WILFRED WU WONDERLAND

Circadian Release of HSCs

noreply@blogger.com (Wilfred Wu) — Thu, 01 May 2008 02:40:00 +0000

Last month, Méndez-Ferrer S et al. published an article on Nature, exploring the circadian pattern of haematopoietic stem cell release.

First, by applying continuous light, continuous dark, and jet-lag environmental cue, the authors showed a regularly circadian pattern of haematopoietic stem cells release, through analyzing colony-forming units in culture (CFU-C) and LSK cells (lineage-negative Sca-1 + c-Kit +) from blood. The peak reaches at 5 hour of Zeitgeber time, and nadir lies 17 hour of Zeitgeber time (5 hours after the start point of darkness). This rhythmic oscillation is maintained in total darkness, gets a shift during jet lag, and becomes arrhythmic in continuous light.

Stemming from that Cxcl12 (SDF-1, stromal cell-derived factor-1) is the only known chmokine capable of directed migration of HSCs, they further investigated the impact on Cxcl2 of bone marrow cells in both protein and mRNA expression by manupilating the circadian cycle. The results obeyed the circadian oscillations. But Cxcl12 flatuations mirrored that of HSCs both in protein and mRNA level, which is consistent with current proposed model.

In advance, the authors digged into the relationship between sympathetic nervous system (SNS) and the circadian pattern of HSCs release, plus Cxcl12 expression. Employing the neurochemical sympathectomy approach with 6-hydroxydopamine (6OHDA), the circadian pattern of HSCs by CFU-Cs was abolished. The authors then did surgical sympathectomy by unilateral microsection of both sciatic and femoral nerves. Compared with the sham-operated side, the circadian pattern of Cxcl2 is detroyed in the denervated side.
Moreover, the authors discerned that this Cxcl12 circadian effect is mediated by β3 adrenergic receptors pharmacologically, with series of in vitro bone marrow stromal cells (MS-5) treated by a variety of adrenergic agonists or antagonists.

This is a very decent paper dissecting the circadian oscillation and release of HSC and Cxcl12 expression. However, this raise a question mark in my mind. First, is adrenaline secreted circadianly? To my knowledge, adrenaline from ANS (autonomic nerve system), or any catecholamine, is not secreted in a circadian pattern. They are usually episodic, elevated when needed such as coping stress. What I can think of most, is that ACTH (adrenocorticotropic hormone) is circadian, driving corticosteroid and minerosteroid to be circadian, and may partly act on medulla and contribute adrenaline from adrenal glands to total adrenaline.

Second, neither sciatic nor femoral nerves is pure sympathetic nerve. Denervation of sciatic and femoral nerves will cause far more downstream physiological effects than just sympathectomy. Denervation itself and subsequent biological changes would be a big topic to be explored. I would challenge this model as an evidence to illustrate adrenaline's role on Cxcl12 expression.

Despite the above-mentioned questioning, it is very important to know that release of HSCs is circadian. I believe that such the finding will benefit medicine in application for either chemotherapy or transplantation.

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Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Biomedical Science, Biological Science, Medical Science, Biological Science, Medicine-Haematology, Medicine-Oncology, Medicine-Transplantation, Medicine-Immunology, Medicine-Molecular Biology, Medicine-Molecular Medicine, Medicine-Cell Biology, Medicine-Developmental Biology, Circadian cycle, HSC, HSCs, Haematopoietic stem cell, Jet-lag, Environmental cue, LSK cells, lin - Sca-1 + c-Kit +, Zeitgeber, CXCL12, Cxcl12, chemokines, Cytokines, bone marrow, SNS, sympathetic nerve system, sympathectomy, 6OHDA, 6-hydroxydopamine, sciatic nerve, femoral nerve, tibia denervation, adrenergic receptor, Medicine-Pharmacology, bone marrow stromal cells, MS-5, ANS, autonomic nerve system, catecholamine, ACTH, adrenocorticotropin, corticosteroid, minerosteroid, medulla, adrenal gland, Medicine-Endocrinology, Denervation, Medicine-Neurology, chemotherapy, Medicine-Cancer Biology, adrenaline

Update of Free Museum Admissions Provided by Bank of America

noreply@blogger.com (Wilfred Wu) — Wed, 30 Apr 2008 05:59:00 +0000

As my last post in regard to Bank of America's promotion, here comes the details.

The unexpected change compared to that of last year is, in contrast to one cardholder can get two tickets at the booth last year, this time the free admission is limited to cardholder only. In other words, friends, or children who do not have Bank of America card will need to pay. Thus the event this year, although still a feast to reward their old customers, is more a campaign to drive more people to create financial relationships with them.

As to the participating museums, it has dropped from 95 to 70. Some big famous museums are no longer on the list, but the good side is they spread out to more cities and more states.

I should say, despite the down sides, this is still a decent deal - the first weekend for every month, and last for one full year! So, get it ready with your Bank of America ATM or Debit or Credit Card (disclaimer: Wilfred Wu Wonderland is not affiliated with Bank of America, her holding company[ies], or her subsidiary[ies]), and remember to bring your photo ID. Line up and get a free ticket to enjoy a mindful of arts or science, with no extra charges.

Their official disclosure webpage: http://www.bankofamerica.com/museums

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Free!, Museum, Admission, Admissions, Museum Admission, Museum Admissions, Free Museum Admission, Free Museum Admissions, Bank of America, Bank of America customers, Cardholder, ATM card, Debit card, Credit card

Is Warburg Effect Determined by Embryonic Isoform of Pyruvate Kinase?

noreply@blogger.com (Wilfred Wu) — Fri, 18 Apr 2008 03:27:00 +0000

It has been more than 75 years since Dr. Otto Warburg disclosed the aerobic glycolysis in tumor cells around 1930. This metabolic phenomenon in tumors, seperating it from Kreb's cycle and anerobic fermentation, features high rates of glucose uptake, but low rates of oxidative phosphorylation, with production of lactic acid even in the presense of oxygen. The principles of aerobic glycolysis has been applied to fancy, popular approach to detect cancer recurrence sucha as PET (Positron Emission Tomography) in nuclear medicine contemporarily. Yet there are more to be explored, and potentially there may be more to be exploited in cancer treatment or prevention.

Christofk HR et al. published a paper on Nature last month which likns Warburg's observation to embryonic isoform of pyruvate kinase, M2. It has been known that cancer cells express embryonic M2 isoform of pyruvate kinase exclusively.

The authros first verified this exclusive expression of M2 isoform in cancer tissue by immunoblotting and immunohistochemistry. Then, using short hairpin RNA (shRNA) knockdown in H1299 cells (a human lung cancer cell line), plus rescue by mouse PKM1 (pyruvate kinase M1 isoform) and PKM2 (pyruvate kinase M2 isoform), they revealed that M2 isoform rescues more, in terms of glycolytic rate and replication. Moreover, M2 cells are mroe resistant to hypoxic circumstances, and mitochondrial ATP synthase inhibitor, oligomycin. Even more, ocygen consumption is lower in cells bearing M2 compensation, and lactate production is significantly higer. These findings succesfully connect M2 isoform of pyruvate kinase to Walburg's aerobic glycolysis as a determinant to escape tricarboxylic acid cycle and to enter the pathway for lactate production.

In the meantime, the authors also employed xenograft study on nude mouse by injecting H1299 tumor cells with M1 or M2 expression. This in vivo model resulted in bigger tumor, and more probablity to form tumors by lung cancer cell line bearing mouse M2 isoform vector.

I should say this is not intuitive, or even a violation of my current knowledge of biochemistry and glucose metabolism. Shouldn't the determining factors for entering citric cycle or lactic acid production lie after pyruvate? Are the end product of pyruvate by different isoform of pyruvate kinase different? Or, does pyruvate kinase act after pyruvate formation, and drive them into distinct destiny according to specific isoform? Or, doses the conformation of pyruvate kinase give it the ability to intervene the downstream reaction? (More spatial and temporal questions to be asked)

If we put aside these questions to clarify and make things consistent and focus on the applications, we may also ask how do cells switch from the adult M1 isoform of pyruvate kinase back to embronic M2 isoform? It is known that M2 isoform is a splice variant of M1, and how do we control than?

Although my questions may sound absurd, but I do take the authors' findings very seriously as an important breakthrough in cancer biology with great potential to further study, cancer treatment, and prevention.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]

Tags: Medicine, Medicine-Oncology, Medicine-Cancer Biology, Medicine-Biochemistry, Medicine-Nuclear Medicine, Medicine-Biomedical Science, Medicine-Biological Science, Medicine-Bioscience, Dr. Otto Warburg, glycolysis, Aerobic glycolysis, citric cycle, citrate cycle, Kerb's cycle, TCA cycle, Tricarboxylic acid cycle, Anaerobic fermentation, Anaerobic glycolysis, Lactate cycle, Pyruvate, Pyruvate Kinase, Glucose metabolism, Cancer Cell metabolism, Pyruvate Kinase, M2 isoform, Embryonic isoform, Medicine-Developmental Biology, M1 isoform, Adult isoform, Immunoblotting, Immunohistochemistry, shRNA knockdown, hypoxia, mitochondrial ATP synthase, nude mouse, xenograft study, conformation change

Bank of America to Offer Free Museum Admissions, Again!

noreply@blogger.com (Wilfred Wu) — Sun, 30 Mar 2008 00:15:00 +0000

If you remember my post last year regarding the free admissions to museums provided by Bank of America, it is back again!

Although the detail has not been disclosed officially, but preliminarily there will be free museum admissions for Bank of America customers in 2008. Unlike the one in 2007, which confined the activity throughout but only in May, it is said the free admissions will be granted for the first weekend for several months.

So far we don't know exactly which museum is on the list or which is not. But I love you soooooo much, Bank of America! I am looking forward to the these coming events!

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Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Free!, Museum, Admission, Admissions, Museum Admission, Museum Admissions, Free Museum Admission, Free Museum Admissions, Bank of America, Bank of America customers, Cardholder

Another Example of Immune System Getting Involved in Development - Neurodegenerative diseases may be regarded as autoimmune diseases

noreply@blogger.com (Wilfred Wu) — Tue, 04 Mar 2008 06:03:00 +0000

In addition to my last post in November, 2007, Beth Stevens et al. published a paper on Cell that adds another example of immune system involved in development, also in central nervous system (CNS).

Inspired by the coincidence of dynamic synaptic refinement with appearance of astrocytes in the postnatal brain, and recent evidence indicating a role for astrocyte-derived signals in synapse development, the authors used gene profiling approach to screen candidate retinal ganglion cells (RGCs) genes that are upregulated by astrocytes. RT-PCR confirmed this finding. And further histology studies also verified that C1q is localized to developing CNS synapse in vivo throughout inner plexiform layer (IPL), retinal ganglion cells (RGCs), distal lateral geniculate nucleus (dLGNs). C1q "tag" unwanted CNS synapses as they opsonize pathogen or antibody, pruning of inappropriate synapses. Further, C1q-deficient (C1qKO) mice have defects in this developement shift of synaptic convergence. Without synapse elimination, LGN neurons remain multiply innervated by RGC axons, and they are defective in eye-specific segregation.

On the other hand, they also revealed that the expression of C1q declines as the nervous system mature. These neuronal C1q are downregulated in adult. However, they "revive" again in a mouse model of glaucoma! Their observation showed that C1q overexpress at early stage of glaucoma, prior to overt neurodegeneration.

This paper underscores the role that the immune system may act against "self" in a normal, physiological way in development. Moreover, it highlights hazardous effect when this immune response went too far, shedding a light on that neurodegenerative diseases may be taken as autoimmune diseases. There are quite a lot questions to be asked. In terms of neurology and neurosciene, can this model be broadened from retina and geniculate nucleus to cortex, midbrain or other part of CNS? Are C1q and complement cascade the mechanism how we forget, and how we reshape our memory? Are they also involved in other neurodegenerative disease, say Alzheimer or Parkinsonism? In terms of rheumatology and immunology, are there any other members of immune system participating in this process other than complement system? Although it has been known that steroid can cause glaucoma, but could we treat it, and other neurodegenerative diseases, from the perspective of autoimmune diseases?

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medical Science, Biomedical Science, Biological Science, Bioscience, Medicine-Immunology, Medicine-Rheumatology, Medicine-Neurology, Medicine-Neuroscience, Medicine-Developmental Biology, CNS, Central Nervous System, Medicine-Developmental Biology-Synapse Convergence, Synapse refinement, Synapse elimination, Astrocyte, Medicine-Rheumatology-Autoimmune disease, Medicine-Neurology-Neurodegenerative Disease, Medicine-Immunology-Complement Cascade, C1q, C1qA, C1qB, C1qC, Astrocyte, Glia cells, RGC, RGCs, Retinal ganglion cells, gene profiling, RT-PCR, IPL, inner plexiform layer, LGN, LGNs, Lateral geneiculate nucleus, Medicine-Ophthalmology-Glaucoma, Medicine-Ophthalmmology, Cortex, Midbrain, Memory, Alzheimer, Parkinsonism, Glucocorticoid, Steroid

Prostatic acidic phosphatase (PAP) Enhances HIV Infection

noreply@blogger.com (Wilfred Wu) — Tue, 26 Feb 2008 04:41:00 +0000

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Münch J et al. published a paper regarding how semen can promote the HIV (human immunodeficiency virus) infection on Cell last December. Inspired by the idea that screening of peptide libraries from human body fluids is a useful approach to discover unknown molecules modulating HIV-1 infection, they turned their attention to semen, an indispensible factor in all STDs (Sexually Transmitted Diseases).

Pooling 183 ml of human semen, they purified and obtained fractions by cation-exchange separation, followed by reversed-phase (RP) chromatography. Then each fraction was tested for respective infectivity for HIV-1 by mixing each fraction with HIV virons to infect engineered cell lines expressed CD4 / CXCR4 / CCR5. They found a fraction, which was then further recognized as a segment of PAP (prostatic acidic phosphatase) by mass spectrometry (MS), significantly increase infectivity of HIV.

They found these PAP fragment are active for HIV infection only after the solutions turned turbid either spontaneously or after agitation. Thioflavin T, Congo red staining, X-ray powder diffraction, and even electron microscopy finally clarified that these PAP fragment formed amyloid fibrils. These fibrils, termed SEVI (Semen-derived Enhancer of Virus Infection), was postulated to capture HIV virons, promote viral attachment to the target cell, and hence facilitate viron fusion, with the support of p24 binding assay and direct visualization by microscope or electron microscope.

The paper further revealed that SEVI is a general enhancer of HIV-1 infection, independent of viral genotype or phenotype, and cell type.

This is a decent paper unveiling the role of semen in HIV transmission. On the other hand, instead of exposing semen directly to cells expressing CD4 / CXCR4 / CCR5, I am more curious what role does semen play in getting HIV virons breaking through vaginal mucosal cells. After all, this is the place where body fluids meet in coital acts, and true infection of T cells or dendritic cells can only happen after that.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine-Microbiology, Medicine-Immunology, Medicine-Infectious Disease, Medicine-Urology, Medicine-Biochemistry, Medicine-Urology-Prostate, Medicine-Urology-STDs, Medicine-Infectious Diseases-STDs, HIV, Human Immunodeficiency virus, Medicine-Proteometrics, Semen, Seminal fluid, HIV-1, Body fluids, Sexually Transmitted Diseases, Chromatography, CD4, CXCR4, CCR5, PAP, Prostatic acidic phosphatase, mass mass spectrometry, Thioflavin T, Congo red, X-ray powder diffration, electron microscopy, amyloid fibrils, beta sheet, SEVI, Semen-derived Enhancer of Virus Infection, p24 binding assay, vaginal mucosal barrier, Medicine, Medicine-Biomedical science, Medicine-Biological Science

GABA beyond the Nervous System!

noreply@blogger.com (Wilfred Wu) — Tue, 12 Feb 2008 06:40:00 +0000

A paper by And鄚g M et al. drew my attention, idicating that GABA (gamma-aminobutyric acid) and GABA receptors also play important roles outside the central nervous system.

Published on Nature last month, the authors showed the impact of GABA upon cell proliferation and cell cycle regulation by the following three models: (1) embryonic stem cells, (2) blastocyst cells, (3) neural crest stem cells (NCS). Starting with expression analysis of these cells for GABA receptors, in addition with electrophysiologic studies, they showed hyperpolarization of the cells upon activation of GABAA receptors by GABA agonist. Then, with pharmacological approaches, they observed that the colonies are smaller, there are fewer cells, and more cells stayed in S stage of cell cycle, when GABAA agonist is given. And it is verified by reversing the effect with GABAA antagonist. Genetically, knocking down GABAA receptor also reverses this negative proliferation effect of GABA.

Digging into the molecular level further, the authors revealed that this regulation by GABA and GABAA receptor is dependent on PIKK (phosphatidylinositol-3-OH kinase-related kinase) family of kinases, including ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia Rad3-related), and DNA-PK (DNA protein kinase). It is also contigent on H2AX (Histone H2A). The authors provided evidences of both pharmacological inhibition and genetical knock-down by RNAi.

Therefore, here is the proposed model: GABA or other GABA agonist activate GABAA receptor, inducinghyperpolarization of these stem cells. Subsequently, it signals through PIKK family such as ATM/ATR/DNA-PK, and histone variant H2AX. These S-phase checkpoint kinases thus block the cell cycle at S phase, resulting in sharp decrease of cell proliferation, and an attenuation of progenies in this stem cell niche.

The findings denote a fundamentally different mechanism of proliferation control of stem cells compared to somatic cells. What impressed me more is that, although shown upstreamingly rather than other terminal-differentiated cells, GABA has her role outside the nervous system. Here we see its importance in early development of an organism.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: GABA, gamma-aminobutyric acid, CNS, Central Nervous System, GABA receptor, GABAA receptor, GABA-A receptor, Cl-, Chloride channel, cell proliferation, Med-Neurology, Med-Neuroscience, Developmental Biology, Med-Developmental Biology, ESC, Embryonic Stem Cell, Blastocyst, NCS, Neural Crest Stem Cells, Electrophysiological studies, patch-clamp technique, Med-Cell Biology, Med-Molecular Biology, Med-Pharmacology, Med-Genetics, siRNA, Knock-down, PIKK, phosphatidylinositol-3-OH kinase-related kinase, ATM, ataxia telangiectasia mutated, ATR, ataxia telangiectasia Rad3-related, DNA-PK, DNA protein kinase, H2AX, Histone H2A, Cell cycle, S phase, checkpoint, BrdU staining, 5-bromo-2-deoxyuridine, PI, Propidium iodide

"Dystrophy" - A Mechanism How Tregs Lead Effector T cells to Apoptosis

noreply@blogger.com (Wilfred Wu) — Tue, 29 Jan 2008 02:38:00 +0000

CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) have been well known to regulate immune responses, including suppress effector CD4+ T cells. However, the molecular mechanisms underlie this process is in debate. Pandiyan P. et al. revealed an inetersting perspective on Nature Immunology, which I interpret it as "dystrophy".

First, the authors reconfirmed that Treg cells induce effector T cells apoptosis, in a time-dependent manner, by in vitro assay with coculuture of Tregs and effector T cells.

Further, they showed that additions of cytokines that signal through the common gamma chain, will rescue, though in different degree, this apoptosis effect. Among these the IL-2 (Interleukin 2) has the greatest effect. On the other hand, the authors uncovered that the supernatant of Tregs cocultured with effector Tcells has much less IL-2 concentration than control. They further proved that it was due to Tregs imbibed far more IL-2 than than naive control T cell did, whereas IL-2 expression by effector T cells remained constant at mRNA and protein level in both circumstances.

Before the effector T cells are killed, they had less expression of cytokine receptors CD25 and CD132, indicating impaired positive feedback loop by IL-2.

Meanwhile, the authors also revealed that Bim-deficient effector T cells were completely protected from apoptosis caused by Tregs. Overexpressing Bcl-2 also protected them. These echoes the findings that Bcl-2 inhibit cytokine deprivation-induced apoptosis, and Bim promotes it.

Using scid mice modeled for inflammatory bowel disease, the authors provided more evidences of apoptosis associated with Tregs, although I didn't see they further clarify the point of cytokine deprivation-mediated apoptosis by this approach.

In conclusion, this is an intriguing paper broaching a concept of "nutrition and malnutrition" in cellular level. Short in IL-2, the dystrophic effector T cells finally go apoptosis, which maintain the immune system in a balanced and homeostatic status.
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Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Dystrophy, Regulatory T cell, Treg, Effector T cell, Apoptosis, Survival, CD4+CD25+Foxp3+ Treg, CD4+ T cells, cytokine, common gamma chain, Interleukin, IL-2, IL-2 receptor, cytokine receptor, CD25, CD132, mRNA expression, protein, Bcl-2 family, Bim, Bcl-2, scid mice, IBD, inflammatory bowel disease, nutrition, malnutrition, immune system, autoimmune disease, Medicine-Immunology, Medicine-Molecular Biology, Medicine-Gastroenterology, Medicine-Rheumatology

Cross Validation in Human and Animal Model for Germinal Matrix Hemorrhage

noreply@blogger.com (Wilfred Wu) — Tue, 22 Jan 2008 06:48:00 +0000

There is an interesting paper published by Ballabh et al. on Nature Medicine regarding germinal matrix hemorrhage, one of major pathologies in premature infants that may lead to cerebral palsy, hydrocephalus, and mental retardation.

Starting with gross and microsopic observation of highly vascularization in germinal matrix by neuroanatomy approach, the authors hypothesize the role of VEGF (vascular endothelial growth factor) in the development of germinal matrix.

By autopsy of human infants suffered from premature death or spontaneous abortion, the authors revealed that VEGF, angiopoietin-2, and endothelial proliferation index, are highly increased in germinal matrix, compared to those in the white matter analagen, or cortical mantle. These histological, biological and genetic findings are then validated in rabbit pups, who were delivered pretermly by cesarean section.

Then the authors further extended the experiments for pharmacology with this rabbit model, whose gestational period is around 31 days. Prenatal treatment with COX-2 inhibitor celecoxib decreased VEGF level, decreased angiopoietin-2 level, decreased germinal matrix enthelial proliferation, and substantially decreased the incidence of germinal matrix hemorrhage. On the other hand, prenatal VEGFR2 inhibitor ZD6474 (vandetanib) treatment also reduced the incidence of germinal matrix hemorrhage.

This is a very interesting paper. First, the experiment design successfully cross validated a disease between human and an animal model. Second, employing the validated animal model, the authors soon bridged the pathogenesis and the treatment solutions together. Third, for selection of angiogenic inhibitors, they not only test ZD6474 as most people would do so intuitively, but also celecoxib, a popular, commonly-seen, and well-developed FDA-labelled drug that clinical trial may be at hand.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medicine-Medical Science, Medicine-Biological Science, Medicine-Translational study, Medicine-Translational Biology, Medicine-Biomedical Science, Medicine-Clinical Study, Medicine-Clinical Trial, GMH, Germinal Matrix Hemorrhage, Preterm, Prematurity, Cerebral palsy, Hydrocephalus, Mental retardation, Gross pathology, Microscopic pathology, Medicine-Neurology, Medicine-Obstetrics, Medicine-OBGYN, Medicine-Pediatrics, Medicine-Neuroanatomy, Medicine-Anatomy, Medicine-Pathology, Medicine-Developmental Biology, VEGF, Vascular endothelial growth factor, Autopsy, Spontaneous abortion, angiopoietin, angiopoietin-2, endothelial proliferation index, white matter analagen, cortical mantle, Medicine-Histology, Medicine-Biochemistry, Medicine-Genetics, Rabbit, animal model, Cesarean section, Medicine-Pharmacology, COX-2 inhibitor, Cyclooxygenase-2 inhibitor, celecoxib, Celebrex, ZD6474, vandetanib, VEGFR2 inhibitor, Zactima, Pathogenesis, FDA, Food and Drug Administration

Entosis - Is it involved in intrinsic tumor suppression, and ductular/tubular structure development?

noreply@blogger.com (Wilfred Wu) — Mon, 07 Jan 2008 06:49:00 +0000

Overholtzer M. et al. published a paper on Cell, describing a "cell eats cell" phenomenon, which they named it "Entosis". In contrast to anoikis, this is a non-apoptotic cell clearance mechanisms, characterized by cell-in-cell invasion.

The authors first observed this cellular behavior in tracking the fate of MCF10A cells (human mammary epithelial cells) in suspension cultures. After detachment, they noticed that some of these human mammary epithelial cells are internalized into their neighbor cells. Investigating cells lost of attachement in other cell lines, including ovarian epithelial cells, mesothelial cells, human umbilical vein endothelium cells, human embryonic kidney cells, and other mammary carcinoma cells, showed similar pictures, but the interalization rate varies. This is a whole new process never found in cell biology before, thus they termed it "entosis".

Further studies of entosis revealed that it is independent of those apoptotic processes that can be seen in anoikis. Although loss of attachment is the premise of entosis, cell-cell adhesion is required. Adherens junctions and cadherins and are indispensible for it. The engulfment-internalization requires actin, myosin II, Rho, and ROCK (downstream effectors of Rho signaling) activity. After entosis, the destiny of entraped cell can be either dead, or can be released! How does the engulfed cell be killed? The authors pointed it to lysosomal enzymes degradation.

This "cell eats cell" picture, or from another point of view, "a cell invades into another cell", as the author mentioned, underlies the frequently-seen "cell-in-cell" or "cannibalism" features in pathology or cytology. They also proposed that this may represent an intrinsic tumor suppression mechanism for cells detached from extracellular matrix.

The paper actually begets many questions to be asked in a variety of dimensions. Since the inward growth of the mucosal cells in a ductular or tubular structure is similar to detachement to the basement membrane or extracellular matrix, I am most curious if newly-discovered process involves in the development of hollow lumen in those ductular or tublar tissue.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Entosis, Medicine-Cell Biology, Tumor, Cancer, Development, Duct development, Tubule development, Anoikis, Apoptosis, Non-apoptotic, breast cancer, mammary cell carcinoma, suspension cultures, cell cultures, extracellular matrix, ECM, basement membrane, ovarian epithelial cells, mesothelial cells, umbilical vein endothelial cells, embryonic kidney cells, actin, myosin, Rho, ROCK, cadherin, adherens junction, lysosome, lysosomal enzyme, cell-in-cell, cannibalism, Pathology, Cytology, Medicine-Pathology, Medicine-cytology, Medicine-Developmental Biology, Medicine-Molecular Biology, Medicine-Biomedical Science, Medicine-Medial Science, Medicine-Biological Science

Vision, Light, and Circadian Clock

noreply@blogger.com (Wilfred Wu) — Sun, 30 Dec 2007 07:03:00 +0000

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Since my last post regarding the paper that studied the sleep of the zebrafish, I was keep thinking of the role of light and photoreceptor in our physiological control. There is a paper in Cell focusing on circadian clock, retina, and vision processing.

Storch K-F et al. first confirmed the intrinsic circadian clock of retina, by whole-genome microarray obtained from whole eyes, with the scenario of constant darkness, or 12:12 hr light-dark cycle.

Then using mice lacking Bmal1, either retina-specific or in all tissue, the authors showed that the gene expression rhythm was wildly disturbed, even the light-dark interval was given. This underscored the autonomy of the local intrinsic circadian clock within the eyes.

On the histology aspect, however, the retinas of these mice with either globally or locally targeted Bmal1 gene, appeared structurally normal by light microscopy, and further by electron microscopy.

The authors then turned to electrophysiological studies. Employing electroretinogram (ERG), they found both the Bmal1-deleted mice manifested defective inner retinal electrical responses to light, but the photoreceptor response was normal. This virtually suggests that the intrinsic circadian clock of the retina may be involved in vision processing.

Back to my original question, do zebrafish have intrinsic clock in her eyes? Or it is overwhelmed by the light?

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Circadian Clock, Circadian rhythm, Vision, Environment, Developmental Biology, Neurology, Ophthalmology, Molecular Biology, Physiology, Electrophysiology, Histology, Whole Genome Microarray, Bioinformatics, ERG, Retina, Medicine, Medical Science, Biomedical Science, Biological Science, Medicine-Ophtalmology, Medicine-Neurology, Medicine-Developmental Biology, Medicine-Molecular Biology, Medicine-Genetics

How does zebrafish sleeep?

noreply@blogger.com (Wilfred Wu) — Sun, 23 Dec 2007 06:04:00 +0000

Zebrafish is one of the most important model organisms in biomedical research, and there is an interesting paper on PLoS Biology studying the sleep of zebrafish.

Yokogawa T. et al. used adult fish sleep recording system (AFSRS), a device videotracking fish illuminated by an infrared source under light and dark conditions, to conduct the behavioral studies. They confirmed that, as in humans, zebrafish sleeps, with the characteristics of reversible periods of immobility, increased arousal threshold, and place preference. Similar to the homeostatic regulation in mammals, rest deprivation, by electrical stimulation, is followed by a sleep rebound, but mostly in the dark. However, rest deprivation by the light does not get obvious sleep rebound afterwards. In fact, light supresses sleep in zebrafish, which is very different from human and mammals, but close to birds.

On the molecular aspect, the authors studied hypocretin receptor and hypocretin, the only neurochemical system known to be involved in narcolepsy, a clear human sleep disorder. Using in situ hybridization, they showed that hypocretin receptor (hcrtr) is widely expressed in the brain of zebrafish embryos and adults. However, histologically, her hypocretin receptor does not colocalize with major monoaminergic cell groups in zebrafish embryos and adults. Neither does it colocalized with cholinergic cell groups. In contrast, it colocalizes with large populations of GABAergic neurons, including a subpopulation of Adra2a-positive GABAergic cells in the anterior hypothalamic area, where nervous system meets endocrine system.

Then they went zebrafish with mutation of hypocretin receptor. These fish lacks hypocretin receptor, and behaves disparately: sleep amounts were decreased by 20% - 30% during the night, 60%-70% increase in the number of sleep-wake transitions, 60% decrease in sleep bout length during the night. In short, hcrtr null mutant fish has short and fragmented sleep.

The authors further employed pharmalogical approaches by intracerebralventricular injection of hypocretin. Injection of hypocretin-2 was inactive due to rapid metabolism. On the other hand, injection of hypocretin-1 begets reduction in locomotor activity, which is dose-dependent. This effect in wild type zebrafish, as imagined, is abolished in hcrtr null mutant.

It seems the endpoint presentation of zebrafish lacking hypocretin receptor is contrary to narcolepsy in human. The pharmalogical outcome of hypocretin is right opposite to that in mammals, which promotes wakeness and increases locomotion. In regard to neuroanatomy, hypocretin receptor in zebrafish colocalizes with inhibitory neurons, rather than stimulating cell groups in mammals. I would like to quote the authors' words, this indicates "molecular diversity in sleep regulatory networks across vertebrates".

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]

Tags: zebrafish, model organism, developmental biology, sleep disorder, insomnia, narcolepsy, neurology, behavior biology, molecular biology, hypocretin, narcolepsy, orexin, hypocretin receptor, histology, hcrtr, hypocretin-1, hypocretin-2, HCRTR, pharmacology, hypothalamus, monoamine, monoaminergic, catecholamine, cholinergic, GABA, GABAergic, intracerebralventricular, evolution, conserved, diversity, phylogenesis, Medicine, Medicine-Molecular Biology, Medicine-Developmental Biology, Medicine-Behavior Biology, Medicine-Pharmacology, Medicine-Histology, Biomedical Science, Medical Science

Toll-like receptor 4 and alarmin high-mobility-group box 1 are essential to activate immune system after chemotherapy and radiotherapy for cancers

noreply@blogger.com (Wilfred Wu) — Sat, 15 Dec 2007 20:36:00 +0000

Immunotherapy for cancer, such as for renal cell carcinoma, has been taken as one of therapy of choice for a long time. The article from Apetoh L. et al. in Nature Medicine provided a molecular perspective of this clinical phenomenon.

Stemming from the paper of Casares N. et al. on The Journal of Experimental Medicine in 2005, they tried to explored how tumor cell death can induce an antitumor immune response. They hypothesized toll-like receptors to mediate this response. The reason for this hypothesis was not specified, but I would do the same! By exposing bone marrow-derived dendritic cells (BM-DCs) to dying ovalbumin-expressing EG7 mouse thymoma cells treated with either oxaliplatin or radiation, they found toll-like receptor 4 (TLR4) is indispensible to this immune reaction.

Moreover, they found the ligand, too. Among a variety of endogenous ligands for TLR4, like heat-shock protein 60 (HSP60), heat-shock protein 70 (HSP70), oxidized LDL, surfactant protein A, hyaluronan breakdown products, fibronectin, beta-defesin-2, and alarmin high-mobility-group box 1 (HMGB1), HMGB1 stands out in the supernatants of dying ovalbumin-expressing EG7 mouse thymoma cells or CT26 colon cancer cells treated with radiation or doxorubicin. Further immunological approaches and siRNA knock-down experiments confirmed that HMGB1 is also indispensible to initiate the immune activity. This is also shown in dying MCA205 sarcoma cells.

The findings underscore the clinical observation that patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy or chemotherapy. These Asp299Gly TLR4 mutation did affect the binding of HMGB1 to TLR4.

However, I don't understand in this scenario, how cytotoxic T-lymphocytes work after the activation of toll-like receptor pathway. It is shown that HMGB1 is not presented on the cellular membrane, but in whole cell lysate or supernatant only. To make it short, what is the signal for those membrane is intact?

On the other hand, this article made me think of those autoimmune disease. Is this dying cell model relevant to the molecular mechanism of those autoimmune disease?

Promoting cancer cells metastasis - The role of mesenchymal stem cells

noreply@blogger.com (Wilfred Wu) — Sun, 25 Nov 2007 03:10:00 +0000

Inspired by the proposal that bone-marrow-derived mesenchymal stem cell is a cell type that is recruited in large numbers to the stroma of developing tumors, Karnoub AE et al. designed a series of experiments and published them on Nature last month.

Using a transwell assay, they first showed a much more avid migration of mesenchymal stem cells towards breast cancer cells than the control media with a 11-fold. In addition, green fluorescent protein-labelled mesenchymal stem cells infused into the venous circulation of mice localized specifically to the growing tumors.

Then the authors mixed these mesenchymal stem cells with several breast cancer lines, and injected into the subcutaneous tissue of immunocompromised mice as a xenograft. That resulted in a marked increase in the numbers of micro-metastases and macro-metastases in lung. However, only one out of three breast cancer cell line (MCF7/Ras) accelerated primary tumor growth.

To understand the crosstalk between breast cancer cells and mesenchymal stem cells, the authors further screened the levels of various cytokines, chemockines, and growth factors within the conditional media. They revealed that CCL5 (also called RANTES) was the only one that expressed synergistically upto 60 fold. Reduced CCL5 expression by short hairpin RNA (shRNA), and neutraliztion of CCL5 by anti-CCL5 monoclonal antibodies, did efface the metastasis capability of tumor cells. Further they came to the major receptor of CCL5, CCR5. Empolying the approaches of knocking down CCR5 with shRNA, the enhanced metastasis was abrogated.

Collectively, the authors demonstrated the role of mesenchymal stem cells to promote lung metastasis in this artificial in vitro mixing - in vivo xenografting model. And the molecular mechanism relies on CCL5 and CCR5 cross talk.

Nevertheless, it is puzzling to me that the recruitment part is not consistent. The authors said the enhanced metastasis ability of breast cancer cell by mesenchymal stem cells cannot be reproduced if they are not commingled, such as injected to contralateral or nearby separate sites. Something is missing here. Are these mesenchymal stem cells recruited to the tumors? How about those successfully recruited by intravenous injection? Are metastasis enhanced in mice intravenously injected with mesenchymal stem cells compared to those are not injected?

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medical Science, Biomedical Science, Biological Science, Medicine-Oncology, Medicine-Pathology, Medicine-Haematology, Medicine-Immunology, Medicine-Cancer Biology, Medicine-Developmental Biology, Medicine-Developmental Biology-Stem cells, Medicine-Cancer Biology-Metastasis, Medicine-Immunology-cytokines, Medicine-Immunology-cytokines-chemokines, C-C chemokines, beta-chemokines, C-C motiff chemokines, CCL5, CCR5, Recruitment, Epithelial-to-mesenchymal transition, EMT

Toll-like receptors mediate neurogenesis

noreply@blogger.com (Wilfred Wu) — Sat, 17 Nov 2007 19:32:00 +0000

Here is another study of toll-like receptor (TLR) in central nervous system, but compared with the previous post, it is focused on development - the neurogenesis process of neural stem/progenitor cells, in one of adult brain neurogenic niche, subgranular zone of hippocampal dentate gyrus.

Rolls et al. started with histology approaches. Immunostaining revealed TLR2 expression in subgranular zone of the hippocampal dentate gyrus. Using TLR2-deficient mice, they found neural stem/progenitor cells tend to differentiate into astrocytes rather than neurons relative to their wild-type controls, whereas oligodentrocytes linage seemed unchaned. In contrast, ligands of TLR2, such as peptidoglycan (PG) and lipopeptide Pam3CysSK4 (P3C), promote differentiation of neural stem/progenitor cells in a dose-dependent manner, and TLR-2 neutralizing antibodies can reduced their effects.

Downstreamingly, they inhibited the major adaptor of TLR, MyD88 (Myeloid Differentiation primary response protein 88), which showed reduced effects of TLR2 ligands. Further more, applying NF-kappaB inhibitors also markedly decrease the neuronal differentiation.

Then the authors turned to TLR4. However, they manifested opposite effect to that of TLR2. Using ligands of TLR4, ultra-purified lipopolysaccharide, neural differentiation were inhibited. In contrast, applying small interfering RNA (siRNA) targeting TLR4 yielded increase in differentiation. TLR4-deficient mice were consistent with this enhanced neural differentiation.
They further suggested MyD88-dependent and MyD88-independent pathways are involved in neural stem/progenitor cells activation by TLR4.

Although not specified in the methods, the authors employed a "mixture" of specific neutralizing antibodies against both TLR2 and TLR4, which resulted in increase in both self-renewal and neuruonal differentiation of neural stem/progenitor cells. MyD88-deficient mice have enhanced neural differentiation. Thus they suggested TLR4 has prediminant effects of TLR2.

Combined with the article dicussed in my last post, toll-like receptors play their role far beyond immune system. Moreovoer, their expression in central nervous system at different stages of cells and different locations, have distinct effects, via disparate pathways. Both studies did not recognize the specific ligans for their experiments. However, they provided a hint that bridges apoptosis, cell fate determination, and differentiation to immune response, either to extrinsic microbes, or to intrinsic compound, which sheds a light on pathogenesis on some human diseases.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medicine-Developmental Biology, Medicine-Pathology, Medicine-Immunology, Medicine-Neurology, Medicine-Histology, Medicine-Genetics, Medicine-Molecular Biology, Bioscience, Biomedical Science, Toll-like receptor, MyD88, NF-kappaB, TLR2, TLR4, Differentiation, Cell fate

Toll-like receptors are expressed on neurons, and mediate hypoglycemic, ischemic, and reperfusion injury

noreply@blogger.com (Wilfred Wu) — Sun, 11 Nov 2007 05:54:00 +0000

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Inspired by the findings that neurons may express at least some Toll-like receptors responsive to viral RNA or bacterial proteins, with some other studies indicating that Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) are upregulated in response to ischemia in the kidney and heart, Tang et al. set off experiments and published the paper on Proceedings of the National Academy of Sciences (PNAS) this August.

In neuron cells, expression of mRNA and positive immunoblot of TLR2, TLR3, and TLR4 confirmed that TLR are expressed on neurons. This expression, as that in microglia cells or others within the immunological system, can be enhanced by interferon-alpha.

Then starting with gene-targeting technique, they found that cultured neurons deficient in TLR2 or TLR4 are resistant to glucose starvation. Downstreaminly, they discovered that these cultured but glucose-deprived neurons deficient in TLR2 or TLR4 exhibit no change response for JNK, and reduced AP-1 DNA-binding activity, compared to robust increase response for wild type cells. Glucose deprivation also resulted in much temperate response in activated (cleaved) caspase-3 for neurons deficient in TLR2 or TLR4. On the other hand, no differences were observed for NF-kB.

Furthermore, they broaden the discoveries in glucose starvation experiment to ischemia and reperfusion mouse model. Stroke-induced brain damage area and clinical neurological deficits, were significantly less in the TLR2 knockout mice and the TLR4 mutant mice compared with wild type controls.

In summary, the authors proposed a proapoptotic signaling pathway for TLR2 and TLR4 in neuron cells. However, I would argue the continuous glucose starvation method, and ischemia-reperfusion model which occluded middle cerebral artery transiently, are different kinds of injury. Thus it may be interesting to study if these two different mechanisms merge together before TLR2 and TLR4. To make the question simpler, what is the ligand, or what are the ligands, of TLR2 and TLR4, under these experimental circumstances?

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine-Immunology, Medicine-Neurology, Medicine-Molecular Biology, Glucose starvation, Glucose deprivation, Ischemia Injury, Reperfusion Injury, I/R Injury, Toll-like receptor, TLR, TLR-2, TLR-4, Peptidoglycan, Lipopolysaccharide, Endotoxin, JNK, AP-1, Innate Immunity, Stroke

Molecular Mechanism for Itch Sensation

noreply@blogger.com (Wilfred Wu) — Sun, 28 Oct 2007 06:05:00 +0000

In a paper published on Nature a few months ago, Sun et al. revealed that gastrin-releasing peptide, and gastrin-releasing peptide receptor, play important roles in mediating itch sensation, or pruitis.

The authors got their idea from the findings that intracerebral administration of bombesin in rodents can elicit grooming behavior, suggeting bombesin is a mediator of pruitis. And gastrin-releasing peptide receptor, is in fact a mammalian homologue of amphibian bombesin-like peptide receptor.

By immunohistochemistry, they showed that gastrin-releasing peptide is specifically expressed in a small subset of peptidergic dorsal root ganglion neurons, colocalized with unmyelinated fibers, peptidergic markers CGRP, and substance P. These neurons also express TRPV1 (The vanilloid receptor subtype 1). Other other hand, gastrin-releasing peptide receptor is expressed in lamina I of the dorsal spinal cord.

For in vivo study, they found the scratching behabior was significantly reduced in gastrin-releasing peptide receptor mutant mice, whereas normal pain response was preserved. In addition, intrathecal injection of gastrin-releasing peptide receptor antagonist significantly inhibited scratching behavior.

This paper brought me to think of the over-grooming behavior in homeobox B8 (HoxB8) knock-out mice. Is this "over-grooming behavior" related to itch sensation? Are homeobox B8 and gastrin-releasing peptide receptor related? Moreover, the molecular mechanism broached by the authors is quite similar to the pathophysiology of some frequency-urgency syndrome such as interstitial cystitis, with manifestation of overactive bladder. Can these LUTS (lower urinary tract syndrome) be considered as a kind of itch sensation? However, the knowledge we have known about this LUTS (lower urinary tract syndrome) is basically in bladder mucosa. Therefore I wonder if the findings in central nervous system can be found in peripheral level, or vice versa.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Itch sensation, Prutitis, gastrin-releasing peptide receptor, bombbesin-like receptor, C-fiber, DRG, dorsal root ganglion, dorsal column of spinal cord, central nervous system, spinothalamic lamina, vanilloid receptor, LUTS, lower urinary tract syndrom, overactive bladder, frequency-urgency syndrom, interstitial cystitis, over grooming behavior, Hox B8 gene, Homeobox B8 gene, Medicine, Medicine-Dermatorlogy, Medicine-Neurology, Medicine-Psychiatry, Medcicne-Urology, Medical science, Biomedical Science, Medicine-Molecular Biology, Medicine-Pathology, Medicne-Histology, Medicine-Genetics

Diet As a Selection Pressure in Our Genome - An Example of Amylase Gene Copy Number Variation

noreply@blogger.com (Wilfred Wu) — Fri, 19 Oct 2007 04:43:00 +0000

There is an intriguing paper on NATURE GENETICS this month, which covered across genetics, evolution and anthropology.

Based on extensive variation in copy number of human salivary amylase gene (AMY1), George H. Perry et al. digged it further to study the relation between this copy number variation and amylase concentration in our saliva. The results is pretty intuitive, they are positively correlated. Moreover, and what is astonishing, the authors linked this genetic and proteometric findings to our food, suggesting it as a positive selection in human's evolution.

They revealed that population with high starch consumption, which is characterized by agricultural societies or hunter-gathers in arid environments, has more copies of human salivary amylase gene. In contrast, rainforest and circum-arctic hunter-gatherers, and some pastoralists, whose starch consumption in their food is traditionally much less, have fewer copy number of AMY1 gene.

As the comments by John Novembre et al., "Adaptive drool in the gene pool", it is amazing to find out shifting to domestication life style and starch-rich diet in some population can play a role of gene selection in human evolutionary history, especially the way it involved is the variation of the copy number of the gene. So, besides the disease such as fragile X syndrome and Huntington's disease, the copy number of a gene also contributed to adaptation of human beings!

It would be interesting to study the presentation of other digestive enzymes. For example, is pancreatic amylase level consistently higher in high starch consumption population, or are pepsin, trypsin, chymotripsin or other protein-degrading enzymes lower? Instead of agricultural revolution, is industrial revolution, or recent information revolution, posing any selection pressure upon our genome? Are we able to recognize it even its advent is relatively a latter-day impact and duration may not be long enough?

On the other hand, it may be instinctive that higher concentration of salivary amylase has more powerful function. But what if there is gene polymorphism in AMY1? Maybe the low concentration of salivary amylase in low-starch diet population is as potent as those high concentration amylase in population with starch-rich diet. It would be helpful to run a functional assay to verify that.

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Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medicine-Genetics, Medicine-Evolution, Medicine-Anthropology, Medicine-Genetics-Gene Copy Number Variation, Medicine-Genetics-Polymorphisim, Medicine-Proteometrics, Medicine-Biochemistry, Biomedical Science, Biological Science, Medical Science, Salivary amylase, AMY1, Fragile X syndrome, Huntington's disease

2007 Nobel Prize in Medicine or Physilogy Went to Gene Knockout Scientists

noreply@blogger.com (Wilfred Wu) — Wed, 10 Oct 2007 01:30:00 +0000

On Monday, October 8, 2007, the Nobel Assembly at the Karolinska Institute, Stockholm, Sweden, announced Dr. Mario R. Capecchi from University of Utah, Dr. Martin J. Evans from Cardiff University, Wales, United Kingdom, and Dr. Oliver Smithies from University of North Carolina at Chapel Hill, the laureates of 2007 Nobel Prize in Medicine or Physiology, "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells".

The trio of scientists are already well-known and highly revered in the community of biomedical science for their discoveries of embryonic stem cells, homologous recombination, and their applications in gene targeting to render gene-knokout mice of any kind that has boosted the understanding in genetics since its debut. The impacts of their groundbreaking works had been recognized by 2001 Lasker Award. And as we can visualize, their breakthroughs will continue to benefit biomedicine studies over many years to come.

This is the second year in a roll that scientists in molecular genetics won the Nobel Prize for Medicine or Physiology. Last year, it awarded Dr. Andrew Z. Fire and Dr. Craig C. Mello, for their discovering RNA interference, and its application in gene knock-down.

Many commentaries said the award is long overdue for Dr. Capecchi, Dr. Evans, and Dr. Smities. Citing Nobel Committee, "Gene targeting in mice has pervaded all fields of biomedicine", I would like to join many others to appreciate them to bring this powerful "magic wand" to the world, kindling light and hope to biomedical research and all mankinds. Congratulations!

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Nobel Prize in Medicine or Physiology, Nobel Assembly at the Karolinska Institute, Dr. Mario R. Capecchi, University of Utah, Dr. Martin J. Evans, Cardiff University, Dr. Oliver Smithies, University of North Carolina at Chapel Hill, embryonic stem cells, biomedical science, homologous recombination, gene targeting, gene knokout mice, genetics, 2001 Lasker Award, biomedicine, molecular genetics, Dr. Andrew Z. Fire, Dr. Craig C. Mello, RNA interference, gene knock-down, magic wand, Congratulations!

Is Developmental Biology the Great Tutor of Tumor Studies?

noreply@blogger.com (Wilfred Wu) — Sat, 29 Sep 2007 05:51:00 +0000

This is the paper published by Hutchin et al. on GENES & DEVELOPMENT. Employing bitransgenic mice with tetracycline controlled transcriptional activation system to express Gli2, the downstream effector of Hedgehog signaling pathyway, they found that basal cell carcinomas of skin, of which nearly all arose from the cutaneous epithelial stem cell harbored in hair folicles, regressed when the trangene was off. In turns, these "silent" tumor reversed their behavior from an increased apoptosis, reduced proliferation status to a malignant appearace upon the transgene was on. Thus they concluded that constitutive Hedgehog signaling drives the development of basal cell carcinomas, and is required to maintain the proliferation and survival of these established BCCs.

Given the knowledge that Hedgehog signaling is indispensable during development for proliferating hair follicle epithelium, and during postnatal hair cycles, though in a temporally and spatially contrained fashion like anagen (growth phase) - catagen (regression phase) - telogen (resting phase), they reiterate that these tumors represent an aberrant form of follicle organogenesis. Their findings did underscore the concept of cancer as a disease of errant organogenesis stemming from defects in critical "developmental" signaling pathways.

William Harvey once said, "Medicine is the great tutor of biology." These inspired me to thinking that "Developmental biology may be the great tutor of tumor studies!"

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medicine-Developmental Biology, Medicine-Oncology, Tumor, Cancer, Biomedical Science, Medical Science, Biological Science, Basal Cell Carcinoma, Hedgehog signaling pathway, Hair follicle, Stem cell, BCC, Medicine-Molecular Biology, Medicine-Molecular Cell Biology

Wnt Signaling: The Killer of Fountain of Youth?

noreply@blogger.com (Wilfred Wu) — Sat, 15 Sep 2007 03:57:00 +0000

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Brack et al. published an intriguing paper last month. Employing a "parabiotic system" on mice stem cells, they infer that Wnt signaling is the key to aging, a killer of fountain of youth.

The first fantastic idea in this paper is the "parabiotic system", in which the mice stem cells are exposed to either isochronic or heterochronic serum. This is an intuitive concept I had been conceiving before, but I was afraid of it being too quixotic. Nonetheless, there they are, a paper on Science!

By means of discerning fibrous tissue from myogenic progenitor, they deduce that youthful serum promotes the regeneration potential, while aged serum tends to transform these tissue into collagen deposition.

Furthermore, what is more astounding, the authors correlated this to Wnt signaling. They measured Axin2, GSK3b (glycogen synthase kinase 3b), and b-catenin, which presented a profile indicative of active Wnt signaling in aged muscle. They even dig the Wnt cascade more by adding agonist Wnt3A, inhibitors Dickkopf-1 (DKK1) and sFRP3 (Frizzled-related protein 3). All these resulted in accordance with each other that initiating Wnt pathway will accelerate myogenic-to-fibrogenic conversion.

The turn from the finding of parabiotic system to Wnt signaling actually bewildered me a lot. How did they come up with this idea? The shift of the thinking process was not depicted explicitly in the article. For me, I would opt for comparing the constituent between young and old serum first, rather than go downstream to study signal pathways.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medical Science, Bioscience, Biomedical Science, Biological Science, Medicine-Aging, Medicine-Molecular Biology, Medicine-Developmental Biology, Medicine-Developmental Biology-Stem Cells, Medicine-Pharmacology, Medicine-Physiology, Medicine-Pathology, Youth, Fountain of Youth, Muscle, Fibrosis, Wnt Signaling, Wnt Pathway

"Resident" Monocytes Patrol Blood Vessels and Respond Earlier than PMN

noreply@blogger.com (Wilfred Wu) — Sun, 09 Sep 2007 02:31:00 +0000

Using intravital confocal microscope, Auffray et. al observed the behavior of the Gr1-, CX3CR1+ monocytes in Cx3cr1 gfp/+ mice and Rag2-/-, γc -/-, Cx3cr1 gfp/+ mice. In the paper they published on Science, they pointed out that these monocytes are, not only rolling along endotehlium as PMNs or lymphocytes do, but crawling to and fro in the blood vessels, even against the blood stream!

In addition, they exerted the inflammation model by exposure to irritants, aseptic wounding, and peritoneal infection with Listeria monocytogenes. As it turned out, these monocytes diapeded and invaded the surrounding tissue pretty soon within one hour, and peaked at the second hour, at the time when PMNs are only beginning to enter the peritoneum, and several hours before Gr1+ monocytes start extravasation.

Although how the monocytes sense the inflammation remains obscure, their ascertainment is shocking enough. First, they illuminated that Gr1- monocytes are the first immune cells arrived in response to inflammation, so far. Moreover, they have unveiled a counterintuitive pattern of motility of "patrolling" in these cells. As they furthered clarified, the movement is dependent upon CX3CR1 and integrin LFA-1.

What else cells can travel against blood stream? Mmm, interesting, sperm, perhaps, though they normally do not enter blood circulation. Contingent on its flagellum powered by a mitochondrion, the sperm actually bears the potential to speed up to more than 100 µm/s, much faster than the average 12µm/min of Gr1- monocytes found in this paper. With no integrin or chemokine receptor (or maybe they do?), is sperm able to swim upstream?

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medical Science, Medicine-Heamatology, Medicine-Haematology, Medicine-Immunology, Medicine-Urology, Medicine-Urology-Andrology, Medicine-Biochemistry, Medicine-Molecular Biology, Monocyte, PMN, Lymphocyte, Medicine-Pathology, Inflammation, Integrin, Chemokine, Chemokine Receptor, Sperm, Sperm speed, Immune Response, Immunity

Breaking News - Spare the Air Day Tomorrow (Wednesday, Aug 29, 2007)!

noreply@blogger.com (Wilfred Wu) — Wed, 29 Aug 2007 06:07:00 +0000

Attention! For those who live in San Francisco Bay area, this is the message for you.

Bay Area Air Quality Management District (BAAQMD) has announced that tomorrow, Wednesday, Aug 29, is a Spare the Air Day! This denotes the first Spare the Air Day this year.

The declaration can be interpreted in neutral from both good and bad sides.

On one hand, transit by participating public transportation agencies will be free tomorrow. What is to be mentioned, compared to all-day-free last year, restriction has been implemented to riding on BART, CalTrain, ACE train, and all participating ferries, which confines the complimentary time from 5 AM to 1 PM.

On the other hand, however, this indicates that the air quality will be poor tomorrow. It has nothing to do with carbon dioxide emission, or global warming issue that some people may bicker with, but the Air Quality Index (AQI) that BAAQMD employed is based on federal standards. Since United States did not signed Kyoto Protocol, carbon dioxide is categorically not on the list. The major pollutants taken into consideration are ozone, carbon monoxide, nitrogen dioxide, sulfur dioxide, and particles, which comprise the orthodox concept of "smog". For patients with atopy or hypersensitivity problems, especially asthma, this is virtually an alert.

So, I would encourage you to take the incentive of free ride - not to drive tomorrow. You can also plan to exploit it moreover with a free trip around bay area, but PLEASE be scrupulous not to produce any extra contamination as if there were no such perks. In addition, for salutary reason, you had better be shrewd enough to shun the area with AQI exceeds 100.

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Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine-Rheumatology, Medicine-Pediatrics, Medicine-Environmental Medicine, Medicine-Rheumatology-Atopy, Medicine-Rheumatology-Asthma, Medicine-Environmental Health, Medicine-Public Health, Medicine-Environment Protection, Medicine-Conservation, Medicine-Environmental Protection-smog, Medicine-Environmental Protection-ozone, Medicine-Environmental Protection-carbon monoxide, Medicine-Environmental Protection-nitrogen dioxide, Medicine-Environmental Protection-sulfur dioxide, Medicine-Environmental Protection-particles, Medicine-Chest, Air Quality, AQI, Kyoto Protocol, UNFCCC, carbon dioxide, global warming, public transportation, free, BART, CalTrain, ferry, San Francisco Bay Area

In terms of embryology, parathyroid glands are, at least two disparate glands!

noreply@blogger.com (Wilfred Wu) — Tue, 28 Aug 2007 04:47:00 +0000

I happened to go through the development of parathyroid gland when reviewing human embryology recently. As to the question I broached in "Parathyroid Glands are Four Different Glands? ", actually there was unique perspective from the standpoint of embryology.
The inferior parathyroid glands are derived from the third pharyngeal pouches, whereas the superior inferior parathyroid glands are stemmed after the forth pharyngeal pouches.
By the sixth week, epithelia of the solid parts originated from the third pharyngeal pouches (the dorsal bulbar portions), begin to be severed from pharynx, and differentiate into inferior parathyroid glands. Undoubtedly at this moment, the "inferior" parathyroid glands are cephalic than the "superior" parathyroid glands. As the epithelia of the hollow parts beget from the third pharyngeal pouches ( the ventral hollow portions) obliterate their cavities, and turn to be thymus tissue, both scions of the third pharyngeal pouches descend, to an extreme that make the inferior parathyroid glands genuinely inferior.
In regard to the superior parathyroid glands, they are transformed from the dorsal portions of the forth pharyngeal pouches in contrast. Also undergoing similar process to be separated from pharynx, to differentiate, and to migrate caudally, they just stop on the thyroid and don't go any further. Thus they bear the name of "superior" thyroid gland, from the standard of anatomy.
I should say with candor that we don't remember everything we've learned. It is really nice to review the books we have read before. Not only it may to help us pick up old stuff, but also incite new ideas.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medicine-Embryology, Medicine-Developmental Biology, Medicine-Anatomy, Medicine-Endocrinology, Medicine-Urology, Medicine-Nephrology, Medicine-Endocrinology-Hyperparathyroidism, Medicine-Urology-Urolithiasis, Medicine-Nephrology-ABG and Electrolytes, Kidney, Kidney stone, Hypercalcemia, Calcium, Elctrolytes Imbalance, Pharyngeal pouch, Pharyngeal arch, Pharynx, Thymus, Thyroid, Mesoderm, Endoderm

Nanobacteria - Fact or Fiction?

noreply@blogger.com (Wilfred Wu) — Tue, 21 Aug 2007 02:45:00 +0000

The earthshaking discovery of Helicobacter pylori as the pathogen of gastric ulcer has edified many medical scientists. Imputing a disease to a known or unknown pathogen becomes a popular, and intuitive speculation. Nanobacteria is one of these.

Notwithstanding its controversiality, nanobacteria, or we should rephrase it as calcifying nanoparticles, have been reported to be associated with several diseases. This purported 2-5 nm particle, bearing the feature to form calcium phosphate crystal at neutral pH, has been related to Alzheimer's disease, atherosclerosis, calciphylaxis, chronic pelvic pain syndrome, gall stones, malignance microcalcifications in breast cancer, periodontal diseases, polycystic kidney disease, and urolithiasis.

There is even a novel comination regimen called "ComET", compriseseds tetracycline, a nutraceutical, and EDTA, demonstrating decreased coronary artery scores in CAD patiens, and improved symptoms scores in CPPS patients.

Although it still sounds like a folklore to me, the concept did provide a fascinating point of view to unravel the dilemma we encountered in well-accepted pathophysiology, at least for urolithiasis. Yet I have disparate "imagination" of this concept, awaiting further clarification.

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Medicine-Microbiology, Medicine-Biochemistry, Medicine-CellBiology, Medicine-Urology, Medicine-Nephrology, Medicine-Cardiology, Medicine-Gastrointestinology, Medicine-Hepatology, Medicine-Neurology, Medicine-Physiology, Medicine-Dentistry, Medicine-Pharmacology, Medicine-Cardiology-CoronaryArteryDisease, Kidney, Helicobacter, H.pylori, Gastric ulcer, Medicine-Microbiology-Antibiotics, Nanobacteria, Calcifying nanoparticles, Calcium Phosphate, Apatite, Alzheimer Disease, Atherosclerosis, Calciphylaxis, Medicine-Immunology, Chronic Pelvic Pain Syndrome, CPPS, Gall bladder stone, Medicine-Oncology, PCKD, Tetracycline, EDTA