1135-1146.

36)  Sarmah BK, Moore A, Tate W, Molving L, Morton RL, Ress DP, Chiaiese P, Chrispeels MJ, Tabe LM, Higgins TJV (2004); Transgenic chickpea seeds expressing high level of a bean α-amylase inhibitor; Molecular Breeding 14: 73-82.

37)  Senthil G, Williamson B, Dinkins RD, Ramsay G (2004); An efficient transformation system for chickpea (Cicer arietinum L.); Plant Cell Reports 23: 297-303.

38)  Shivani I, Hari M, Susan E (2007); Genetic transformation of chickpea (Cicer arietinum L.) with insecticidal crystal protein gene using particle gun bombardment; Plant Cell Reports 26: 755-763.

39)  Smartt J, Kaul AK, Araya WA, Rahman MM and Kearney J (1994); Grass pea (Lathyrus sativus L.) as a potential safe legume food crop; Expanding the production and use of cool season food legumes (F.J. Muehlbauer and W.J. Kaiser, eds.):144-155, Kluwer Academic Publishers, Netherlands.

40)  Srinivasan, Mridula, Gupta N and Chopra VL (1988) Agrobacterium mediated genetic transformation of chickpea, Cicer arietinum L.; Indian Journal Of Experimental Biology 29: 758-761.

41)  Talukdar Dibyendu (2009); Recent progress on genetic analysis of novel mutants and aneuploid research in grass pea (Lathyrus sativus L.); African Journal of Agricultural Research 4 (13), 1549-1559.

42)  Zambre M, Chowdhury B, Kuo YH, Montagu M van, Angenon G and Lambein F (2002); Prolific regeneration of fertile plants from green nodular callus induced from meristematic tissues in Lathyrus sativus L. (grass pea); Plant Science 163: 1107–1112.
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Review of Ayn Rand’s “Atlas Shrugged”

Atlas ShruggedAtlas Shrugged by Ayn Rand
My rating: 4 of 5 stars

This is the first time I read Ayn Rand. She might be a philosopher, but this book feels like the love-child of a fantasy and philosophy, if it there ever was one. Yeah, I liked her view of the world and her philosophy of objectivity, but then I liked Harry Potter which seemed to have more sense than this novel. I didn’t mean to compare them, sorry. But, Ayn’s view of a world where the productive geniuses are the Atlases of the world-the dethroned superkings, fighting to get back their claim by striking against the world…seems…well..illogical. I agree with the protagonist, Dagny Taggart. Even I would not have given up my struggle till the last moment even if the ones benefiting were my enemies, at least she showed some human characteristic and that’s the main reason I still liked her even though she was a completely wooden character. The main fallacy of the book is that it considered just super-humans like Dagny, Rearden, Galt, Franscisco, Danneskjold, etc.(who were geniuses, had superhuman strength to bear every torture, hardship, needing no sleep,..) and inhuman creatures like James, Mouch, Morrison, Scudder, etc. (who just wanted to destroy life as they themselves weren’t worthy of it). Humans were either missing from the novel or if there like Eddie Willers, Cherryl Brooks, etc. were in few numbers and having the least power over their destiny. So, the setting of the novel was completely unrealistic. I agree that productive geniuses exist, and even the inhuman populace is really strong in both power and number. But, humans still make up the population. Ayn’s fantasy world was bound to collapse as she had set it so. Moreover, there are may more problems in this world than production woes. I am an engineer myself wishing to be an industrialist someday, but even I know such a world ain’t possible.

But apart from the unrealistic approach of the book, I liked several points of her philosophy of life.
1) Her superhuman characters might be wooden n just speak philosophy if they ever spoke..but they seem kind of the heroes one ought to be inspired from in these times. We should learn to understand and accept one’s originality and individualism. At least, from now on I am tired and don’t feel like facing the struggle any more, I can say that if Dagny could do that, I could as well (I don’t wish to be like her but nevertheless she inspires me with her strength and will to survive).
2) Love is basically the unification of one’s mind and values. I realized that even I believed it but never really accepted it.
3)Selfishness is the driving power of this world. Yeah, I agree. Being selfless is the worst kind of selfishness there can be. No one should have to bear the pain of being dependents and living on the pity of someone else. I would die before I get to that position. In a society, everyone is dependent on each other but every person has to do some work to bear the bargain of survival. A person who does no work, has no right to survive. But, again, I have a question-what about handicapped people, old men, who actually cannot work even if they wanted to? Maybe, they could do something else, productive in some other sense. Ayn just missed out them..

I think, the main error Ayn Rand made was to give a classification to the race of men when actually there is too much randomness and uniqueness in them. In real world, there can never exist four characters like Galt, Francisco, Rearden and Dagny who are so much alike and value and despise the same things-its against probability and variance…:(

Though the book was really too long, I liked it as a fantasy story, as it taught me to remember some very important points and not to loose heart when faced by insurmountable stupidity. I tend to discard things which I don’t like and treasure the good things. Thus, the book was like a tarnished jewel for me…so, four stars..:):)

View all my reviews

An Incomplete Story

There it goes, there I see,

What I wished for, what I aimed to be,

I gave my best, I faced the worst,

Obstacles; yeah, its not always just.

But I went on and on, till the end,

Until I reached my desired bend

In my path, my route to glory.

Yeah, its still an incomplete story.

I start again after some rest,

To be better than my best,

To reach another bend, face another challenge.

It may seem as strange to some,

But this is my life, its beauty lies

In the way I live it; I won’t die

With the regret of not trying, not doing

Something I wanted, by hiding

From the unknown, from the darkness,

Afraid of my fears. No, I’ll live as

Who I really am, who I am meant to be,

I am just me, just me…

Just Friends-book review

Just FriendsJust Friends by Sumrit Shahi

My rating: 3 of 5 stars

Hmm..I read it while killing time waiting for my flight and then on my flight(Coincidentally the story starts in airport). Easy read though childish way of writing. But well, that’s what made me give it 3 stars. The story was simple and easy to relate..best friends vs lovers vs best friends as lovers (well, my best friend turned my boyfriend and is now my ex-bf yet my best friend…so yeah man, I could easily relate). The author used his colloquial lingo of school-where everyone tries to play smartass-to describe the bumpy ride of life of two different teenagers with different lives but similar problems. It sweetly shows the great feeling of camaraderie and trust between best friends, the joys and vulnerability of first love, the feeling that one can conquer anything for the one person, the tug of war between attraction and emotion, the dawning of the realization that whatever happens you do love your best friend, final decision to choose which love is greater and who you cannot absolutely live without. The book left the decision to the reader. Well, for me true friendship is much more important than a relationship..as true love may be rare but true friends, my dear, are rarer still, especially in today’s cutthroat world. I will, however, always want my love to be a really good friend first. But then, every situation is different, right?

View all my reviews

Applying to PhD abroad

Applying for PhD abroad is a very long process and takes real hard work due to the following factors-deciding why u want to do PhD as you have to express yourself well in your Statement of Purpose (SoP); deciding which area u wish to work in; choosing universities u wish to apply to matching your interests, your goals, your financial scenario, your profile, courses offered, research being carried out and the funding it gets, professors, student intake rates, environment for international students, etc.; give and get good scores in GRE and TOEFL; get good recommendations; getting your transcripts; filling in the application, sending the application, etc.

The Universities see your overall profile including your CGPA, your GRE n TOEFL scores, your research experience, your study background, your strong SOP and LORs(Letter of Recommendations), papers published or presented. So showcase a good profile and you can surely make it…best of luck to all!!!!

And I am still applying, so wish luck to me as well…:):)

India Towards Universal Health Care

India Towards Universal Health Care | Socyberty.

Universal Healthcare: Dream or Reality? Are the government’s promises of cheaper and better health care possible in a country still plagued by the pangs of hunger, lack of space and infestation of corruption?

Read more: http://socyberty.com/politics/india-towards-universal-health-care/#ixzz259rRNEgV

<a href="Harry Potter and the Deathly Hallows (Harry Potter, #7)Harry Potter and the Deathly Hallows by J.K. Rowling
My rating: 5 of 5 stars

View all my reviews ” title=”Harry Potter and the Deathly Hallows-book and films”>Harry Potter and the Deathly Hallows-book and films

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A Simple Collection of My Random Thoughts Dreams and Sarcastic Reality

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