Stem Cell Clinic

Similarities in human and pig embryos provide clues to early stages of development – Phys.Org

By Embryonic Stem Cells

June 8, 2017 Developing human primordial germ cells (each small green and red cell is a PGC). Credit: Walfred Tang/Surani lab

Scientists have shown how the precursors of egg and sperm cells the cells that are key to the preservation of a species arise in the early embryo by studying pig embryos alongside human stem cells.

In research published today in Nature, researchers at the University of Cambridge and the University of Nottingham demonstrate how pig embryos and human embryonic cells show remarkable similarities in the early stages of their development. By combining these two models, they hope to improve our understanding of the origins of diseases such as paediatric germ cell tumours and fetal abnormalities.

Primordial germ cells, the precursors of eggs and sperm, are among the earliest cells to emerge in human embryos after implantation, appearing around day 17, while the surrounding cells go on to form the rest of the human body. However, little is understood about how they originate. Currently, the law prohibits culture of human embryos beyond 14 days, which prevents investigations on this and subsequent events such as gastrulation, when the overall body plan is established.

Now, researchers have used a combination of human and pig models of development to shed light on these events. They have shown for the first time that the interplay between two key genes is critical for the formation of the germline precursors and that this 'genetic cocktail' is not the same in all species.

First, by using human pluripotent embryonic stem cells in vitro, scientists led by Professor Azim Surani at the Wellcome Trust/Cancer Research UK Gurdon Institute established a model that simulates genetic and cellular changes occurring up to gastrulation. Human pluripotent embryonic stem cells are 'master cells' found in embryos, which have the potential to become almost any type of cell in the body.

As these stem cells can be multiplied and precisely genetically manipulated, the model system provides a powerful tool for detailed molecular analysis of how human cells transform into distinct cell types during early development, and which changes might underlie human diseases.

The work shows that when an embryo progresses towards gastrulation, cells temporarily acquire the potential to form primordial germ cells, but shortly afterwards lose this potential and instead acquire the potential to form precursors of blood and muscle (mesoderm) or precursors of the gut, lung and the pancreas (endoderm). The model also tells us that while the genes SOX17 and BLIMP1 are critical for germ cell fate, SOX17 subsequently has another role in the specification of endodermal tissues.

For an accurate picture of how the embryo develops, however, it is necessary to understand how cells behave in the three-dimensional context of a normal embryo. This cannot be achieved by studies on the most commonly used mouse embryos, which develop as egg 'cylinders', unlike the 'flat-disc' human embryos. Pig embryos, on the other hand, develop as flat discs (similar to human embryos), can be easily obtained, and are ethically more acceptable than working with non-human primate (monkey) embryos.

Researchers from the University of Nottingham dissected whole flat discs from pig embryos at different developmental stages and found that development of these embryos matches with the observations on the in vitro human model, as well as with non-human primate embryonic stem cells in vitro. For example, pig germ cells emerge in the course of gastrulation just as predicted from the human model, and with the expression of the same key genes as in human germ cells. Human and pig germ cells also exhibit key characteristics of this lineage, including initiation of reprogramming and re-setting of the epigenome modifications to our DNA that regulate its operations and have the potential to be passed down to our offspring which continues as germ cells progress towards development into sperm and eggs.

The combined human-pig models for early development and cell fate decisions likely reflect critical events in early human embryos in the womb. Altogether, knowledge gained from this approach can be applied to regenerative medicine for the derivation of relevant human cell types that might be used to help understand and treat human diseases, and to understand how mutations that perturb early development can result in human diseases.

Dr Ramiro Alberio, from the School of Biosciences at the University of Nottingham, says: "We've shown how precursors to egg and sperm cells arise in pigs and humans, which have similar patterns of embryo development. This suggests that the pig can be an excellent model system for the study of early human development, as well as improving our understanding of the origins of genetic diseases."

Dr Toshihiro Kobayashi in the Surani lab at the Gurdon Institute, adds: "We are currently prevented from studying human embryo development beyond day 14, which means that certain key stages in our development remain a mystery. The remarkable similarities between human and pig development suggest that we may soon be able to reveal the answers to some of our long-held questions."

Explore further: Mapping pluripotency differences between mice, monkeys, and humans

More information: Toshihiro Kobayashi et al. Principles of early human development and germ cell program from conserved model systems, Nature (2017). DOI: 10.1038/nature22812

Journal reference: Nature

Provided by: University of Cambridge

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Similarities in human and pig embryos provide clues to early stages of development - Phys.Org

Abused pup receives cutting-edge stem cell therapy | fox5sandiego … – fox5sandiego.com

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SAN DIEGO Abused orphan pup "Dwyane," who has severe disfigurements, is on the road to recovery after stem cell therapy by a Poway-based company.

The one-year-old puppy was reportedly kicked, beaten and forced to wear a wire muzzle before he was rescued in Tijuana.

Last month, he was taken to Helen Woodward Animal Center in Rancho Sante Fe. Since then, the dog has undergone several procedures, including a hip surgery Tuesday.

Animal hospital officials said Dwaynes work isnt over yet, as he still needs major reconstruction to his elbow and additional facial surgeries to help him breathe easier.

There is no risk involved because we use the dog's own tissue to isolate the stem cell, said Dr. Jeffrey Schaffer with VetStem of Poway.

Today, we gave the injection of the stem cells in the hip and then a slow one through the vein," said Dr. Patricia Carter, chief veterinarian at Helen Woodward Animal Center. "Then we gave him something that made him unsleepy, but hes still recovering from the surgery two days ago.

Dwayne is a warrior and shows his love to those who have love to give.

He is adorable, sweet and with everything that is going on, he wants to give you kisses and love, Schaffer said.

Over $40,000 has been donated to Dwayne for medical costs from around the world, including Paris. He also has had plenty of people giving well wishes and dropping off toys at the animal hospital.

The animal center posts updates on Dwayne and other orphan pets on itswebsite.

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Abused pup receives cutting-edge stem cell therapy | fox5sandiego ... - fox5sandiego.com

Chinese cell therapy effective in small multiple myeloma trial | Reuters – Reuters

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By Deena Beasley | CHICAGO

CHICAGO A small trial conducted in China found that an experimental therapy using altered cells to recruit the body's immune system to attack cancer can induce remission in most patients with advanced multiple myeloma, a blood plasma cancer.

The study of 35 patients tested a chimeric antigen receptor T-cell (CAR-T) therapy developed by China's Nanjing Legend Biotech Co.

The drug candidate, known as LCAR-B38M, targets a protein called BCMA found on cancerous blood plasma cells - the same target being pursued by Bluebird Bio Inc and Celgene Corp with their CAR-T called bb2121.

CAR-T therapies require a complicated process of extracting immune system T cells from an individual patient, altering their DNA to sharpen their ability to spot and kill cancer cells, and infusing them back into the same patient.

The American Society of Clinical Oncology, which featured the data here at its annual meeting, said that out of 19 trial patients followed for more than four months, 14 reached complete remission. One patient had a partial response and four patients reached "very good partial remission," but the cancer did get worse in one of those patients.

Multiple myeloma "is a disease you can treat pretty well with other drugs, but this could be long-term remission," said Dr. Bruce Johnson, chief clinical research officer at Boston's Dana-Farber Cancer Institute and ASCO's incoming president.

Eighty five percent of trial patients experienced cytokine release syndrome (CRS), a potentially life-threatening inflammatory condition, but researchers said the side effect was temporary and manageable in most patients. Two people had severe CRS, but recovered after treatment with Actemra, an anti-inflammatory drug.

The study is being conducted at Second Affiliated Hospital of Xi'an Jiaotong University in Xi'an, China.

The largest investor in Nanjing Legend Biotech is Genscript Biotech, a multinational provider of contract research services to pharmaceutical companies and others, according to Dr. Frank Fan, chief scientific officer at Nanjing Legend.

He said the company plans to enroll a total of 100 patients in the Chinese trial and to start a similar trial in the United States in early 2018.

"At ASCO I will hope to find collaborators in the U.S.," Fan told Reuters. "We are open for collaboration at different levels."

So far two companies have filed for U.S. approval of CAR-T drugs targeting a different protein called CD19. Kite Pharma Inc expects the Food and Drug Administration to decide by Nov. 29 whether to approve axicabtagene ciloleucel for advanced non-Hodgkin lymphoma, a cancer that starts in white blood cells.

The FDA is also reviewing Novartis AG's tisagenlecleucel-T for pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

(Reporting by Deena Beasley; Editing by Phil Berlowitz)

WASHINGTON As the United States battles a growing opioid abuse crisis, the Food and Drug Administration on Thursday asked Endo International Plc to withdraw from the market its long-lasting opioid painkiller, Opana ER, sending Endo's shares down more than 12 percent.

GENEVA A polio outbreak has been confirmed in an area of Syria partly held by Islamic State, the first re-emergence of the virus in Syria since 2014, the Global Polio Eradication Initiative and the World Health Organization said on Thursday.

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Chinese cell therapy effective in small multiple myeloma trial | Reuters - Reuters

Berkeley Stem Cell Center – Research UC Berkeley

By Stell Cell Research

The Berkeley Stem Cell Center supports research and teaching in stem cell biology, engineering, and medicine at UC Berkeley, Lawrence Berkeley National Laboratory, and Children's Hospital and Research Center at Oakland. Activities sponsored by the Center include seminars, roundtables, and an annual retreat. The Center's CIRM funded Shared Stem Cell Research Laboratories in Stanley Hall and LSA provide investigators with fully equipped stem cell tissue culture and flow cytometry facilities and outstanding technical expertise. Its CIRM Center of Excellence, located in the Li Ka-Shing Center for Biomedical and Health Sciences, provides additional state of the art laboratory space and core facilities for tissue culture and flow cytometry, as well as molecular and cellular and whole animal imaging. Through its CIRM training program, the Center annually awards stem cell research fellowships to 16 highly talented pre-doctoral, postdoctoral, and physician scientists in training. The Siebel Stem Cell Institute - UC Berkeley supports stem cell research collaborations between Berkeley Stem Cell Center and Stanford University investigators, and provides funding to bring notable visiting scholars to campus.

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Berkeley Stem Cell Center - Research UC Berkeley

Scientists Starting Dangerous Embryonic Stem Cell Trials With Cells That Could Mutate in Patients – LifeNews.com

By Stell Cell Research

China will begin trialling the use of embryonic stem-cells (ES) to treat Parkinsons disease and macular degeneration, in a move that has met with criticism from international experts.

The trials, which come in the wake of new stem-cell regulations introduced in China in 2015, will test the efficacy of injecting ES-derived cells into damaged areas of the brain and eyes.

In one trial, ES-derived neuronal-precursor cells will be injected into the areas of the brain affected by Parkinsons disease in attempt to regenerate dopamine-producing tissue. In another trial, the ES-derived retinal cells will be injected into eyes of people with age related macular degeneration. It is believed that the retinal cells may be able to replace cells damaged as a result of epithelial tissue degeneration.

It will be a major new direction for China, Pei Xuetao, a stem-cell scientist at the Beijing Institute of Transfusion Medicine who is on the central-government committee that approved the trials, told Nature.

Keep up with the latest pro-life news and information on Twitter.

Other researchers who work on Parkinsons disease, however, worry that the trials might be misguided.

Jeanne Loring, a stem-cell biologist at the Scripps Research Institute in La Jolla, California, who is also planning stem-cell trials for Parkinsons, is concerned that the Chinese trials use neural precursors and not ES-cell-derived cells that have fully committed to becoming dopamine-producing cells. Precursor cells can turn into other kinds of neurons, and could accumulate dangerous mutations during their many divisions, says Loring. Not knowing what the cells will become is troubling.

Lorenz Studer, a stem-cell biologist at the Memorial Sloan Kettering Cancer Center in New York City, says that support is not very strong for the use of precursor cells. I am somewhat surprised and concerned, as I have not seen any peer-reviewed preclinical data on this approach, he told Nature.

LifeNews Note: This appeared at Bioedge.org and is reprinted with permission.

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Scientists Starting Dangerous Embryonic Stem Cell Trials With Cells That Could Mutate in Patients - LifeNews.com

Using Stem Cells to Heal Broken Bones – Healthline

By Stem Cell Medical Center

A promising new method for regenerating bones using the body's own stem cells may possibly eliminate the need for bone grafts.

When a fracture will not heal, people are typically left with two options.

One is bone grafting, the other is surgery.

A new treatment that uses gene and stem cell therapies could promise success with a less-invasive procedure.

Researchers led by a team from Cedars-Sinai Medical Center in Los Angeles, tested the therapy on laboratory animals and found that it triggered bones to regrow their own tissue.

If it is found safe in humans, the process could replace bone grafting as the gold standard treatment.

We are just at the beginning of a revolution in orthopedics, Dan Gazit, co-director of the Skeletal Regeneration and Stem Cell Therapy Program in the Department of Surgery and the Cedars-Sinai Board of Governors Regenerative Medicine Institute, said in a statement.

The study was published in the journal Science Translational Medicine.

Bone grafts can result in gaps between fracture edges, and often require surgery to relocate bone from other places in the body to fill in the spaces.

Bone can come from the patient or a cadaver.

But healthy bone isnt always available, and surgeries can lead to other complications.

Read more: First aid for broken bones

The new method involves implanting a collagen matrix made up of bone-inducing genes into stem cells.

It is inserted into the gap over a two-week span. An ultrasound pulse and microbubbles help the matrix get into the cells.

Our method relies on the bodys own repair cells [stem cells], Gadi Pelled, senior author, and an assistant professor of surgery at Cedars-Sinai, told Healthline. We recruit them to the injury site and then activate them to regenerate bone in an efficient way.

The uniqueness of our method is that it is injectable and minimally invasive, Pelled said.

Researchers found that the fractures were healed eight weeks after the procedure. The bone that grew into the empty space was as strong as surgical bone grafts.

We showed that our method was equivalent, in terms of fracture healing, to the use of an autograft [bone graft obtained from the patients own body], which is the gold standard today, Gazit said. Our method does not require the harvest of bone, which often leads to prolonged pain and hospitalization and risk of infection, and that is our advantage.

Read more: Get the facts on broken bones

Because the process uses stem cells from the patients body without external manipulation, it may not face many of the hurdles that other stem cell treatments come up against.

But obviously we will need to show that our method is not toxic and is safe to use in people before it is approved for use in the clinic, added Zulma Gazit, PhD, co-director of the Skeletal Regeneration and Stem Cell Therapy Program in the Department of Surgery and the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

Read more: Stem cell research advancing rapidly

In cases where there are large gaps or fractures unable to heal, the method can be repeated to grow more bone.

Thats something that will need to be reproduced in additional studies, but the latest study is the first to show that this ultrasound-mediated gene delivery can be used to treat nonhealing bone fractures, Pelled added.

David Forsh, an assistant professor of orthopedics at the Icahn School of Medicine at Mount Sinai, and chief of orthopedic trauma at Mount Sinai St. Lukes, said the breakthrough needs to be reproduced before it goes mainstream.

Similar research has been conducted in the past, but the way this was done is something new, according to his knowledge.

It sounds good, Forsh told Healthline. Its very promising that they were able to achieve this.

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Using Stem Cells to Heal Broken Bones - Healthline

Cell Transplantation : The Regenerative Medicine Journal

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Future issues are now being published by SAGE. Please visit their website for new issues:

https://us.sagepub.com/en-us/nam/cell-transplantation/journal203416

(Scroll down to view tables of contents for all Volumes and Issues)

Volume 26, Number 6 Reviews Pig-to-Primate Islet Xenotransplantation: Past, Present, and Future 925Zhengzhao Liu,Wenbao Hu, Tian He,Yifan Dai, Hidetaka Hara, RitaBottino, David K. C. Cooper,Zhiming Cai, andLisha Mou

Using Electrical Stimulation to Enhance the Efficacy of Cell Transplantation Therapies for Neurodegenerative Retinal Diseases: Concepts, Challenges, and Future Perspectives 949Abby LeighManthey, Wei Liu,Zhi Xin Jiang, MarcusHiu Kong Lee, Jian Ji, Kwok-Fai So, JimmyShiu Ming Lai, Vincent Wing Hong Lee, and Kin Chiu

Original Contributions

OlfactoryEnsheathing Cells Inhibit Gliosis in Retinal Degeneration by Downregulation of the Mller Cell Notch Signaling Pathway 967JingXie,Shujia Huo,Yijian Li,Jiaman Dai,Haiwei Xu, and Zheng Qin Yin

EarlySubretinal Allograft Rejection Is Characterized by Innate Immune Activity 983Kevin P. Kennelly, Toby M. Holmes, Deborah M. Wallace, ClionaOFarrelly, and David J. Keegan

Human Dental Pulp Stem Cells Are More Effective Than Human Bone Marrow-Derived Mesenchymal Stem Cells in Cerebral Ischemic Injury 1001Miyeoun Song, Jae-Hyung Lee,Jinhyun Bae,Youngmin Bu, andEun-Cheol Kim

The Timing of Immunomodulation Induced by Mesenchymal Stromal Cells Determines the Outcome of the Graft in Experimental RenalAllotransplantation 1017Ana Merino, Elia Ripoll, Laura de Ramon,Nuria Bolaos, Montserrat Goma, OriolBestard,Nuria Lloberas,Josep M.Grinyo, and JuanTorras Ambrs

Human Umbilical Cord Mesenchymal Stem Cells Inhibit T Follicular Helper Cell Expansion Through the Activation ofiNOS in Lupus-Prone B6.MRL-Faslpr Mice 1031Zhuoya Zhang,Ruihai Feng,Lingying Niu,Saisai Huang, Wei Deng,Bingyu Shi,Genhong Yao,Weiwei Chen,Xiaojun Tang, Xiang Gao,Xuebing Feng, andLingyun Sun

CD34 Antigen and the MPL Receptor Expression Defines a Novel Class of Human Cord Blood-Derived Primitive Hematopoietic Stem Cells 1043Yoshikazu Matsuoka, Masaya Takahashi, KeisukeSumide, Hiroshi Kawamura,Ryusuke Nakatsuka, Tatsuya Fujioka, and YoshiakiSonoda

Long-Term Follow-Up of Patients After Autologous Bone Marrow Cell Infusion for Decompensated Liver Cirrhosis 1059Ja Kyung Kim, Soo-Jeong Kim, Yuri Kim, YongEun Chung, YoungNyun Park, Hyun Ok Kim,Jin Seok Kim,Mi-Suk Park, IsaoSakaida, Do Young Kim, Jung Il Lee, SangHoon Ahn, KwanSik Lee, and Kwang-HyubHan

Calcium Concentration in Culture Medium as a Nondestructive and Rapid Marker of Osteogenesis 1067Yohei Tanikake, ManabuAkahane, Akira Furukawa,Yasuaki Tohma, Yusuke Inagaki, Tsutomu Kira, andYasuhito Tanaka

Cisplatin-ImpairedAdipogenic Differentiation of Adipose Mesenchymal Stem Cells 1077Yu-Hsun Chang, Hwan-Wun Liu, Tang-Yuan Chu, Yao-Tseng Wen,Rong-Kung Tsai, and Dah-Ching Ding

Effects of Different Cell-Detaching Methods on the Viability and Cell Surface Antigen Expression of Synovial Mesenchymal Stem Cells 1089Kunikazu Tsuji,Miyoko Ojima, KojiOtabe,Masafumi Horie, Hideyuki Koga, Ichiro Sekiya, and TakeshiMuneta

Human Muscle Precursor Cells Overexpressing PGC-1a Enhance Early Skeletal Muscle Tissue Formation 1103DeanaHaralampieva, SouzanSalemi, IvanaDinulovic,Tullio Sulser, Simon M.Ametamey, ChristophHandschin, and DanielEberli

Volume 26, Number 5

GeoffreyRaisman, 19392017: Opening a Scientific Door and Giving Hope 733 Paul R.Sanberg

Review

Conceptual Design and Procedure for an AutonomousIntramyocardial Injection Catheter 735 Weyland Cheng and Peter K. Law

Original Contributions

Hydrogen Sulfide Reduces Recruitment of CD11b+Gr-1+Cells in Mice With Myocardial Infarction 753 Ting Wu, Hua Li, Bing Wu, Lei Zhang, San-wu Wu,Jia-ning Wang, and You-en Zhang

Developing a Rapid Algorithm to Enable Rapid Characterization of Alginate Microcapsules 765 Ka Hei Chan, Rahul Krishnan, Michael Alexander, and Jonathan R. T.Lakey

StemCell Keep Is Effective for Cryopreservation of Human Embryonic Stem Cells byVitrification 773 Akemi Ota, Kazuaki Matsumura, Jun-Jae Lee,Shoichiro Sumi, andSoung-Hyu Hyon

In VitroMicrovibration Increases Implantation Rate After Embryonic Cell Transplantation 789 VladimirIsachenko, KarlSterzik, RobertMaettner,Evgenia Isachenko,Plamen Todorov,Gohar Rahimi, PeterMallmann, ErwinStrehler, IgorPereligin, Jos LuisAlabart, and MarkusMerzenich

Changes in Sexual Behavior ofOrchidectomized Rats Under Influence ofAllotransplantation of Testicular Interstitial Cell Suspension 795 Bo Deng, TatyanaBondarenko, andOleksandr Pakhomov

Precise Regulation of miR-210 Is Critical for the Cellular Homeostasis Maintenance and Transplantation Efficacy Enhancement of Mesenchymal Stem Cells in Acute Liver Failure Therapy 805 Yingxia Liu,Yongjia Xiong,Feiyue Xing,Hao Gao,Xiaogang Wang,Liumin He,Chaoran Ren, Lei Liu, Kwok-Fai So, andJia Xiao

Human Muse Cells,Nontumorigenic Pluripotent-Like Stem Cells, Have Liver Regeneration Capacity Through Specific Homing and Cell Replacement in a Mouse Model of Liver Fibrosis 821 Masahiro Iseki, YoshihiroKushida,Shohei Wakao, Takahiro Akimoto,Masamichi Mizuma,Fuyuhiko Motoi,Ryuta Asada,Shinobu Shimizu, MichiakiUnno, GregorioChazenbalk, and MariDezawa

Phenotypical and Functional Characteristics of In Vitro-Expanded Adipose-Derived Mesenchymal Stromal Cells From Patients With Systematic Sclerosis 841 ChiaraCapelli, EleonoraZaccara, Paola Cipriani, Paola Di Benedetto, WandaMaglione, RominaAndracco, Gabriele Di Luca, FrancescaPignataro, RobertoGiacomelli, MartinoIntrona,ClaudioVitali, and Nicoletta Del Papa

Are Adipose-Derived Stem Cells From LiverFalciform Ligaments Another Possible Source of Mesenchymal Stem Cells? 855 Sang Woo Lee, JaeUk Chong,Seon Ok Min,Seon YoungBak, and KyungSik Kim

Effect of Bone Marrow Aspirate ConcentratePlatelet-Rich Plasma on Tendon-Derived Stem Cells and Rotator Cuff Tendon Tear 867 SunJeong Kim, Da Hyun Song, JongWook Park, Silvia Park, and Sang Jun Kim

Human Bone Progenitor Cells for Clinical Application: What Kind of Immune Reaction Does Fetal Xenograft Tissue Trigger in Immunocompetent Rats? 879 Tanja C.Hausherr,Katja Nuss, Eric Thein, Lee A. Applegate, and Dominique P.Pioletti

Clinical Study ofNeuroRegen Scaffold Combined With Human Mesenchymal Stem Cells for the Repair of Chronic Complete Spinal Cord Injury 891 Yannan Zhao,Fengwu Tang,Zhifeng Xiao,Guang Han,NuoWang, Na Yin, Bing Chen,Xianfeng Jiang, Chen Yun,Wanjun Han, Changyu Zhao,Shixiang Cheng, Sai Zhang, andJianwu Dai

Transgenic Expression of Glucagon-Like Peptide-1 (GLP-1) and Activated Muscarinic Receptor (M3R) Significantly Improves Pig Islet Secretory Function 901 Nizar I.Mourad, AndreaPerota,Daela Xhema, Cesare Galli, and PierreGianello

Transplantation of Cultured Olfactory Bulb Cells Prevents Abnormal Sensory Responses During Recovery From Dorsal Root Avulsion in the Rat 913 Andrew Collins, Daqing Li, Stephen B. McMahon, GeoffreyRaisman, and Ying Li

SPECIAL ISSUE 24th MEETING OF THE AMERICAN SOCIETY FOR NEURAL THERAPY AND REPAIR (ASNTR)Recent Progress in Cell Therapy and Regenerative Medicine for Neurological Disorders: Introduction to the ASNTR Special Issue From the 2016 Meeting 529 Cesar V.Borlongan

Is Immune Modulation the Mechanism Underlying the Beneficial Effects of Amniotic Cells and Their Derivatives in Regenerative Medicine? 531 Antonietta R.Silini, MartaMagatti, AnnaCargnoni, and OrnellaParolini

Human Amnion Epithelial Cells Protect Against White Matter Brain Injury After Repeated Endotoxin Exposure in the Preterm Ovine Fetus 541 TamaraYawno,Tharani Sabaretnam,Jingang Li, Courtney McDonald, Rebecca Lim, Graham Jenkin, Euan M. Wallace, and Suzanne L. Miller

Repetitive and Prolonged Omega-3 Fatty Acid Treatment After Traumatic Brain Injury Enhances Long-Term Tissue Restoration and Cognitive Recovery 555 Hongjian Pu,Xiaoyan Jiang,Zhishuo Wei,Dandan Hong,Sulaiman Hassan,Wenting Zhang,Jialin Liu,Hengxing Meng,Yejie Shi, Ling Chen, and Jun Chen

A Novel CXCR4 Antagonist CX549 Induces Neuroprotection in Stroke Brain 571 Kuo-Jen Wu,Seong-Jin Yu,Kak-Shan Shia,Chien-Huang Wu, Jen-Shin Song,Hsuan-HaoKuan, Kai-ChiaYeh,Chiung-Tong Chen,Eunkyune Bae, and Yun Wang

A Comparative Study of Three Different Types of Stem Cells for Treatment of Rat Spinal Cord Injury 585 JiriRuzicka, LuciaMachova-Urdzikova, JohnGillick, TakashiAmemori,Nataliya Romanyuk,Kristyna Karova,Kristyna Zaviskova, JanaDubisova,Sarka Kubinova, RajMurali, EvaSykova,Meena Jhanwar-Uniyal, andPavla Jendelova

Fate of Neural Progenitor Cells Transplanted Into Jaundiced andNonjaundiced Rat Brains 605 Fu-Chen Yang, Sean M. Riordan, Michelle Winter, Li Gan, Peter G. Smith, Jay L. Vivian, Steven M. Shapiro, and John A. Stanford

Real-Time Intraoperative MRI Intracerebral Delivery of Induced Pluripotent Stem Cell-Derived Neurons 613 Scott C.Vermilyea,Jianfeng Lu, Miles Olsen, Scott Guthrie,Yunlong Tao, Eva M.Fekete, Marissa K. Riedel, Kevin Brunner, Carissa Boettcher,Viktorya Bondarenko, Ethan Brodsky, Walter F. Block, Andrew Alexander, Su-Chun Zhang, and Marina E.Emborg

A Comparison of Exogenous Labels for the Histological Identification of Transplanted Neural Stem Cells 625 Francesca J. Nicholls, Jessie R. Liu, and MichelModo

Transplantation of Mesenchymal Stromal Cells in Patients With Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial 647 EvaSykov, PetrRychmach, IvanaDrahordov,imona Konrdov,Kateina Rikov, IvanVoek,Serhiy Forostyak,Ale Homola, and MartinBojar

Step Sequence Is a Critical Gait Parameter of Unilateral 6-OHDA Parkinsons Rat Models 659 Heather A. Baldwin,Pyry P.Koivula, Julie C.Necarsulmer, Keith W. Whitaker, and Brandon K. Harvey

Brilliant Blue G, But Not Fenofibrate, Treatment RevertsHemiparkinsonian Behavior and Restores Dopamine Levels in an Animal Model of Parkinsons Disease 669 Enas G.Ferrazoli,Hllio D.N. de Souza, Isis C.Nascimento,gatha Oliveira-Giacomelli,Telma T.Schwindt, Luiz R.Britto, and Henning Ulrich

A Subpopulation of Dopaminergic NeuronsCoexpresses Serotonin in Ventral Mesencephalic Cultures But Not AfterIntrastriatal Transplantation in a Rat Model of Parkinsons Disease 679 Stefano Di Santo, Stefanie Seiler,Anglique D.Ducray, Morten Meyer, and Hans RudolfWidmer

Regulator of Cell Cycle (RGCC) Expression During the Progression of Alzheimers Disease 693 Scott E. Counts and Elliott J.Mufson

Abstracts for the 24th Annual Meeting of the American Society for Neural Therapy and Repair 703

Volume 26, Number 3

Precision Therapy: Cell Therapy and Development of New Drugs 379 ShinnZong Lin

The Regulatory Effects of Transforming Growth Factor- on Nerve Regeneration 381 Shiying Li,Xiaosong Gu, and Sheng Yi

GSK-3 Inhibition Induced Neuroprotection, Regeneration, and Functional Recovery After Intracerebral Hemorrhagic Stroke 395 Yingying Zhao, ZhengZachory Wei, JamesYa Zhang,Yongbo Zhang,Soonmi Won,Jinmei Sun, Shan Ping Yu,Jimei Li, and Ling Wei

Neuroprotection of Granulocyte Colony-Stimulating Factor for Early Stage Parkinsons Disease 409 Sheng-Tzung Tsai, Sung-Chao Chu, Shu-Hsin Liu, Cheng-Yoong Pang, Ting-WenHou, Shinn-Zong Lin, and Shin-Yuan Chen

Chondrogenic Differentiation of Mesenchymal Stem Cells in Three-Dimensional Chitosan Film Culture 417 Tsai-Jung Lu, Fang-Yao Chiu, Hsiao-Ying Chiu, Ming-Chau Chang, and Shih-Chieh Hung

Pre-S2 Mutant-Induced Mammalian Target of Rapamycin Signal Pathways as Potential Therapeutic Targets for Hepatitis B Virus-Associated Hepatocellular Carcinoma 429 Chiao-FangTeng, Han-Chieh Wu,Woei-Cherng Shyu, Long-BinJeng, andIh-Jen Su

Mesenchymal Stem Cells: The Magic Cure for Intraventricular Hemorrhage? 439 Won Soon Park, So YoonAhn, Se In Sung,Jee-YinAhn, and Yun Sil Chang

Commercial Production of Autologous Stem Cells and Their Therapeutic Potential for Liver Cirrhosis 449 Yi-Chun Lin,Horng-Jyh Harn, Po-Cheng Lin, Ming-Hsi Chuang, Chun-Hung Chen, Shinn-Zong Lin, andTzyy-WenChiou

Novel Therapeutic Transplantation of Induced Neural Stem Cells for Stroke 461 Toru Yamashita,Wentao Liu, Yoshiaki Matsumura,Ryosuke Miyagi, YunZhai,Momoko Kusaki,Nozomi Hishikawa,Yasuyuki Ohta, Sung Min Kim, Tae HwanKwak, DongWook Han, and Koji Abe

Neural Stem Cell-Conditioned Medium Suppresses Inflammation and Promotes Spinal Cord Injury Recovery 469 Zhijian Cheng, Dale B. Bosco, Li Sun,Xiaoming Chen,Yunsheng Xu,Wenjiao Tai, Ruth Didier, Jinhua Li,Jianqing Fan,Xijing He, and Yi Ren

Cell Therapy Regulation in Taiwan 483 Yuan-Chuan Chen,Hwei-Fang Cheng, and Ming-KungYeh

Adiponectin Potentially Contributes to theAntidepressive Effects ofBaduanjin Qigong Exercise in Women With Chronic Fatigue Syndrome-Like Illness 493 Jessie S. M. Chan, Ang Li, Siu-man Ng, Rainbow T. H. Ho,Aimin Xu,Tzy-jyun Yao, Xiao-Min Wang, Kwok-Fai So, and Cecilia L. W. Chan

Treatment of Spinocerebellar Ataxia With Mesenchymal Stem Cells: A Phase I/IIa Clinical Study 503 Yun-An Tsai, Ren-Shyan Liu,Jiing-FengLirng, Bang-Hung Yang, Chin-Hao Chang, Yi-Chen Wang, Yu-Shan Wu, Jennifer Hui-Chun Ho, Oscar K. Lee, and Bing-Wen Soong

Imbalanced Production of Reactive Oxygen Species and Mitochondrial Antioxidant SOD2 inFabry Disease-Specific Human Induced Pluripotent Stem Cell-Differentiated Vascular Endothelial Cells 513 Wei-Lien Tseng, Shih-Jie Chou, Huai-Chih Chiang, Mong-Lien Wang, Chian-Shiu Chien,Kuan-Hsuan Chen,Hsin-BangLeu,Chien-Ying Wang,Yuh-Lih Chang, Yung-Yang Liu,Yuh-Jyh Jong, Shinn-Zong Lin, Shih-HwaChiou,Shing-Jong Lin, and Wen-Chung Yu

Volume 26, Number 2

Human Adipose-Derived Stem Cells Suppress Elastase-Induced Murine Abdominal Aortic Inflammation and Aneurysm Expansion Through Paracrine Factors 173 Jie Xie, Thomas J. Jones,Dongni Feng, Todd G. Cook, Andrea A. Jester, Ru Yi,Yameena T. Jawed, CliffordBabbey, Keith L. March, and Michael P. Murphy

CXCR4 Overexpression in Human Adipose Tissue-Derived Stem Cells Improves Homing and Engraftment in an Animal Limb Ischemia Model 191 MiJung Kim, Dong-Ik Kim,Eun Key Kim, and Chan-Wha Kim

ALLogeneic HeartSTem Cells to Achieve Myocardial Regeneration (ALLSTAR) Trial: Rationale and Design 205 Tarun Chakravarty, Raj R.Makkar, Deborah D.Ascheim, Jay H. Traverse, Richard Schatz, AnthonyDeMaria, Gary S. Francis, Thomas J.Povsic, Rachel R. Smith, Joao A. Lima, Janice M.Pogoda, LindaMarbn, and Timothy D. Henry

A Nerve Conduit Containing a Vascular Bundle and Implanted With Bone Marrow Stromal Cells and Decellularized Allogenic Nerve Matrix 215 YukitoshiKaizawa,Ryosuke Kakinoki,Ryosuke Ikeguchi,Soichi Ohta, Takashi Noguchi,Hisataka Takeuchi, Hiroki Oda, HirofumiYurie, and Shuichi Matsuda

Bone Marrow Stromal Cells Combined With SodiumFerulate andn-Butylidenephthalide Promote the Effect of Therapeutic Angiogenesis via Advancing Astrocyte-Derived Trophic Factors After Ischemic Stroke 229 Qian Zhang, Zhen-Wei Chen, Yong-Hua Zhao, Bo-Wen Liu,Nai-Wei Liu, Chien-ChihKe, and Hong-Mei Tan

Secondary Release of Exosomes From Astrocytes Contributes to the Increase in Neural Plasticity and Improvement of Functional Recovery After Stroke in Rats Treated With Exosomes Harvested From MicroRNA 133b-Overexpressing Multipotent Mesenchymal Stromal Cells 243 Hongqi Xin,Fengjie Wang,Yanfeng Li, Qing-e Lu, Wing Lee Cheung, Yi Zhang, Zheng Gang Zhang, and MichaelChopp

Efficacy of Two Delivery Routes for Transplanting Human Neural Progenitor Cells (NPCs) Into the Spastic HanWistar Rat, a Model of Ataxia 259 Toni L.Uhlendorf, Ruslan L.Nuryyev, Alex O.Kopyov, Jessica Ochoa, ShahabYounesi, Randy W. Cohen, and Oleg V.Kopyov

Establishment and Characterization of Immortalized Minipig Neural Stem Cell Line 271 Sung S. Choi,Seung-Bin Yoon, Sang-Rae Lee, Sun-Uk Kim, YoungJoo Cha, Daniel Lee,Seung U. Kim,Kyu-Tae Chang, and Hong J. Lee

Safety of Intra-Arterial Injection With Tumor-Activated T Cells to the Rabbit Brain Evaluated by MRI and SPECT/CT 283 Johan Lundberg, EmmaJussing, Zhenjiang Liu,Qingda Meng, Martin Rao, ErikSamn,Rikard Grankvist, PeterDamberg, ErnestDodoo, MarkusMaeurer, andStaffan Holmin

Significantly Accelerated Wound Healing of Full-Thickness Skin Using a Novel Composite Gel of Porcine Acellular Dermal Matrix and Human Peripheral Blood Cells 293 Vijay K. Kuna, Arvind M. Padma,Joakim Hkansson, JanNygren, RobertSjback,Sarunas Petronis, andSuchitra Sumitran-Holgersson

Human Recombinant Antithrombin (ATryn) Administration Improves Survival and Prevents Intravascular Coagulation After Intraportal Islet Transplantation in a Piglet Model 309 ValeryGmyr, Caroline Bonner, ErickaMoerman, AntoineTournoys, NathalieDelalleau, AudreyQuenon, JulienThevenet, MikaelChetboun, Julie Kerr-Conte, FranoisPattou, Thomas Hubert, andMerce Jourdain

Monocyte-Derived Dendritic Cells Impair Early Graft Function Following Allogeneic Islet Transplantation 319 Kevin V. Chow, Emma M. Carrington,Yifan Zhan, Andrew M. Lew, and Robyn M. Sutherland

Thrombospondin-1-Derived Peptide RFYVVMWK Improves the Adhesive Phenotype of CD34+ Cells From Atherosclerotic Patients With Type 2 Diabetes 327 SylvieCointe, ricRhaume, Catherine Martel, Olivier Blanc-Brude,Evemie Dub, Florence Sabatier, FranoiseDignat-George, Jean-Claude Tardif, and ArnaudBonnefoy

Fetal Tissues Tested for Microbial Sterility by Culture- and PCR-Based Methods Can be Safely Used in Clinics 339 Yakov Vitrenko,Iryna Kostenko,Kateryna Kulebyakina,Alla Duda,Mariya Klunnyk, and KhrystynaSorochynska

Adult-Derived Human Liver Stem/Progenitor Cells Infused 3 DaysPostsurgery Improve Liver Regeneration in a Mouse Model of Extended Hepatectomy 351 Astrid Herrero, JuliePrigent, Catherine Lombard,Valrie Rosseels, MartineDaujat-Chavanieu,Karine Breckpot, MustaphaNajimi,Gisle Deblandre, and Etienne M.Sokal

-Catenin Accumulation Is Associated With Increased Expression ofNanog Protein and Predicts Maintenance of MSC Self-Renewal 365 Sang-Jin Yu, Hyun-Je Kim,Eui Seok Lee, Chung-Gyu Park, SuJin Cho, andSoung-Hoo Jeon

Volume 26, Number 1

Original Contributions

Identification of Donor Origin and Condition of Transplanted IsletsIn Situ in the Liver of a Type 1 Diabetic Recipient 1Cornelis R. van der Torren, Jessica S.Suwandi,DaHae Lee, Ernst-Jan T.vant Wout, GabyDuinkerken,Godelieve Swings,Arend Mulder, Frans H. J.Claas,Zhidong Ling, Pieter Gillard, BartKeymeulen, Peterint Veld, and Bart O.Roep

Physiologic Doses of Bilirubin Contribute to Tolerance of Islet Transplants by Suppressing the Innate Immune Response 11Christopher A. Adin, Zachary C.VanGundy, Tracey L. Papenfuss, Feng Xu, MostafaGhanem, JonathanLakey, and Gregg A. Hadley

Active Subjects With Autoimmune Type 1 Diabetes Have Better Metabolic Profiles Than Sedentary Controls 23M.Adamo, R.Codella, F. Casiraghi, A.Ferrulli, C.Macri, E.Bazzigaluppi, I.Terruzzi, L.Inverardi, C.Ricordi, and L.Luzi

Effect of Manufacturing Procedures on Human Islet Isolation From DonorPancreata Standardized by the North American Islet Donor Score 33Chun-Chieh Yeh, Ling-jia Wang, James J.McGarrigle, Yong Wang,Chien-Chang Liao, MustafaOmami, Arshad Khan, MohammadNourmohammadzadeh, Joshua Mendoza-Elias, Benjamin McCracken,Enza Marchese, BarbaraBarbaro, and JoseOberholzer

Transplantation of Human Placenta-Derived Mesenchymal Stem Cells Alleviates Critical Limb Ischemia in Diabetic Nude Rats 45Lu Liang,Zongjin Li, Tao Ma,Zhibo Han,Wenjing Du,Jie Geng,Honghong Jia, Meng Zhao,Jimin Wang,Bingjing Zhang,Jie Feng,Lanzhen Zhao, AlainRupin,Youwei Wang, andZhong Chao Han

Excluding Anti-cytomegalovirus Immunoglobulin M-Positive Cord Blood Units Has a Minimal Impact on the Korean Public Cord Blood Bank Inventory 63Sue Shin,Eun Youn Roh,Sohee Oh,Eun Young Song,Eui Chong Kim, and Jong Hyun Yoon

Control of IBMIR Induced by Fresh and Cryopreserved Hepatocytes by Low Molecular Weight Dextran Sulfate Versus Heparin 71Elisabet Gustafson, Sana Asif, HudaKozarcanin, GracielaElgue,Staffan Meurling, Kristina N.Ekdahl, and Bo Nilsson

Poor Mobilization in T-Cell-Deficient Nude Mice Is Explained by Defective Activation of Granulocytes and Monocytes 83MarcinWysoczynski, MateuszAdamiak,Malwina Suszynska, Ahmed Abdel-Latif, JaninaRatajczak, andMariusz Z.Ratajczak

Differences inTfh Cell Response Between the Graft and Spleen With Chronic Allograft Nephropathy 95Jian Shi,Xianlin Xu,Fengbao Luo,Qianqian Shi,Xiaozhou He, and Ying Xia

Improved Transplanted Stem Cell Survival in a Polymer Gel Supplemented With Tenascin C Accelerates Healing and Reduces Scarring of Murine Skin Wounds 103Cecelia C. Yates, AustinNuschke, Melanie Rodrigues, Diana Whaley, Jason J.Dechant, Donald P. Taylor, and Alan Wells

Effect of Gelatin on Osteogenic Cell Sheet Formation Using Canine Adipose-Derived Mesenchymal Stem Cells 115Ah young Kim,Yongsun Kim,Seung Hoon Lee,Yongseok Yoon, Wan-Hee Kim, and Oh-Kyeong Kweon

Biliary Polyunsaturated Fatty Acids andTelocytes in Gallstone Disease 125Artur Pasternak,Jolanta Bugajska,Mirosaw Szura, Jerzy A.Walocha, AndrzejMatyja,Mariusz Gajda, KrystynaSztefko, and Krzysztof Gil

Cellular Evidence ofTelocytes as Novel Interstitial Cells Within the Magnum of Chicken Oviduct 135Ping Yang,Xudong Zhu,Lingling Wang,Nisar Ahmed,Yufei Huang, Hong Chen, Qian Zhang,Shakeeb Ullah,Tengfei Liu,Dawei Guo,Sarfaraz AhmedBrohi, andQiusheng Chen

Pivotal Role of Brain-Derived Neurotrophic Factor Secreted by Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage in Newborn Rats 145So YoonAhn, Yun Sil Chang, Dong Kyung Sung, Se In Sung,Jee-YinAhn, and Won Soon Park

Intramyocardially Transplanted Neonatal Cardiomyocytes (NCMs) Show Structural and Electrophysiological Maturation and Integration and Dose-Dependently Stabilize Function of Infarcted Rat Hearts 157MartinaMaass, BenjaminKrausgrill, SimonEschrig, TobiasKaluschke,Katja Urban, GabrielPeinkofer, Tobias G.Plenge, SimonOeckenpohler, MartinRaths, DennisLadage, MarcelHalbach,Jurgen Hescheler, andJochen Muller-Ehmsen

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Cell Transplantation : The Regenerative Medicine Journal

The Nobel Prize in Physiology or Medicine for 2001 – Press …

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8 October 2001

The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2001 jointly to&

Leland H. Hartwell, R. Timothy (Tim) Hunt and Paul M. Nurse

for their discoveries of "key regulators of the cell cycle"

All organisms consist of cells that multiply through cell division. An adult human being has approximately 100 000 billion cells, all originating from a single cell, the fertilized egg cell. In adults there is also an enormous number of continuously dividing cells replacing those dying. Before a cell can divide it has to grow in size, duplicate its chromosomes and separate the chromosomes for exact distribution between the two daughter cells. These different processes are coordinated in the cell cycle.

This year's Nobel Laureates in Physiology or Medicine have made seminal discoveries concerning the control of the cell cycle. They have identified key molecules that regulate the cell cycle in all eukaryotic organisms, including yeasts, plants, animals and human. These fundamental discoveries have a great impact on all aspects of cell growth. Defects in cell cycle control may lead to the type of chromosome alterations seen in cancer cells. This may in the long term open new possibilities for cancer treatment.

Leland Hartwell (born 1939), Fred Hutchinson Cancer Research Center, Seattle, USA, is awarded for his discoveries of a specific class of genes that control the cell cycle. One of these genes called "start" was found to have a central role in controlling the first step of each cell cycle. Hartwell also introduced the concept "checkpoint", a valuable aid to understanding the cell cycle.

Paul Nurse (born 1949), Imperial Cancer Research Fund, London, identified, cloned and characterized with genetic and molecular methods, one of the key regulators of the cell cycle, CDK (cyclin dependent kinase). He showed that the function of CDK was highly conserved during evolution. CDK drives the cell through the cell cycle by chemical modification (phosphorylation) of other proteins.

Timothy Hunt (born 1943), Imperial Cancer Research Fund, London, is awarded for his discovery of cyclins, proteins that regulate the CDK function. He showed that cyclins are degraded periodically at each cell division, a mechanism proved to be of general importance for cell cycle control.

Cells having their chromosomes located in a nucleus and separated from the rest of the cell, so called eukaryotic cells, appeared on earth about two billion years ago. Organisms consisting of such cells can either be unicellular, such as yeasts and amoebas, or multi-cellular such as plants and animals. The human body consists of a huge number of cells, on the average about one billion cells per gram tissue. Each cell nucleus contains our entire hereditary material (DNA), located in 46 chromosomes (23 pairs of chromosomes).

It has been known for over one hundred years that cells multiply through division. It is however only during the last two decades that it has become possible to identify the molecular mechanisms that regulate the cell cycle and thereby cell division. These fundamental mechanisms are highly conserved through evolution and operate in the same manner in all eukaryotic organisms.

The cell cycle consists of several phases (see figure). In the first phase (G1) the cell grows and becomes larger. When it has reached a certain size it enters the next phase (S), in which DNA-synthesis takes place. The cell duplicates its hereditary material (DNA-replication) and a copy of each chromosome is formed. During the next phase (G2) the cell checks that DNA-replication is completed and prepares for cell division. The chromosomes are separated (mitosis, M) and the cell divides into two daughter cells. Through this mechanism the daughter cells receive identical chromosome set ups. After division, the cells are back in G1 and the cell cycle is completed.

The duration of the cell cycle varies between different cell types. In most mammalian cells it lasts between 10 and 30 hours. Cells in the first cell cycle phase (G1) do not always continue through the cycle. Instead they can exit from the cell cycle and enter a resting stage (G0).

For all living eukaryotic organisms it is essential that the different phases of the cell cycle are precisely coordinated. The phases must follow in correct order, and one phase must be completed before the next phase can begin. Errors in this coordination may lead to chromosomal alterations. Chromosomes or parts of chromosomes may be lost, rearranged or distributed unequally between the two daughter cells. This type of chromosome alteration is often seen in cancer cells.

It is of central importance in the fields of biology and medicine to understand how the cell cycle is controlled. This year's Nobel Laureates have made seminal discoveries at the molecular level of how the cell is driven from one phase to the next in the cell cycle.

Leland Hartwell realized already at the end of the 1960s the possibility of studying the cell cycle with genetic methods. He used baker's yeast, Saccharomyces cerevisiae, as a model system, which proved to be highly suitable for cell cycle studies. In an elegant series of experiments 1970-71, he isolated yeast cells in which genes controlling the cell cycle were altered (mutated). By this approach he succeeded to identify more than one hundred genes specifically involved in cell cycle control, so called CDC-genes (cell division cycle genes). One of these genes, designated CDC28 by Hartwell, controls the first step in the progression through the G1-phase of the cell cycle, and was therefore also called "start".

In addition, Hartwell studied the sensitivity of yeast cells to irradiation. On the basis of his findings he introduced the concept checkpoint, which means that the cell cycle is arrested when DNA is damaged. The purpose of this is to allow time for DNA repair before the cell continues to the next phase of the cycle. Later Hartwell extended the checkpoint concept to include also controls ensuring a correct order between the cell cycle phases.

Paul Nurse followed Hartwell's approach in using genetic methods for cell cycle studies. He used a different type of yeast, Schizosaccharomyces pombe, as a model organism. This yeast is only distantly related to baker's yeast, since they separated from each other during evolution more than one billion years ago.

In the middle of the 1970s, Paul Nurse discovered the gene cdc2 in S. pombe. He showed that this gene had a key function in the control of cell division (transition from G2 to mitosis, M). Later he found that cdc2 had a more general function. It was identical to the gene ("start") that Hartwell earlier had identified in baker's yeast, controlling the transition from G1 to S.

This gene (cdc2) was thus found to regulate different phases of the cell cycle. In 1987 Paul Nurse isolated the corresponding gene in humans, and it was later given the name CDK1 (cyclin dependent kinase 1). The gene encodes a protein that is a member of a family called cyclin dependent kinases, CDK. Nurse showed that activation of CDK is dependent on reversible phosphorylation, i.e. that phosphate groups are linked to or removed from proteins. On the basis of these findings, half a dozen different CDK molecules have been found in humans.

Tim Hunt discovered the first cyclin molecule in the early 1980s. Cyclins are proteins formed and degraded during each cell cycle. They were named cyclins because the levels of these proteins vary periodically during the cell cycle. The cyclins bind to the CDK molecules, thereby regulating the CDK activity and selecting the proteins to be phosphorylated.

The discovery of cyclin, which was made using sea urchins, Arbacia, as a model system, was the result of Hunt's finding that this protein was degraded periodically in the cell cycle. Periodic protein degradation is an important general control mechanism of the cell cycle. Tim Hunt later discovered cyclins in other species and found that also the cyclins were conserved during evolution. Today around ten different cyclins have been found in humans.

The three Nobel Laureates have discovered molecular mechanisms that regulate the cell cycle. The amount of CDK-molecules is constant during the cell cycle, but their activities vary because of the regulatory function of the cyclins. CDK and cyclin together drive the cell from one cell cycle phase to the next. The CDK-molecules can be compared with an engine and the cyclins with a gear box controlling whether the engine will run in the idling state or drive the cell forward in the cell cycle.

Most biomedical research areas will benefit from these basic discoveries, which may result in broad applications within many different fields. The discoveries are important in understanding how chromosomal instability develops in cancer cells, i.e. how parts of chromosomes are rearranged, lost or distributed unequally between daughter cells. It is likely that such chromosome alterations are the result of defective cell cycle control. It has been shown that genes for CDK-molecules and cyclins can function as oncogenes. CDK-molecules and cyclins also collaborate with the products of tumour suppressor genes (e.g. p53 and Rb) during the cell cycle.

The findings in the cell cycle field are about to be applied to tumour diagnostics. Increased levels of CDK-molecules and cyclins are sometimes found in human tumours, such as breast cancer and brain tumours. The discoveries may in the long term also open new principles for cancer therapy. Already now clinical trials are in progress using inhibitors of CDK-molecules.

This year's Nobel Laureates, using genetic and molecular biology methods, have discovered mechanisms controlling the cell cycle. CDK-molecules and cyclins drive the cell from one phase to the next. The CDK-molecules can be compared with an engine and the cyclins with a gear box controlling whether the engine will run in the idling state or drive the cell forward in the cell cycle.

See also high resolution images:

Cell cycle, English version Cellcykel, Swedish version Leland H. Hartwell R. Timothy (Tim) Hunt Paul M. Nurse

To cite this page MLA style: "The Nobel Prize in Physiology or Medicine for 2001 - Press Release". Nobelprize.org. Nobel Media AB 2014. Web. 8 Jun 2017. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/press.html>

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The Nobel Prize in Physiology or Medicine for 2001 - Press ...

CAR T-cell therapy Why it’s too soon to speculate about a ‘cure’ for multiple myeloma – HealthNewsReview.org

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Kathlyn Stone is an associate editor at HealthNewsReview.org. She tweets as @KatKStone.

An experimental immunotherapy treatment for multiple myeloma from a biotech company in China captured wide attention at the just-concluded American Society of Clinical Oncology (ASCO) meeting.

Weve been following news reports from the meeting closely since it kicked off last Friday:

ASCOs news release on the new treatment, a form of CAR T-cell therapy, noted that the phase 1 results are preliminary and that the small trial was short-term. But then it blew past those cautions by speculating that the treatment could send multiple myeloma into long-term remission and might represent a cure for this incurable disease. The treatment costs werent included, either.

Andrae Vandross, MD, a hematology/oncology fellow at UCLA and a contributor to HealthNewsReview.org, said the news release had some important details, such as a discussion of adverse events, particularlycytokine release syndrome (CRS), which affected many patients.

But overall, I wish more attention was paid to the fact that this small trial was to examine safety and efficacy and that much more needs to be done to make statements regarding clinically meaningful impact on disease, Vandross said.

The shortcomings of the news release can be found repeated in some of the news coverage.

Reuterss story, Chinese cell therapy effective in small multiple myeloma trial didnt explain harms well nor mention costs.

FierceBiotechs article played up the horse race aspect of the pharmaceutical industry where competing companies race to get media and investor attention for their preliminary research, ASCO dark horse Nanjing Legend Biotech shines with promising CAR-T data. But costs didnt make it into the discussion.

Nor was the price tag mentioned in The Scientists piece, CAR T-Cell trials boast promising results.

Deborah Korenstein, MD, an internist at Memorial Sloan-Kettering Cancer Center, who did attend the meeting, found some of the reports on the CAR-T study lacking.

None of these articles mentions cost, though CAR-T therapy is very expensive. They do note that the follow-up is short-term so far, though they also talk about long-term remission (in the case of the Reuters piece) or cure (in the ASCO press release), which at the very least sends a mixed message.

NBC News piece, CAR-T Cancer Approach Has Surprising Success in Multiple Myeloma, reflects some of this mixed messaging.After reporting that the results were impressive and remarkable and that the study brings hope of a possible cure, the NBC story eventually broaches the issues of adverse effects and costs: The treatment is expected to cost $200,000 to $300,000, and whos going to pay for that is a big issue, according to a study author.

What does Korenstein think news organizations and public relations people could do better?

Stick to the evidence at hand, avoid speculating about outcomes that havent been determined, and make sure that potential harms are described as thoroughly as benefits.

Certainly there is no evidence so far to support those claims about longer term outcomes. They say it in a hedgy way but to me they shouldnt be mentioning it at all. They also play down the fact that the huge majority of patients had CRS, even if it was often not severe which is generally defined as requiring hospitalization. Its not clear here what severe means.

Dr. Korenstein disclosed that her spouse consults for Vedanta Biosciences.

Kevin Lomangino is the managing editor of HealthNewsReview.org. He tweets as @KLomangino. You'll be tempted

This week we begin a slow roll-out of a new offer of help to those

Today kicks off the annual meeting of the American Society of Clinical Oncology, the world's

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CAR T-cell therapy Why it's too soon to speculate about a 'cure' for multiple myeloma - HealthNewsReview.org

Novartis touts new T-cell therapy data in race for FDA approval – Reuters

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ZURICH Novartis on Wednesday touted new data from its T-cell therapy CTL019, saying it is on a par with results of experimental molecules from Kite Pharma and Juno Therapeutics that also target aggressive blood cancers.

Three months after infusion, the overall response rate (ORR)among 51 adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) was 45 percent, Novartis said, with 37 percent complete responses (CR), or no sign of disease.

Novartis aims for $1 billion in annual sales for CTL019, a drug made by taking T cells from a patient, reprogramming them in the lab to fight cancer, and re-infusing them. The field is crowded, with Kite and Juno also hunting for approval for drugs whose per-patient costs could top $500,000.

"When you look across the three competitors' data sets, they're all in a similar range of responses," Novartis drug development chief Vas Narasimhan said in an interview. "What's critical is to see the data sets fully mature... and look at the overall safety profile."

Narasimhan said no deaths were linked to CTL019, though three patients died from disease progression within 30 days of infusion. Seven suffered severe neurological events.

While so-called "CAR-T therapies" from Novartis, Kite and Juno are now last resorts for patients who have failed other treatments, more doctors are growing convinced they have promise. Globally, there are some 183 CAR-T trials underway.

In March, Novartis filed CTL019 with the U.S. Food and Drug Administration for fast-track approval in B-cell acute lymphoblastic leukemia (ALL) in young patients. The FDA has scheduled a July 12 public meeting for that.

Novartis could file for FDA approval in DLBCL, the most common form of non-Hodgkin lymphoma (NHL) in adults, around October, with European filings planned about the same time.

Rival Kite Pharma's experimental drug axi-cel is also under expedited U.S. review against advanced NHL, with additional trials underway in leukaemia patients.

Kite has said 41 percent of NHL patients responded to axi-cel treatment at the six-month cutoff, with 36 percent in complete response.

Though Juno Therapeutics has suffered significant setbacks -- patient deaths forced it to abandon its lead CAR-T molecule this year -- the company released fresh data last week on another drug, JCAR017, against NHL.

Novartis is studying why some patients respond to CTL019 while others' cancers avoid detection.

Additional trials are planned, including with newer CAR-Ts combined with other drugs.

"There's just a lot of science that's yet to be understood," Narasimhan said. "I hope we have better answers next year ... for what's going on in the non-responders."

(Reporting by John Miller, editing by Louise Heavens)

VIENTIANE Dozens of fertility clinics have mushroomed in land-locked Laos after scandals over commercial surrogacy have spurred wealthier southeast Asian neighbors to ban the controversial procedure since 2015.

Automakers could help prevent accidental deaths of small children left in hot cars by installing devices to remind drivers to check their back seats for passengers before getting out, three U.S. lawmakers sponsoring a safety measure said on Wednesday.

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Novartis touts new T-cell therapy data in race for FDA approval - Reuters

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