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Reproducibility has always been a serious challenge when medical researchers in both academia and industry have tried to build upon previously published discoveries. Blindly chasing faulty results has incurred a huge waste of human and monetary resources. The damage to the progress of scientific discoveries, as well as their application to human well-being, cannot be overestimated. According to two reports by Bayer and Amgen published in 2011 and 2012, 64-89% of the socalled "landmark" results could not be reproduced in their pre-clinical validation experiments. One plausible explanation for this out of proportion irreproducibility is related to the intricacy of the scientific experiments, including the sourcing of reagent antibodies and cell lines, which are major sources of variations. To make validation meaningful, the study materials used in the original studies need to be authenticated so that variations due to the faulty materials can be prevented during follow-up studies. However, the technical complexity and the costs of authentication often discourage this practice in research laboratories. In addition to these obstacles, researchers are left with no standards to follow when validating their reagents and cell lines. Nevertheless, the ever-growing irreproducibility has created a sense of urgency in the medical research field, and the root of faulty science has to be tackled. Two recent commentaries in Nature and Nature Methods highlighted the importance of the quality control of antibody reagents and cell lines. Both commentaries extensively discussed the existing quality problems associated with antibody reagents and cultured cell lines. The authors followed their discussions by advocating policy solutions, as well as feasible standards, towards better authentication and validation. The main impetus of these discussions will certainly raise the awareness of these problems, and may change the attitudes among researchers, toward the goal of improving the sourcing of antibodies and cell lines.

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We devote this short piece to highlight one recent article published in Cell Stem Cell, reporting the correction of large chromosomal inversions of the factor VIII (F8) gene in cells from Hemophilia A patients using the CRISPR-Cas9 technology, one of the first attempts to edit large segments of chromosomes in patient cells using such methodology. The corrected cells were found free of off-target mutations and producing functional factor VIII in hemophilia mouse model. This work heralds another major advance in bringing CRISPR closer to the therapeutic reality.

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The advent of induced pluripotent stem cells (iPSCs) marked a giant step forward towards the reality of converting one type of primary somatic cells into different lineages capable of clinically repairing damaged tissues and organs. However, the major drawbacks of iPSCs hinder their quick translation to the bedside. These drawbacks include the time-, cost-, and labor-intensive process in production of clinical products from iPSCs, and the inherent risk of long-term tumorigenesis due to the forced expression of transcription factors associated with pluripotency, which are often implicated as aberrations within the cancerous gene circuitry.

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Breast cancer is the second-most prevalent cancer in the United States, with 234, 190 new cases projected to be diagnosed in 2015.The initial diagnosis is commonly made early in its disease course due to the use of routine screening mammography. Combined with advances in adjuvant chemotherapy, this has led to promising overall outcomes, including a 5-year survival rate of 89.4% and a 10%-12% rate of locoregional recurrence at 20 years for stage I/II disease. By comparison, prognosis remains poor for patients with metastatic disease at diagnosis or for those who present after initial cure of disease with distant recurrence. Among cases of distant recurrence, skeletal recurrence occurs frequently and can be accompanied by hypercalcemia, pain, and functional compromise often requiring a protracted course of palliative therapy.

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The existence of adult stem cells was first described in tissues with high proliferation rates, such as the hematopoietic system and the intestine. Since then, stem cells have been found in almost all adult tissues, including the nervous system. Adult neurogenesis is supported by multipotent neural stem cells (NSCs), which maintain some of the cellular and molecular characteristics of their embryonic counterparts. Because of their suggestive appeal as therapeutic agents and their presumed relevance for cognition in health and disease, adult neurogenesis is attracting considerable attention from neuroscientists.

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Increasing prostaglandin E2 by knocking out its inhibitor 15-hydroxyprostaglandin dehydrogenase (15-PDGH) or administering a compound that inhibits 15-PDGH was recently found to improve healing in hematopoietic stem cell transplants, colitis recovery, and hepatogenesis after transection in mice. These results are suggestive of pharmacologic therapies or even genetic therapy that could improve patient outcomes, especially since the excess PGE2 and the 15-PDGH inhibitor have proven to be non-toxic. However, elevated levels of PGE2 are associated with increased risk of cancer and blood clotting problems. It would be un-acceptable to treat a cancer patient with chemotherapy and replenish the hematopoietic stem cells with the help of PGE2, only to have increased expression of PGE2 and induce another cancer. Therefore, to assess the most therapeutic aspects of PGE2, it is important to consider effects that could induce disease.

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Gemcitabine is the first-line treatment for pancreatic ductual adenocarcinoma (PDAC) as well as acts against a wide range of other solid tumors. Patients usually have a good initial response to gemcitabine-based chemotherapy but would eventually develop resistance. To improve survival and prognosis of cancer patients, better understanding of the mechanisms responsible for gemcitabine resistance and discovery of new therapeutic strategies are in great need. Amounting evidence indicate that the developmental pathways, such as Hedgehog (Hh), Wnt and Notch, become reactivated in gemcitabine-resistant cancer cells. Thus, the strategies for targeting these pathways may sensitize cancer cells to gemcitabine treatment. In this review, we will summarize recent development in this area of research and discuss strategies to overcome gemcitabine resistance. Given the cross-talk between these three developmental signaling pathways, designing clinical trials using a cocktail of inhibitory agents targeting all these pathways may be more effective. Ultimately, our hope is that targeting these developmental pathways may be an effective way to improve the gemcitabine treatment outcome in cancer patients.

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Defects of articular cartilage present a unique clinical challenge due to its poor self-healing capacity and avascular nature. Current surgical treatment options do not ensure consistent regeneration of hyaline cartilage in favor of fibrous tissue. Here, we review the current understanding of the most important biological regulators of chondrogenesis and their interactions, to provide insight into potential applications for cartilage tissue engineering. These include various signaling pathways, including fibroblast growth factors (FGFs), transforming growth factor β (TGF-β) /bone morphogenic proteins (BMPs), Wnt/β-catenin, Hedgehog, Notch, hypoxia, and angiogenic signaling pathways. Transcriptional and epigenetic regulation of chondrogenesis will also be discussed. Advances in our understanding of these signaling pathways have led to promising advances in cartilage regeneration and tissue engineering.

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During the last two decades numerous research teams demonstrated that skeletalmuscles function as an exercise-dependent endocrine organ secreting dozens of myokines. Variety of physiological and pathophysiological implications of skeletal muscle myokines secretion has been described; however, upstream signals and sensing mechanisms underlying this phenomenon remain poorly understood. It is well documented that in skeletal muscles intensive exercise triggers dissipation of transmembrane gradient of monovalent cations caused by permanent activation of voltage-gated Na⁺ and K⁺ channels. Recently, we demonstrated that sustained elevation of the [Na⁺]_i/[K⁺]_i ratio triggers expression of dozens ubiquitous genes including several canonical myokines, such as interleukin-6 and cyclooxygenase 2, in the presence of intra- and extracellular Ca²⁺ chelators. These data allowed us to suggest a novel [Na⁺]_i/[K⁺]_i-sensitive, Ca²⁺_i-independent mechanism of excitation-transcription coupling which triggers myokine production. This pathway exists in parallel with canonical signaling mediated by Ca²⁺_i, AMP-activated protein kinase and hypoxia-inducible factor 1α (HIF-1α). In ourmini-reviewwe briefly summarize data supporting this hypothesis as well as unresolved issues aiming to forthcoming studies.

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Cartilage defects are a challenge to treat clinically due to the avascular nature of cartilage. Low immunogenicity and extensive proliferation and multidifferentiation potential make fetal stem cells a promising source for regenerative medicine. In this study, we aimed to determine whether fetal synovium-derived stem cells (FSDSCs) exhibited replicative senescence and whether expansion on decellularized extracellular matrix (dECM) deposited by adult SDSCs (AECM) promoted FSDSCs' chondrogenic potential. FSDSCs from passage 2 and 9 were compared for chondrogenic potential, using Alcian blue staining for sulfated glycosaminoglycans (GAGs), biochemical analysis for DNA and GAG amounts, and real-time PCR for chondrogenic genes including ACAN and COL2A1. Passage 3 FSDSCs were expanded for one passage on plastic flasks (PL), AECM, or dECM deposited by fetal SDSCs (FECM). During expansion, cell proliferation was evaluated using flow cytometry for proliferation index, stem cell surface markers, and resistance to hydrogen peroxide. During chondrogenic induction, expanded FSDSCs were evaluated for tri-lineage differentiation capacity. We found that cell expansion enhanced FSDSCs' chondrogenic potential at least up to passage 9.Expansion on dECMs promoted FSDSCs' proliferative and survival capacity and adipogenic differentiation but not osteogenic capacity. AECM-primed FSDSCs exhibited an enhanced chondrogenic potential.

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Craniosynostosis, a condition in which the cranial sutures prematurely fuse, can lead to elevated intracranial pressure and craniofacial abnormalities in young children. Currently surgical intervention is the only therapeutic option for patients with this condition. Craniosynostosis has been associated with a variety of different gene mutations and chromosome anomalies. Here we describe three cases of partial deletion of chromosome 19p. Two of the cases present with syndromic craniosynostosis while one has metopic ridging. A review of the genes involved in the rearrangements between the three cases suggests several gene candidates for craniosynostosis. CALR and DAND5, BMP regulators involved in osteoblast differentiation, and MORG1, a mediator of osteoclast dysregulation may play a role in abnormal cranial vault development. Additionally, CACNA1A, a gene that when mutated is associated with epilepsy and CC2D1A, a gene associated with non-syndromic mental retardation may contribute to additional phenotypic features seen in the patients we describe. In addition, these findings further support the need for genetic testing in cases of syndromic craniosynostosis.

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The authors regret that an error was made in citing Reference#57. The correct citation is "Lavial F, Bessonnard S, Ohnishi Y, Tsumura A, Chandrashekran A, Fenwick MA, Tomaz RA, Hosokawa H, Nakayama T, Chambers I, Hiiragi T, Chazaud C, Azuara V. Bmi1 facilitates primitive endoderm formation by stabilizing Gata6 during early mouse development. Genes Dev.2012 Jul 1; 26 (13): 1445e1458". In the text on p.229 right column, Line14, the first author's name should be Lavial. The authors would like to apologize for any inconvenience and confusion caused by the error.

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