In The Name Of God
The Books That Authored And Translated by
Edited by:Mohammad Hezarkhani MD,Urologist
Board-Certified of Urology,Tehran University ,The Member of Iranian Urological Association
Madaen Hospital Tehran Iran
Tehranclinic Hospital Tehran Iran
www.Hezarkhani.blogfa.com hosted in Washington DC, United States
AEG-1 is involved in HIF-1alpha mediated angiogenesis. AEG-1 also interacts with SND1 and involved in RNA-induced silencing complex (RISC) and plays very important role in RISC and miRNA functions. AEG-1 induces an oncogene called Late SV40 factor (LSF/TFCP2) which is involved in thymidylate synthase (TS) induction and DNA biosynthesis synthesis. Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).
AEG-1 acts as an oncogene in melanoma, malignant glioma, breast cancer and hepatocellular carcinoma. It is highly expressed in these cancers and helps in progression and development of these cancers. It is induced by c-Myc oncogene and plays very important role in anchorage independent growth of cancer cells.
Elevated expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers, is associated with poor clinical outcomes. MTDH has a dual role in promoting metastatic seeding and enhancing chemoresistance. MTDH is therefore a potential therapeutic target for enhancing chemotherapy and reducing metastasis.
LSF/TFCP2 plays multifaceted role in chemo resistance, EMT, allergic response, inflammation and Alzheimer’s disease. AEG-1 controls many hallmarks of oncogenes and cancer. AEG-1/MTDH induces hepato steatosis in mouse liver. The MTDH knockdown by artificial microRNA interference functions as a potential tumor suppressor in breast cancer. Astrocyte elevated gene-1/MTDH undergoes palmitoylation in normal and abnormal physiology of the cell .The microgrooved biomaterial titanium substrata can alter the expression of AEG-1 in human primary cells .
In particular, the degree to which MTDH may contribute to malignant progression in vivo is lacking. Here,researchers report that MTDH is amplified frequently in human prostate cancers where its expression levels are tightly correlated with prostate cancer progression and poor disease-free survival.
Furthermore, studies show that genetic ablation of MTDH in the transgenic adenomcarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer blocks malignant progression without causing defects in the normal development of the prostate. Germline deletion of Mtdh in TRAMP mice prolonged tumor latency, reduced tumor burden, arrested progression of prostate cancer at well-differentiated stages, and inhibited systemic metastasis to distant organs, thereby decreasing cancer-related mortality ∼10-fold. Consistent with these findings, direct silencing of Mtdh in prostate cancer cells decreased proliferation in vitro and tumor growth in vivo, supporting an epithelial cell–intrinsic role of MTDH in prostate cancer.
Together, the findings establish a pivotal role for MTDH in prostate cancer progression and metastasis and define MTDH as a therapeutic target in this setting.
1- Genetic Ablation of Metadherin Inhibits Autochthonous Prostate Cancer Progression and Metastasis
Liling Wan1, Guohong Hu1,2, Yong Wei1, Min Yuan1, Roderick T. Bronson3, Qifeng Yang4, Javed Siddiqui5, Kenneth J. Pienta6, and Yibin Kang1,7,*1Department of Molecular Biology, Princeton University, Princeton, New Jersey. 2Institute of Health Sciences, Shanghai, China. 3Department of Pathology, Harvard Medical School, Boston, Massachusetts. 4Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong Province, P.R. China. 5Department of Pathology, University of Michigan, Ann Arbor, Michigan. 6Department of Urology and Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland. 7Tumor Progression and Genomic Instability Program, The Cancer Institute of New Jersey, New Brunswick, New Jersey. Cancer Res; 74(18); 5336–47. ©2014 AACR. June 29, 2014. ©2014 American Association for Cancer Research
2- protein LYRIC or astrocyte elevated gene-1 protein/ Wikipedia, the free encyclopedia/ 4 August 2014
1 An open-label, phase 2 trial of bicalutamide dose escalation from 50 mg to 150 mg in men with CAB and castration resistance. A Canadian Urology Research Consortium Study Prostate Cancer & Prostatic Diseases, September 15, 2014
6 Change in the risk stratification of prostate cancer after Slide Review by a uropathologist: The experience of a reference center for the treatment of prostate cancer Full Text International Braz J Urol, September 15, 2014
14 The cost of photoselective vaporization of the prostate compared to transurethral resection of the prostate: Experience in a large public Australian teaching centre Journal of Clinical Urology, September 15, 2014
18 Use of the probability of stone formation (PSF) score to assess stone forming risk and treatment response in a cohort of Brazilian stone formers Full Text International Braz J Urol, September 15, 2014
19 Transurethral resection of fibrotic scar tissue combined with temporary urethral stent placement for patients with in anterior urethral stricture Full Text International Braz J Urol, September 15, 2014
7 Clinical characteristics of breast cancers in African-American women with benign breast disease: A comparison to the surveillance, epidemiology, and end results program The Breast Journal, September 15, 2014
10 Changes over time in the utilization of disease-related internet information in newly diagnosed breast cancer patients 2007 to 2013 Full Text Journal of Medical Internet Research, September 15, 2014
13 Differences in risk factors for second and third degree hypospadias in the national birth defects prevention study Birth Defects Research Part A: Clinical and Molecular Teratology, September 15, 2014
16 Expanding the mutational spectrum associated to neural tube defects: Literature revision and description of novel VANGL1 mutations Birth Defects Research Part A: Clinical and Molecular Teratology, September 15, 2014
2 SodiUm SeleniTe Adminstration IN Cardiac Surgery (SUSTAIN CSX(R)-trial): study design of an international multicenter randomized double-blinded controlled trial of high dose sodium-selenite administration in high-risk cardiac surgical patients Full Text Trials, September 15, 2014
4 Efficacy and safety of a booster dose of influenza vaccination in solid organ transplant recipients, TRANSGRIPE 1-2: study protocol for a multicenter, randomized, controlled clinical trial Full Text Trials, September 15, 2014
7 Time trends in single versus concomitant neck and back pain in Finnish adolescents: results from national cross-sectional surveys from 1991 to 2011 Full Text BMC Musculoskeletal Disorders, September 15, 2014
8 Efficacy and time-to-hemostasis of antegrade femoral access closure using the ExoSeal vascular closure device: a retrospective single-center study European Journal of Vascular and Endovascular Surgery, September 15, 2014
12 Mid-term outcomes and aortic remodelling after thoracic endovascular repair for acute, subacute, and chronic aortic dissection: The VIRTUE Registry European Journal of Vascular and Endovascular Surgery, September 15, 2014
Research Article Sep.14,2014
Characterization of Desmoglein Expression in the Normal Prostatic Gland. Desmoglein 2 Is an Independent Prognostic Factor for Aggressive Prostate Cancer
Alison G. Barber, Mireia Castillo-Martin mail, Dennis M. Bonal, Benjamin A. Rybicki, Angela M. Christiano, Carlos Cordon-Cardo mail June 04, 2014 DOI: 10.1371/journal.pone.0098786PLoS ONE 9(6): e98786. doi:10.1371/journal.pone.0098786
Desmosomes are a type of cell-cell anchoring junction found in tissues that undergo a high degree of mechanical stress, and loss of desmosomal adhesion is associated with diseases affecting the skin, hair, and heart.
In the desmosome, the cadherin family of proteins is represented by the so-called “non-classical” cadherins, which include desmogleins (DSG 1–4) and desmocollins (DSC 1–3). Desmogleins and desmocollins play a dual role in the formation of desmosomes. In the extracellular space, desmogleins and desmocollins on opposing cells interact in a heterophilic calcium-dependent manner via their cadherin repeat domains.
Intracellularly, the cadherins bind to plakoglobin and plakophilin, which in turn bind to desmoplakin. Desmoplakin then binds to intermediate filaments, thereby securing the entire structure to the cytoskeleton . While clearly important in maintaining the integrity of adult tissues, the role of desmosomal cadherins in cancer progression is less well understood. Loss of heterozygosity near the chromosomal region containing the desmosomal cadherin gene cluster has been reported in esophageal cancer as well as head and neck squamous cell carcinoma.
Alterations in the expression of desmogleins have been reported for a variety of cancers. Reduced expression of DSG2 has been reported in gastric and pancreatic carcinomas. Conversely, overexpression of DSG2 and DSG3 has been reported in squamous cell carcinomas of the skin as well as head and neck cancer, respectively.
The expression of desmosomal cadherins has been thoroughly characterized in the epidermis, hair follicle, and arachnoidal tissue. While the expression of DSG2 is known to be ubiquitous in all desmosome-forming tissues, the expression of the remaining desmosomal cadherins outside of the epidermis and hair follicle is poorly understood. A study by Whittock and Bower in 2003 utilized RT-PCR to analyze the expression of DSG4 in a panel of tissues and found that DSG4 could be detected in several tissues including the prostate, suggesting that the desmoglein expression profile of the prostate may extend beyond the ubiquitous expression of DSG2.
The downregulation or loss of cell-cell adhesion proteins — such as the classical cadherin, E-cadherin — is a common feature of a variety of cancers, including prostate cancer, and can be caused by a variety of different mechanisms. Conversely, though the aberrant expression of desmogleins has been reported in several types of cancer, the expression of these cadherins in prostate cancer has only been reported in cell lines to date.
In this study we characterize for the first time the expression of desmogleins in normal human prostate tissue specimens and determine the specific cell type in which prostate specific desmogleins are expressed. We then analyze the expression of DSG2 in a well-characterized prostate cancer patient cohort, and examine the association between DSG2 expression and patients' clinical outcome. Our results reveal that DSG2 and DSG4 are specifically expressed in the luminal cells of normal human prostate, whereas DSG1 and DSG3 are not expressed in the prostate epithelium. Further, reduced expression of DSG2 was found to be independently associated with a shorter biochemical recurrence, highlighting the potential utility of DSG2 expression as a prognostic biomarker of prostate cancer aggressiveness.
Urology news Sep.14,2014
Mieke Van Hemelrijck mail, Anita Feller, Hans Garmo, Fabio Valeri, Dimitri Korol, Silvia Dehler, Sabine Rohrmann /July 21, 2014/DOI: 10.1371/journal.pone.0102596 /PLoS ONE 9(7): e102596. doi:10.1371/journal.pone.0102596
The current study assessed in detail the risk of second primary tumours for men diagnosed with PCa in the Canton of Zurich. We found a weak increased risk for overall cancer, but a complex pattern was observed when looking at specific cancer types and PCa treatment and stage. Urological cancers were consistently more prevalent among men with PCa, irrespective of their cancer treatment or cancer stage. The increased risk of second primary tumours increased over time and was most pronounced 10 years post diagnosis for men who underwent radiotherapy.
Another Swiss study based on the Cancer Registries of the Cantons of Vaud and Neuchâtel already investigated the risk of second primary tumours in 1999. They compared men diagnosed with PCa between 1974 and 1994 with the general population and found an SIR of 0.8 (95%CI: 0.6–0.8). A more recent Swiss study based on the Geneva Cancer Registry showed that the overall SIR of secondary cancer in PCa patients treated with radiotherapy was 1.35 (p = 0.056), with elevated SIRs especially for colon cancer (4.0 (95%CI: 1.8–7.6)).
Our results confirm these more recent findings; however the SIR for colon cancer was only 1.40 and not statistically significant. The latter may be partly due to a smaller sample size. When we computed SIRs by study period, we observed a lower SIR of 1.05, which was not statistically significant, for cancers diagnosed between 1980 and 1995. Thus, our inconsistency with the results by Levi et al. might be due to the fact that in former times, PCa was often diagnosed at an advanced stage with shorter survival. The chance of developing a second primary tumour was lower than today. This is also consistent with our observation of the highest SIR in men diagnosed with stage I PCa, but a not statistically significant SIR among men diagnosed with advanced, i.e., stage III and stage IV, cancers.
Moreover, our results are similar compared to a Bavarian study, which observed that the overall risk of second primary tumours for men with PCa was significantly increased by 14% compared with the general male population. With regard to specific cancer types, a significantly increased risk was found for cancer of the bladder, kidney, pancreas, thyroid, small intestine, brain/nervous system, and melanoma of skin, leukemia, and myeloma. In the Swedish study comparing all men diagnosed with PCa between 1997–2006 and the male background population, there was also an overall increased risk of second primary tumours .
This study did not look at all cancer types as discussed in the current project. However, they also found an increased risk for colon, bladder, and brain cancers, as well as melanoma and non-hodgkin lymphoma. They found a lower risk for kidney cancer, but data reported in the Swedish study focused on the specific time frame of five years post PCa diagnosis, whereas in our study we have a longer follow-up. Interestingly, when investigating fatal cancer outcomes, an American study focused on men who underwent radical prostatectomy, found inverse association for all deaths due to second primary malignancies. These results can however not be compared to our findings as this study by Eifler et al. focused on fatal events in a subset of men with PCa, who are likely to be healthier than the total PCa population and the total male population.
Overall, there was an increased SIR for almost all cancer types. The SIRs were especially increased for kidney, bladder, and thyroid cancer as well as non-Hodgkin's lymphoma. An increased risk of urological cancers is consistent with previous findings and most likely reflects the related increased diagnostic activity for PCa men.
Interestingly, stratification by treatment showed some different patterns whereby the SIRs for thyroid cancer were high for men undergoing surgery, radiotherapy, or surveillance. Similarly, non-Hodgkin's lymphoma had SIRs >2 for men undergoing surveillance and radiotherapy. In the latter group the SIR for leukemia was also of this size. The observations for men undergoing surveillance are difficult to interpret in this setting as we could not distinguish between those on surveillance and those with missing data for treatment.
However, the findings for radiotherapy are consistent with findings from the American SEER database. Compared with men who received no PCa-directed radiation, men who received external beam radiation therapy were at increased risk of bladder, rectum, colon, brain, stomach, melanoma, and lung cancer .As already mentioned, the lack of a statistically significant association for colon cancer may be due to the lack of statistical power.
Patterns by disease stage also need to take into account patterns by treatment as lower grade tumours are more likely to be treated curatively with surgery or radiotherapy. Nevertheless, the SIRs for urological cancers were consistent across grade and only slightly higher for those undergoing radical prostatectomy; again confirming the increased diagnostic activity for PCa men. Furthermore, stratification by treatment as well as time since diagnosis confirmed previous findings by Murray et al. .The overall SIR for men on radiotherapy was 1.19, but increased to 2.56 for men followed up for more than 10 years, whereas this increase over time was much less pronounced for men who underwent surgery or ADT.
With respect to aetiological mechanisms, our analysis for those cancers thought to be associated with IGF-1 showed a consistent increased risk, also when stratified by treatment. Only for men on ADT, there was no difference with the background population. Men on ADT most likely had a more severe tumour and thus lower life expectancy, which is also reflected in the analysis for IGF-1 related cancer stratified by tumour stage. This observational study cannot claim causality, but it supports further evidence for the hypothesis that the IGF-1 pathway is involved in development of epithelial cancers, as was also demonstrated in a study for second primary tumours in patients with a head and neck cancer .Higher IGF-1 levels were associated with and increased risk of second primary tumours with a hazard ratio of 2.78 (95%CI: 1.62–4.77).
Hurley, Susana; Goldberg, Debbiea; Nelson, Davida; Hertz, Andrewa; Horn-Ross, Pamela L.a; Bernstein, Leslieb; Reynolds, Peggya,c
Background: There is convincing evidence that circadian disruption mediated by exposure to light at night promotes mammary carcinogenesis in rodents. The role that light at night plays in human breast cancer etiology remains unknown. We evaluated the relationship between estimates of indoor and outdoor light at night and the risk of breast cancer among members of the California Teachers Study.
Methods: Indoor light-at-night estimates were based on questionnaire data regarding sleep habits and use of nighttime lighting while sleeping. Estimates of outdoor light at night were derived from imagery data obtained from the US Defense Meteorological Satellite Program assigned to geocoded addresses of study participants. Analyses were conducted among 106,731 California Teachers Study members who lived in California, had no prior history of breast cancer, and provided information on lighting while sleeping. Five thousand ninety-five cases of invasive breast cancer diagnosed 1995–2010 were identified via linkage to the California Cancer Registry. We used age-stratified Cox proportional hazard models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for breast cancer risk factors and neighborhood urbanization and socioeconomic class.
Results: An increased risk was found for women living in areas with the highest quintile of outdoor light-at-night exposure estimates (HR = 1.12 [95% CI = 1.00–1.26]; test for trend, P = 0.06). Although more pronounced among premenopausal women (HR = 1.34 [95% CI = 1.07–1.69]; test for trend, P = 0.04), the associations did not differ statistically by menopausal status (test for interaction, P = 0.34).
Conclusions: Women living in areas with high levels of ambient light at night may be at an increased risk of breast cancer. Future studies that integrate quantitative measurements of indoor and outdoor light at night are warranted.
Source: Epidemiology:September 2014 - Volume 25 - Issue 5 - p 697-706doi: 10.1097/EDE.0000000000000137Cancer
Urology news Sep.14,2014
Prostate Cancer, Prostate Cancer Death, and Death from Other Causes, Among Men with Metabolic Aberrations.
Häggström, Christel; Stocks, Tanja; Nagel, Gabriele; Manjer, Jonas; Bjørge, Tone; Hallmans, Göran; Engeland, Anders; Ulmer, Hanno; Lindkvist, Björn; Selmer, Randi; Concin, Hans; Tretli, Steinar; Jonsson, Håkan; Stattin, Pär
Background: Few previous studies of metabolic aberrations and prostate cancer risk have taken into account the fact that men with metabolic aberrations have an increased risk of death from causes other than prostate cancer. The aim of this study was to calculate, in a real-life scenario, the risk of prostate cancer diagnosis, prostate cancer death, and death from other causes.
Methods: In the Metabolic Syndrome and Cancer Project, prospective data on body mass index, blood pressure, glucose, cholesterol, and triglycerides were collected from 285,040 men. Risks of prostate cancer diagnosis, prostate cancer death, and death from other causes were calculated by use of competing risk analysis for men with normal (bottom 84%) and high (top 16%) levels of each factor, and a composite score.
Results: During a mean follow-up period of 12 years, 5,893 men were diagnosed with prostate cancer, 1,013 died of prostate cancer, and 26,328 died of other causes. After 1996, when prostate-specific antigen testing was introduced, men up to age 80 years with normal metabolic levels had 13% risk of prostate cancer, 2% risk of prostate cancer death, and 30% risk of death from other causes, whereas men with metabolic aberrations had corresponding risks of 11%, 2%, and 44%.
Conclusions: In contrast to recent studies using conventional survival analysis, in a real-world scenario taking risk of competing events into account, men with metabolic aberrations had lower risk of prostate cancer diagnosis, similar risk of prostate cancer death, and substantially higher risk of death from other causes compared with men who had normal metabolic levels.
Source: Epidemiology: doi: 10.1097/EDE.0000000000000174 September 9, 2014
(C) 2014 by Lippincott Williams & Wilkins, Inc
Early Detection and Diagnosis of prostate cancer Sep.14,2014
Circulating tumor cell telomerase activity as a prognostic marker for overall survival in SWOG 0421: A phase 3 metastatic castration resistant prostate cancer trial
Amir Goldkorn1,*, Benjamin Ely2, Catherine M. Tangen2, Yu-Chong Tai3, Tong Xu1, Hongli Li2, Przemyslaw Twardowski4, Peter J. Van Veldhuizen5, Neeraj Agarwal6, Michael A. Carducci7, J. Paul Monk III8, Mark Garzotto9, Philip C. Mack10, Primo Lara Jr.10, Celestia S. Higano11, Maha Hussain12, Nicholas J. Vogelzang13, Ian M. Thompson Jr.14, Richard J. Cote15 andDavid I. Quinn/DOI: 10.1002/ijc.29212 Copyright © 2014 UICC
Circulating tumor cells (CTC) are promising biomarkers in metastatic castration resistant prostate cancer (mCRPC), and telomerase activity (TA) is a recognized cancer marker. Therefore, we hypothesized that CTC TA may be prognostic of overall survival (OS) in mCRPC.
To test this, we used a novel Parylene-C slot microfilter to measure live CTC TA in S0421, a phase 3 SWOG-led therapeutic trial. Blood samples underwent CTC capture and TA measurement by microfilter, as well as parallel enumeration by CellSearch (Janssen/J&J). Cox regression was used to assess baseline (pre-treatment) TA vs. OS, and recursive partitioning was used to explore potential prognostic subgroups and to generate Kaplan-Meier (KM) OS curves.
Samples were obtained from 263 patients and generated 215 TA measures. In patients with baseline CTC count ≥5 (47% of patients), higher CTC TA was associated with hazard ratio 1.14 (p=0.001) for OS after adjusting for other clinical covariates including CTC counts and serum PSA at study entry. Recursive partitioning identified new candidate risk groups with KM OS curve separation based on CTC counts and TA. Notably, in men with an intermediate range baseline CTC count (6-54 CTCs/7.5ml), low vs. high CTC TA was associated with median survival of 19 vs. 12 months, respectively (p=0.009). Baseline telomerase activity from CTCs live-captured on a new slot microfilter is the first CTC-derived candidate biomarker prognostic of OS in a large patient subgroup in a prospective clinical trial.
CTC telomerase activity thus merits further study and validation as a step towards molecular CTC-based precision cancer management.
International Journal of Cancer© 2014 Wiley Periodicals, Inc.
Edited by:Mohammad Hezarkhani MD,Urologist
Board-Certified of Urology,Tehran University ,The Member of Iranian Urological Association
Madaen Hospital Tehran Iran
Tehranclinic Hospital Tehran Iran
www.Hezarkhani.blogfa.com hosted in Washington DC, United States
Background---The first member of the aquaporin family to be extensively described was the channel-like integral membrane protein CHIP28, the 28 kDa protein of the human erythrocyte membrane. On the basis of functional analyses, it was later renamed aquaporin-1 (AQP1) .Hydropathy plot analyses of the primary sequence predicted six transmembrane helices (I-VI) connected by five loops .Loops A, C and E are extracellular and loops B and D are intracellular.
The protein comprises two internal tandem repeats, covering roughly the amino- and carboxy-terminal halves of the protein. Each repeat consists of three transmembrane helices and a highly conserved loop following the second transmembrane helix (loops B and E, respectively). This loop includes a conserved signature motif, asparagine-proline-alanine (NPA). Loops B and E form short α helices that fold back into the membrane, with loop B entering the membrane from the cytoplasmic side and loop E from the extracellular side. A seventh transmembrane domain in which the two NPA boxes are orientated 180 degrees to each other is thus formed, creating an aqueous pathway through the proteinaceous pore .
This 'hourglass model' has been confirmed by three-dimensional maps of AQP1 using cryoelectron microscopy .These maps also showed that aquaporins have a tetrameric organization: the four subunits are arranged in parallel, forming a fifth pore in the center of the tetramer. It is generally accepted that all aquaporin-like proteins assemble into tetramers. Each monomer alone can facilitate water flow, however. Recent experiments have indicated conductance of ions (K+, Cs+, Na+ and tetramethylammonium) through the central pore of the AQP1 tetramer .
Localization and function---Since the discovery of the Escherichia coli water channel AqpZ, the pathway of rapid water fluxes through membranes by which microorganisms adapt to abrupt changes in osmolarity has begun to be understood .This channel is selectively permeable to water, has a role in both the short-term and the long-term osmoregulatory response, and is required by rapidly growing cells. AqpZ-like proteins seem to be necessary for the virulence of some pathogenic bacteria. Microbial aquaporins are also likely to be involved in spore formation and/or germination.
The diversity of aquaporins in multicellular organisms highlights the diverse requirements for osmoregulation and transmembrane water movement in different tissues, organs and developmental stages. In mammals, aquaporins are localized in epithelia that need a high rate of water flux, such as the collecting duct of the kidney, the capillaries of the lung and the secretory cells of the salivary glands. Mammalian aquaporins differ in their transcriptional regulation, post-transcriptional regulation and subcellular distribution.
Members of the aquaporin family are implicated in numerous physiological processes . In the kidney, for example, AQP1 is extremely abundant in both the apical and the basolateral membranes of the renal proximal tubules and in the capillary endothelium. It contributes to the counter-current mechanism for urine concentration.
In the salivary gland, AQP3 is found in basolateral membranes, where water is taken up from the interstitium, and AQP5 is in the apical membrane, where water is released. A wide range of clinical disorders have been attributed to the loss or dysfunction of aquaporins, including abnormalities of kidney function, loss of vision, onset of brain edema and starvation .AQP1 was recently shown to be involved in angiogenesis, wound healing, organ regeneration and carcinogenesis .
Our knowledge of the molecular functions of plant aquaporins with regard to their specificity for water and small neutral solutes has increased substantially in recent years .In plant cells, the cytoplasm is in fact enclosed between two membranes: the plasma membrane, which forms the outer boundary of the cell, and the tonoplast, which surrounds the vacuolar compartment. Aquaporins located in the plasma membrane (PIPs) or tonoplasts (TIPs) contribute to intracellular water balance and transcellular water flow.
NIPs, which were initially found in the peribacteroid membrane of legume symbiotic root nodules, are presumed to be involved in exchange of metabolites between the host and the symbiont; the subcellular localization and physiological function of NIPs in non-leguminous plants is not known. SIPs have recently been localized to endoplasmic reticulum membranes; their physiological functions remain to be elucidated .
Much of our information on the physiological relevance of aquaporins in plants comes from analyses of transgenic plants with modified expression of various aquaporins, or from analysis of aquaporin mutants. The first evidence for a function in cellular water uptake and whole-plant water transport came from plants expressing antisense RNA for PIP proteins, which developed a larger root system than the controls .In tobacco, the plasma-membrane aquaporin NtAQP1 was shown to be important for hydraulic conductivity and water stress resistance in roots .Studies on plants with impaired expression of two different aquaporins (PIP1 and PIP2) indicated that these proteins are important in the recovery from water deficiency .
Overexpression of an Arabidopsis plasma-membrane aquaporin in tobacco resulted in increased growth rates under optimal irrigation ,which was interpreted as the sum of effects on water uptake and photosynthesis. Besides their function in water management, plant aquaporins have a role during leaf movement, a process involving high rates of cellular water transport .
In addition to their role in water transport and osmoregulation, some aquaporins facilitate the passage of gases such as CO2 and NH3 across membranes (reviewed in .The physiological significance of AQP1-facilitated CO2 transport is still a matter of debate. AQP1 knockout mice did not show differences in CO2 exchange rates in lung and kidney ,but plants with impaired expression of a PIP1 aquaporin showed several differences, not only in water transport but also in CO2-limited processes such as photosynthesis and stomatal conductance .Studies with inhibitors of aquaporin function in plants suggest that NIPs are involved in NH3 permeability and perhaps in nutrient exchange between the host plant and endosymbiotic bacteria.
Mechanism---Given that all aquaporins are structurally related and have highly similar consensus regions, particularly in the pore-forming domains, a similar transport mechanism can be assumed. The hydrophobic domain created by the loops B and E has been suggested to be involved in substrate specificity and/or size restriction. The pathway through the aquaporin monomer is lined with conserved hydrophobic residues that permit rapid transport of water in the form of a single-file hydrogen-bonded chain of water molecules .
The pore contains two constriction sites: an aromatic region comprising a conserved arginine residue (Arg195) forms the narrowest part of the pore, and the highly conserved NPA motifs form a second filter, where single water molecules interact with the two asparagine side chains .Because of a direct interaction between water molecules and the NPA motifs, the dipolar water molecule rotates 180 degrees during passage through the pore. Both filter regions build up electrostatic barriers, which prevent the permeation of protons .In human AQP1, a hydrophobic phenylalanine side chain (Phe24) intrudes into the pore and enhances the interaction of single permeating water molecules with the NPA loops.
In the bacterial glycerol facilitator GlpF, this residue is replaced by the smaller amino acid leucine (Leu21). Phe24 acts as a size-exclusion filter, preventing the passage of larger molecules such as glycerol through AQP1 .
The water permeability and selectivity of aquaporins varies considerably, however. The water permeabilities for human aquaporins have been estimated to be between 0.25 × 10-14 cm3/sec for AQP0 and 24 × 10-14 cm3/sec for AQP4 .Plant plasma-membrane aquaporins also have differing levels of aquaporin activity .
Coexpression and heteromerization of PIP1 and PIP2 isoforms from maize induced an increase in permeability above that obtained for expression of single isoforms .Heteromerization seems to be important not only in heterologous expression systems, but also in the plant, as was demonstrated by analysis of PIP1 and PIP2 antisense Arabidopsis plants .
The mechanism by which aquaglyceroporins promote glycerol transport has been investigated for the E. coli glycerol facilitator GlpF .This protein also contains the conserved NPA motifs at comparable positions to those in the water-selective aquaporins, but the preference for glycerol is achieved by aromatic amino acids at the periplasmic side. Trp48, Phe200 and Arg206 form a constriction, and the arginine residue forms hydrogen bonds with two hydroxyl groups of the glycerol molecule.
As a result, the carbon backbone of the glycerol molecule faces into the cavity assembled by the two aromatic amino acids (Phe200 and Trp48). Glycerol is separated from other linear polyols and passes the pore in a single file. The GlpF pore is completely amphipathic, with polar residues opposite a hydrophobic wall.The aim of the present study is to elucidate whether the expression of AQP5 is a strong prognostic biomarker for prostate cancer, and the potential role in the progression of prostate cancer cells.
Conclusions---The researchers concluded that AQP5 in prostate cancer was an independent prognostic indicator. AQP5 over-expression was likely to play a role in cell growth and metastasis. These conclusions suggest that AQP5 may be an effective therapeutic target for prostate cancer.
2- Over-expression of a poor prognostic marker in prostate cancer: AQP5 promotes cells growth and local invasion/Jianping Li, Ziming Wang, Tie Chong, Haiwen Chen, Hechen Li, Gang Li, Xiaoqiang Zhai and Youfang Li /World Journal of Surgical Oncology 2014, 12:284 doi:10.1186/1477-7819-12-284/13 September 2014
Latest news Sep.14.2014
September 10, 2014
The American Society for Clinical Oncology (ASCO), in conjunction with Cancer Care Ontario (CCO), has just issued revised guidelines for the management of metastatic prostate cancer. You can access all the relevant details about the new guidelines through any of the following links:
The bottom line is pretty much as follows:
- Continuous androgen deprivation (also known as “hormone” therapy, whether pharmaceutical or surgical) should be continued indefinitely regardless of additional therapies.
- Multiple additional therapies with demonstrated benefits in terms of survival and quality of life can be offered, including
- Abiraterone acetate (Zytiga) + prednisone
- Enzalutamide (Xtandi)
- Radium-223 (Xofigo) for men with bone metastases
- Docetaxel and prednisone
- Other therapies with demonstrated survival benefits but benefits that are less clear in terms of quality of life include
- Sipuleucel-T (Provenge) for men who are asymptomatic or minimally symptomatic
- Cabazitaxel (Jevtana) + prednisone for men who experience progression with docetaxel + prednisone
- A treatment that has quality-of-life benefit but no demonstrated survival benefit is
- Mitoxantrone + prednisone
- Other therapies that have biologic activity but no clear survival or quality of life benefits (when used on their own) include
- Antiandrogens (e.g., bicalutamide, flutamide, nilutamide)
- Low-dose corticosteroid monotherapy
- Certain specific therapies tested in the past appear to have no demonstated survival or quality-of-life benefit and should not be offered to patients:
- Bevacizumab (Avastin)
- Sunitinib (Sutent)
- Palliative care services
- Palliative care should be offered to all patients, particularly to those exhibiting symptoms or quality-of-life (QOL) decrements, regardless of treatment type.
Note that this set of guidelines does not specifically address the use of drugs designed for use in combination with androgen deprivation therapy to prevent known side effects of androgen deprivation (e.g., drugs like zoledronic acid/Zometa and denosumab/Xgeva that can be used to lower risk for bone loss and related skeletal events such as fractures). Use of such drugs is considered to be a part of the guidance on palliative care, above-mentioned.