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Hearings present opportunities
By JIM CUNNINGHAM
One of the unique aspects of Nebraska's Unicameral Legislature is that with very few exceptions every legislative bill is given a public hearing during the session in which the bill is introduced. In each instance, the hearing is a significant opportunity for citizens to tell legislators just what they think about the various proposals for changing public policy.
The varied items of substantive legislation are scheduled for hearings by the chairpersons of the standing committees with respective jurisdiction over the subject matter. A committee of the legislature's Executive Board assigns the bills.
In some instances the public hearings accommodate diverse and competing viewpoints; other times it's a 'love fest." Sometimes testimony is emotional, while at other times it's more humdrum. It's all part of an important process.
The current session of the Nebraska Legislature has moved to that stage when public hearings are under way at the State Capitol in Lincoln.
An example of a legislative bill that will have a public hearing this session is LB 769, introduced by Sen. Mike Friend of District 10 in Omaha. His bill proposes to establish modest tax relief for parents and guardians who incur expenses in providing for the education of their children at the elementary and secondary levels.
The tax relief takes the form of a state income tax credit for a prescribed percentage of qualified expenditures, up to a maximum credit of $250 per year per elementary student and $500 per year per secondary student. The proposal is best described as an education expense tax credit. It would apply to expenses that include tuition, textbooks, various fees for academic courses and labs, and transportation costs. It would be available to all those who pay such costs at any elementary or secondary school, public or private, operated legally under the laws of Nebraska. There is plenty of legal precedent and support for the constitutionality of such a policy.
Friend's LB 769 presents a particularly important opportunity for parents and guardians who determine that the best way for them to fulfill their state-law obligation to provide for the education of their children is by enrolling them in a non-governmental school, whether religiously affiliated or otherwise. These are Nebraska taxpayers, who, except in rare instances, are doubly burdened, paying for education through taxes and through tuition and fees. The hearing is an opportunity for parents who face these circumstances to make a case for tax justice, either orally or in writing.
A great deal of attention is being given in Nebraska these days to the organization and financing of elementary and secondary education, in both urban and rural settings. Typically overlooked in these considerations is the fact that nearly 40,000 students are enrolled in non-governmental schools. If policy makers are sincerely interested in achieving educational equity, then their deliberations ought to include ways of recognizing and supporting the value of parents choosing non-tax-supported alternatives. Investing in true educational choice is an idea deserving of consideration. Parents who make these choices need to speak out and be heard. LB 769 provides that opportunity.
The date for the Revenue Committee's public hearing on this bill had not been set as of the deadline for this column, but such information can be obtained by monitoring the Legislature's website: www.unicam.state.ne.us. In addition, anyone interested in additional information about LB 769, as well as other legislation pertaining to education, is welcome to contact the Nebraska Catholic Conference office, 402/477-7517, or email@example.com. Also, the conference's website, www.nebcathcon.org, has a link to education issues and to the Nebraska Federation of Catholic School Parents.
Another bill that awaits a public hearing in front of the Revenue Committee is LB 810, introduced by the committee's chairman, Sen. David Landis of Lincoln. This bill proposes state-level implementation of something that has already proven effective and successful at the Federal level: an earned income tax credit. This provides tax-based benefits for those who are employed, but whose earned income falls below certain prescribed levels. It puts tax dollars back into the hands of low-income working families. Having this at the state level would enhance the value even more.
Regarding the earned income tax credit that already exists "" the federal one "" now is an important time for anyone who thinks they might qualify for this to seek information in time for the April 15 filing deadline.
The legislature spent almost all of its first eight days introducing new bills and giving-first round consideration to just three bills carried over from 2005. All three proved to be contentious.
The third of these, LB 57, is Sen. Mike Foley's bill proposing to define and establish penalties for the crime of assault of an unborn child. It is a logical extension of legislation enacted in 2004, which established the crime of homicide of an unborn child. (Legislation, by the way, that has already resulted in at least four prosecutions.)
LB 57 addresses circumstances in which the intentional or reckless actions of a third-party perpetrator cause serious, but non-lethal, bodily injury to an unborn child.
If, for example, a baby was born with a permanent disfigurement and there was evidence that the condition was caused while the child was in utero, by the intentional or reckless conduct of someone other than the mother, and other than a medical provider performing a medical procedure with the mother's consent "" in order to avoid conflict with abortion rights "" then that could be prosecuted as a crime of assault of an unborn child. The unborn child would be regarded as a separate victim of criminal conduct.
Such legislation is constitutional and it's meritorious public policy.
Jim Cunningham is executive director of the Nebraska Catholic Conference, headquartered in Lincoln. . He can be contacted at his office in Lincoln at (402) 477-7517.


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Wish I'd said that - April 21, 2019
"Man is condemned to be free. Condemned because he has not created himself – and is nevertheless free. Because having once been hurled into the world, he is responsible for everything he does."
Jean-Paul Sartre, quoted by Alberto Knox in Jostein Gaarder, Sophie's World: A Novel About the History of Philosophy

subset: commoncrawl


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Batman Jump is an Action game. You can play Batman Jump in your browser for free.
Description: Dora Doctor Slacking is an Other game. You can play Dora Doctor Slacking in your browser for free. Dora go to the doctor. She is very naughty. She feel boring and she want to fun ! Use your mouse or keboard to complete the activies, help Dora slack at the doctos room but then the doctor looks over you should out to keep her out of trouble.
 Control: Use your mouse to play.

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Examples from the Web for hegel
It used to be that when intellectuals heard the word "derivative," they thought about what Marx took from Hegel.
An old joke went that only two people in history understood Hegel, and even they misunderstood him.
There is a saying of Hegel's, frequently quoted, that "a great man condemns the world to the task of explaining him."
Patriots in all nations were encouraged; and the Swiss cantons became more democratic; but Hegel was frightened to death.Liberty In The Nineteenth Century|Frederic May Holland
Under his influence Serov began to take an interest in modern German philosophy and particularly in the doctrines of Hegel.The Russian Opera|Rosa Newmarch
Hegel was the first man to make a proper explanation of the relations of freedom and necessity.
In the first place Hegel says that "sensation is the specific differentiation, the distinguishing mark of the animal."


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* * * Updated as of Sept. 16* * *
As the Downtown Revitalization project begins and construction crews start mobilizing, it is important to raise awareness of the new traffic patterns. Beginning Wednesday, September 11th between 9:30 and 10:00 am, Main Street will be closed down to one lane of through traffic with no parking. East Jackson from Main Street to the railroad tracks will also be closed. No right turns from Main Street will be allowed at this time.
Monday Sept. 16, at the intersection of Jackson and Main crews will start upgrading the stormwater system. Jackson St will reopen to traffic Friday evening 9/20. Storm drain work will continue working toward 5th St at the rate of approximately 2 weeks per block.
Please utilize side street and alley parking during this time as well as any public parking lots. We understand that construction can be inconvenient but we appreciate your patience during this time. Please drive with added caution and be aware of construction workers as well as new traffic patterns.
If issues arise, please feel free to reach out to Courtney or Taylor in the Economic Development Office or Rich Urquidi, Director of Public Works.
Taylor Hurley - Economic Development Office – Courtney Lewis & Taylor Hurley - Phone: 208-587-2173 - Email: email@example.com
Public Works Director – Rich Urquidi - Phone: 208-587-2107 - Email: firstname.lastname@example.com


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According to the bellereport.com
15-Time Stellar Award Winning Artist BEN TANKARD
Is Back With New Album FULL TANK 3: CanTANKerous
Fresh off the heels of his 2016 best-selling book: The Full Tank Life: Fuel Your Dreams-Ignite Your Destiny, the Godfather of Gospel Jazz Ben Tankard is back with the third installment of his Stellar Award winning FULL TANK album series. His new FULL TANK 3: CanTANKerous album features an all-star cast of special guests including multi-award winning saxophonist Gerald Albright, guitarist Phil Hughley, saxophonist Cord Martin, Grammy® award winning group Take-6 and song contributions from Judith Christie McAllister, Faith Hill and Sean P-Diddy Combs and Sting.
"It is super tough carving out time to be in the studio to record when you have reality TV cameras around you all day, but I have to say this record was a fun and rewarding experience," says the Grammy®, Dove, SoulTrain awarded artist, producer and Reality TV Dad. "I am especially excited about my gospel instrumental rendition of 'Like The Dew' featuring Gerald Albright on sax."
"I am also excited about my Smoothjazz single "Remember Wayman" which I wrote and produced in honor of my old NBA buddy and Smoothjazz artist the late Wayman Tisdale."
Tankard again gives Jazz and Gospel music fans an stunning album of soothing originals, worshipful favorites and groovin' arrangements of Urban music favorites. FULL TANK 3: CanTANKerous is available in Walmart and Target stores and online everywhere Friday, May 12. The album is released by Tankards' label Ben-Jamin' Universal Music with distribution from Central South Distribution.
Whether serving locally with pastoral duties at their thriving church The Destiny Center, shooting the next reality TV show season with his wife Jewel and their wonderfully wild, whacky and adventurous blended family, to piloting his airplane across the country to speak and play concerts, you can rest assured that the Tankards will always live life on a FULL TANK!


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Starting is the hardest
Starting is the hardest part.
Six months ago, I was starting, waving familiarity goodbye from the window of the plane I almost didn't catch on my way to San Diego, where the next morning I would begin my attempt at hiking the Pacific Crest Trail in its entirety. Boxes of belongings still sat in my vacated apartment because Cameron and I had prioritized fun with friends over completing the moving process, which I never regretted but Cam might have since he was the one left to finish the job.
Now, I sit writing at the house on Gladwood: Cameron's house, where my far-fetched goal of hiking a long-distance trail slowly became a viable plan over many nights spent discussing what I really wanted in life. Now, I'm back here, reflecting on how that plan developed into a six-month, constantly evolving reality. The house has changed, too. Once a charming old gathering place for friends and family, the Glad Pad is now a dilapidated old gathering place for rats and for sale by owner. I'm writing for the first time in over a week, contemplating the moves I have to make. From a life alone in a tent to one with my boyfriend and two roommates, from one house to another. I'm starting again, this time attempting a happy and fulfilling life back in the fake world.
It starts with the new house on Ledgestone. I like the nature theme of the streets I'm living on. Gladwood and Ledgestone. The former implies, first and most obviously, a sort of pleasantness. That's how I would describe "glad," anyway. Googling "define:glad," my preferred method of lazy denotation discovery, yielded the result "pleased; delighted." So we agree! Then there's "wood," as in the wood, which to me implies a surroundedness.
I've moved into a house of three boys with a neighbor, collectively referred to as "Neighbs," who is Kimmy Gibbler-esque in the sense that he visits frequently and without announcement. Also Cameron's cousin is visiting. I've gone from living alone in a downtown loft, surrounded by skyscrapers and strangers, to alone in the woods, surrounded by trees and chipmunks, to very much not alone at the Gladwood, pleasantly surrounded by furniture and men.
Then there's Ledgestone. This one feels more risky. You're standing not only on the ledge, but on a single stone on the ledge, which Google defines as "a narrow horizontal surface projecting from a wall, cliff, or other surface." So there's a single stone on a narrow surface projecting from some other, larger high-up surface, and that's what you're standing on. You're teetering. You could fall. But maybe falling is a good thing, because you could fall either direction. You either fall back onto the hard, solid ground from which you stepped onto this ledgestone, or you fall forward, into the wide open space, no idea how long or far you'll fall or where you'll land. Or, as some do, you teeter forever, looking back and forth from flat safety to apparent peril, experiencing nothing but indecision and visions of what could be.
Back in the environment I left, which hasn't changed much though I have, irreversibly, I find myself trying to re-insert myself into my old life. Trying to rebuild a life with the same old pieces even though the blueprint has changed completely. It's like putting on an old pair of jeans you once loved and wore everyday, and they still fit and you're excited they still fit, but you can't wear them. They just don't look good anymore. Your taste isn't the same, styles have changed, and it's over between the two of you. That was going to be a metaphor until I realized I've had that exact experience as I've gone through all the boxes of clothes.
Here I am, in the same house, with all my stuff everywhere. After carrying everything I needed on my back for six months, I'm motivated to get rid of as much as I can, and it's even easier to do that since we're moving and have to find a new place for everything anyway. But you can only get rid of so much stuff before it stops making a change in your life. Eventually, if you still feel cluttered, you have to change yourself.
I thought about this today when I unzipped a bag and discovered all my makeup. On the trail, I never gave much more thought to how I looked than wondering if the amount of dirt on my face was appropriate for the restaurant I was about to eat in. Now, back in a world where people get made up, I suddenly feel like I need to have makeup. The thing is, I like the way I look without makeup. I know I don't need it. Two weeks ago when I was still living out of a 40-liter sack, I would have thrown out all of it but the trademark blue mascara I wear to concerts.
But I'm not living out of a sack anymore. My new bathroom has a shit ton of storage space, and the makeup I have still isn't that much, even if I keep all of it. I'm just at odds with myselves. Or maybe the problem is I don't know yet how to integrate my trail self with my off-trail self. Or maybe there aren't two selves at all, just different environments and responses to those environments. Maybe what I do is just keep adapting. Keep the ~dontcareaboutmakeup~ confidence and the four lipsticks because sometimes there are occasions where lipstick is fun and not every color lipstick goes with everything and no one said you have to carry it up Mt. Whitney or like anywhere at all, that's what all those cabinets are for.
I like my life in Dallas. I liked it before the trail, I liked it on the trail, and I like it now. But there are parts of it that don't fit anymore and parts that never fit to begin with. There are parts that used to fit really well that now just fit sometimes. I'll move those parts to smaller spaces and make room for new things. For the new parts I brought back with me. Ones that aren't physical, that won't fit on a bookshelf or in a drawer, that I carried with me home from the trail and that I'll try to carry on with me into the future. The great thing about these parts is that, though they can't be held in my hand or framed or stored away in a safe-deposit box, they can be lost and found again and again in different places and people and experiences. Once you know they're there, they're yours. And they weigh literally nothing.
Part of the beauty of any human experience is its singularity. I could never make anyone understand what I went through on the PCT or how I changed or what I learned. Fortunately and unfortunately, that is a non-transferrable understanding. But I want to share what I can, however I can. When you buy a piece of art, no one else can get in your head and understand the intricacies of why it spoke to you, but if you hang it up on the wall, you can at least give others a chance to find something in that piece that speaks to them, even if it has nothing to do with the reason you bought it. Appreciation of an experience can be as singular as the experience itself.
As I look back through my collection of PCT mementos, I find the physical is limited to a wad of bandanas and a stack of stickers from stops along the route, three rolls of film, a handful of rocks, a holey trash bag of tattered, torn, dirt-stained, sun-faded clothes, and a bruise on my hip that seems unlikely to ever go away. The rest is an abstract blur of memories, friendships, and lessons I've tried and failed again and again to accurately express in words.
I didn't take beautiful pictures on a fancy camera and I didn't record many conversations with other hikers. I didn't track my location with GPS or take a selfie at all the iconic waypoints. I didn't live blog my journey or diligently record every mile every day. I didn't call home enough or post to the Facebook group of friends and family I promised to update regularly. I didn't hike every mile of the PCT. I didn't even complete a single state. But despite whatever I didn't do, I started. I took one huge step from a flat, safe surface to a single stone on the ledge and looked out into the foggy depths of the unknown. I stood wobbling on the stone for months, glancing back and forth from that rock-hard stability to the heart palpitation-inducing uncertainty in front of me, and when I could teeter no longer, I jumped.
For six months I fell, from shining rays of novelty, ecstasy, and fun, through a mist of curiosity and wonder and into dark clouds of boredom, sadness, loneliness, and disappointment. There bolts of rage and claps of frustration energized me and I kept falling, a single drop in a shower of connection and self-discovery. Eventually I was slowed way down by a canopy of peace that lowered me gently into an old-growth forest of acceptance and gratitude.
I experienced it all, mostly by myself, and a lot of it was the good things I mentioned but a lot of it was those other, darker things. A big part of my experience was getting through the experience. Maintaining my will and desire to do what was necessary to achieve the goal, day after day. Doing what was necessary even when I couldn't find the will or desire. Learning and re-learning to be kind to myself. Never giving up. Giving up for half a day to get it out of my system. Trying to stay sane. Going insane and then writing it all down and reading it back to myself in the hopes of finding my sanity somewhere on the page. Usually it helped.
So I jumped from the ledge stone and landed back at some version of the glad wood, and though I don't have a detailed log of the fall, I do have notebooks full of sporadic recordings of the feelings I felt as I fell. I want to share what I wrote, because it's the truest expression of what my journey along the trail was. I'll remember the views and the people and the lifestyle, but a lot of what I'll remember most from this first thru-hike attempt (yes, I expect there will be more), is what I learned about myself through the experience. My biggest fear is forgetting, and I hope to gain some insight into what I learned and what the experience meant to me by going back through all my journal entries and sharing what I find I found. I'll hang it here on proud display, and though you may not see what I see, I hope we can stand next to each other staring at this weird piece of art, tilt our heads to the side and go, "Hmm."


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Access to SDL
The School of Medicine Office of Communications will grant access to any School of Medicine or School of Public Health employee to edit a YSM/YSPH website upon approval from the department's administrator. Before granting access, new users must view the SDL Video Series. Additional training materials are available in the SDL Support section of our website.
While SDL can have a steep learning curve for users unfamiliar with the web, those who have previously used content management systems or use SDL on a regular basis (at least once a week) learn to use the system quickly. The Web Group has generated a tremendous amount of support materials, including written instructions for every template available and video instructions for all major aspects of the system. Visit the SDL Support website for more information.
Students, casual employees, and temporary employees are not allowed access to SDL.
Please contact firstname.lastname@example.com to request access to a SDL website.
Gain Access to SDL Tridion
Anyone seeking access to Tridion must either watch the videos on this site or review the support pages and successfully complete two quizzes.
Additionally, no new users are granted access to Tridion until they have received the University Content Editor Accessibility Training.
Once you've completed these tasks, please contact firstname.lastname@example.com, indicating the site(s) you'll be editing so we can grant you the appropriate access.


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AITOM – comprehensive solutions for your website.
From initial study, through website development to internet marketing. Your website's results are our responsibility.
Selected references
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And over the past eight years we have done much more »
Our work for you will make sense, otherwise it wouldn't make sense for us.
We focus on a comprehensive solution, remaining in total control at every step.
We work hard and have countless projects under our belts.


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1. Application
As electronic equipment becomes smaller and more sophisticated, integrated circuit (IC) and large-scale integration (LSI) packages on printed-circuit boards (PCBs) need to be downsized. To meet the needs of this trend, a technique called flip-chip bonding where an IC chip is directly mounted facedown on a printed-circuit board has become important. In addition, three-dimensional packaging using stacked chips is also important for creating smaller electronic devices. These techniques rely on creating small solder bumps on the microchips to serve as connection terminals. The bumps have a height of about 20 μm, although this can vary depending on the chip size. If the bumps are too small, the bond between the microchips may not be complete. To prevent defects during the PCB bonding process and short circuits after the process, it is essential to accurately measure the height of the bumps.
2. Olympus' solution
Olympus' STM7 measuring microscope is one of the best tools for quickly and accurately measuring these bumps. The microscope's highly rigid guide, resistant to deterioration with age, is equipped with a high-precision scale, enabling accurate height measurement with a resolution of 0.1 μm. The most notable characteristic of the STM7 microscope is the auto focus function, that can obtain accurate data for the top and bottom positions of a bump (Figures 1 and 2). The tracking mode makes it easy to measure the height of the bumps in just a few seconds simply by moving the XY stage. The autofocus' light source uses a laser, enabling you to narrow down the focus point to a micron-sized area, making it possible to securely focus on an area as small as the top of a wafer bump.
Figure 1. The top position of a bump.
Figure 2. The bottom position of a bump.


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England's Greg Owen has never had a piece of a 54-hole lead on the PGA Tour. Now he hopes he can stay relaxed with the great short game that has him in position to win his first title in his 214th tour event.
And winning would mean so much more than simply having a title on every tour Owen's ever played.
"Just a huge, huge relief that what you've been striving for your whole life you can say you've achieved," Owen said Saturday.
Owen and Fabian Gomez of Argentina each shot a 3-under-par 67 to share a one-stroke lead after 54 holes at the St. Jude Classic in Memphis, tied at 9-under 201.
Swirling wind and tough pins kept everyone guessing on a hectic day at TPC Southwind, where as many as six players had a piece of the lead.
Both Owen and Gomez putted well on the firm greens despite hitting only 11 of 18 greens. Owen needed 26 putts in making four birdies and one bogey, while Gomez had 24 putts despite three bogeys. He had six birdies.
Brooks Koepka had at least a piece of the lead through the first two rounds and got to 10 under. He finished with a 71 and was tied with Scott Brown (68) for second at 202.
"It was swirling, swirling so much we couldn't even figure out a wind direction," Koepka said. "We knew it was coming from the south. Downwind, threw grass up, hit you in the face two seconds later. You never really knew where the wind was."
Matt Jones (68) and Austin Cook (72) were tied at 204, and David Toms (69) and Camilo Villegas (66) were tied with six others at 205. Phil Mickelson (69) was in a group tied at 207.
Park overtakes Kim
South Korean stars Inbee Park and Sei Yong Kim added another chapter to their friendly rivalry.
Park shot a 7-under 66 and overtook Kim on the final hole to take a two-stroke lead into the final round of the KPMG Women's PGA Championship in Harrison, N.Y.
Kim, a rookie who came into the day with a one-stroke lead, shot a 69. The two had battled all afternoon each went into the final hole at 13-under par. But Park, who needed just 28 putts Saturday, made her seventh birdie of the day on 18, and Kim missed a 4-foot putt for par.
A win could allow Park to catch top-ranked Lydia Ko in the rankings. She could also join Annika Sorenstam as the only golfers to claim this title in three consecutive years.
Langer leads by eight
Bernhard Langer shot a 4-under 67 in the third round of the Senior Players Championship to open an eight-stroke lead in Belmont, Mass.
Langer is trying to become the first golfer to defend his title in this tournament since Arnold Palmer in 1984-85.
Russ Cochran was even for the day and in second in the third Champions Tour major of the year at 8 under. Scott Verplank shot a 66 to move into a four-way tie for third. He was tied with Colin Montgomerie, Jeff Hart and Guy Boros.


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design studio Stocks and Companies
The following are stocks or mutual funds tagged as design studio. When researching companies, it is important to know what companies have a similar focus. The stocks below have been categorized as "design studio" by either user submission or electronic means.
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Alton Brown teaches the proper technique for trussing a turkey. This video is part of Thanksgiving Videos with Alton Brown show hosted by Alton Brown . SHOW DESCRIPTION :This video is only available online at Foodnetwork.com
7 Replies to "How to Truss a Turkey-Food Network"
I use this technique for rotisserie chickens … keeps everything tucked in; and not a-danglin'.
My mom and I watch this video EVERY YEAR as we truss our turkey 🙂 I don't know what I would do without it!
Dy you stuff the bird before or after trussing?
Eating turkey any time soon? This is the best trussing video I've seen yet!!
(Did Mary cook a nice big HAM on Jesus's birthday's? )
AB is #1. Thanks buddy. Happy Thanksgiving
Awesome, just saved the day! #Tgiving2013
Alton, you the man!!! Each year I need a refresher and this is the ONLY way to truss! Works great for rotisserie!!! Thanks-Jim


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Purpose: Irinotecan (CPT-11) induced diarrhea occurs frequently in patients with cancer and limits its usage. Bacteria β-glucuronidase (GUS) enzymes in intestines convert the nontoxic metabolite of CPT-11, SN-38G, to toxic SN-38, and finally lead to damage of intestinal epithelial cells and diarrhea. We previously reported amoxapine as a potent GUS inhibitor in vitro. To further understand the molecular mechanism of amoxapine and its potential for treatment of CPT-11–induced diarrhea, we studied the binding modes of amoxapine and its metabolites by docking and molecular dynamics simulation, and tested the in vivo efficacy on mice in combination with CPT-11.
Experimental Design: The binding of amoxapine, its metabolites, 7-hydroxyamoxapine and 8-hydroxyamoxapine, and a control drug loxapine with GUS was explored by computational protocols. The in vitro potencies of metabolites were measured by Escherichia coli GUS enzyme and cell-based assay. Low-dosage daily oral administration was designed to use along with CPT-11 to treat tumor-bearing mice.
Results: Computational modeling results indicated that amoxapine and its metabolites bound in the active site of GUS and satisfied critical pharmacophore features: aromatic features near bacterial loop residue F365′ and hydrogen bond toward E413. Amoxapine and its metabolites were demonstrated as potent in vitro. Administration of low dosages of amoxapine with CPT-11 in mice achieved significant suppression of diarrhea and reduced tumor growth.
Conclusions: Amoxapine has great clinical potential to be rapidly translated to human subjects for irinotecan-induced diarrhea. Clin Cancer Res; 20(13); 3521–30. ©2014 AACR.
Translational Relevance
Irinotecan (CPT-11) is a cytotoxic drug that has wide applicability and usage in cancer treatment. Despite its success, patients suffer dose-dependent diarrhea, limiting the drug's efficacy. No effective therapy is available for this unmet medical need. Bacteria β-glucuronidase (GUS) enzyme in the intestines plays a pivotal role in CPT-11–induced diarrhea via reactivating the non-tox CPT-11 metabolite, SN-38G, back to toxic SN-38. Here, we report the molecular mechanism for an identified GUS inhibitor (GUSi) amoxapine and the corresponding animal studies using amoxapine in combination with CPT-11. Because amoxapine metabolites are potent GUSis, the use of amoxapine significantly delayed or suppressed diarrhea in vivo at a dose remarkably lower than normal use. Rapid translation to human subjects may be achievable for this old drug to alleviate CPT-11 drug toxicity and improve efficacy.
Irinotecan (CPT-11) is a commonly used chemotherapeutic agent for the treatment of malignances, such as cancers of brain, colon, and lung, and refractory forms of leukemia and lymphoma (1). However, 88% of patients receiving CPT-11 suffer from diarrhea, with 20% to 30% of them having severe diarrhea (CTCAE grades 3 and 4; ref. 2). This side effect increases patient suffering and, more importantly, prevents dose intensification and efficacy in a significant fraction of patients undergoing irinotecan treatment (3). Some patients with severe diarrhea are forced to delay further treatment or stop therapy altogether. No effective therapy exists to overcome such diarrhea, and the US Food and Drug Administration (FDA) defines this situation as an unmet medical need (http://www.fda.gov).
The underlying mechanism of CPT-11–induced diarrhea has been extensively investigated. As a prodrug with a carbamate-linked dipiperidino moiety, CPT-11 is hydrolyzed by carboxylesterases (CES) in vivo to remove the dipiperidino group and it is then converted to its therapeutically active form SN-38. SN-38 inhibits type I DNA topoisomerase thereby killing rapidly proliferating tumor cells (4, 5). SN-38 undergoes further metabolism in both liver and intestine by UDT-glucuronosyltransferase (UGT), which conjugates it with glucuronic acid to form the inactive SN-38G (6, 7). This nontoxic form of the drug is then eliminated into gastrointestinal (GI) tract (8). In intestines, bacterial β-glucuronidase (GUS) enzymes in the microbiota, such as Escherichia coli, remove the glucuronide group of SN-38G for a carbon source, regenerating cytotoxic SN-38 (9). Elimination of bacteria by antibiotics significantly reduced the SN-38 concentration in GI, showing the pivotal role of bacterial GUS (10). The accumulation of SN-38 in the intestinal lumen causes damage to intestinal epithelial cells and subsequently induces dose-dependent diarrhea (11, 12).
Given the essential role of bacterial GUS in the process of SN-38G reactivation, GUS inhibitor (GUSi) is expected to mitigate CPT-11–induced diarrhea. A GUS activity–based high-throughput assay has identified several compounds as potent bacterial GUSis (13–15). X-ray crystallography studies further revealed that the contacts between the inhibitors and a unique 17-residue "bacterial" loop lead to the selectivity of these compounds without affecting the mammalian GUS (13). Proof of concept studies have indicated that 2 of these compounds decreased the occurrence of diarrhea in mice receiving CPT-11 (13, 14). However, these compounds will require prolonged lead optimization, in vitro and in vivo testing and high failure rate evaluations, including pharmacokinetic (PK)/pharmacodynamics (PD) studies and toxicity profiles for the single compound and in combination with CPT-11 before clinical trials can begin. Known drugs, having been used clinically, are believed to be good sources for new indications with clearly understood safety and toxicity profiles (16). Therefore, we screened about 1,000 FDA-approved drugs for the ability to inhibit the enzymatic activity of purified bacterial GUS. The antidepressant drug amoxapine (AMOX) was identified as a potent in vitro GUSi and determined to be one of the most promising potential drugs against bacterial GUS (17).
The chemical structure of amoxapine is different from previously reported GUSis, inhibitor 1 and inhibitor 2 (Supplementary Fig. S1), but has similar potency for inhibiting GUS in vitro (17). As an old drug, amoxapine has known PK/PD properties and toxicity profile, which would facilitate its translation to human subjects. However, the in vivo efficacy of amoxapine against CPT-11–induced diarrhea remains unknown. 7-Hydroxyamoxapine (7-OHAMOX) and 8-hydroxyamoxapine (8-OHAMOX) are the major metabolites of amoxapine (18). The metabolites may contribute to the in vivo efficacy. This motivated us to explore the exact binding mode of amoxapine and its metabolites with bacterial GUS, as well as the in vitro efficacy of the metabolites. According to the in silico and in vitro results, the administration of low-dosage amoxapine along with CPT-11 was designed to treat tumor-bearing mice.
Materials and Methods
Computational details
Molecular docking protocol.
The complex structure of bacterial GUS with inhibitor 2 was taken from the Protein Data Bank (PDB) database (PDB ID: 3LPF; ref. 13) and systematic operation was applied to get the tetramer, the functional unit of GUS. The 2 monomers, which constitute the ligand-binding site were kept in the following docking experiments as receptor. Glide 5.7 program from Schrodinger Suite was used to perform the docking experiments (19). Two water molecules forming hydrogen bonds with the natural ligand in the crystal structure were kept in the receptor. Then, the structure model was subjected to "Protein Preparation Wizard" workflow in Maestro (version 9.2) to assign hydrogens. The docking grid was generated using "Receptor Grid Generation" with center on the original ligand and internal size of 10 × 10 × 10 Å. The ligands were prepared using Ligprep 2.5 with MMFF force field from Schrodinger suite (19). Glide SP parameter set was applied in the docking protocol. The top ranking models by glide score were selected as the final binding mode.
Molecular dynamics simulation.
The docking poses were used as the initial structure in MD simulation. The ligands were optimized at the Hartree-Fock level with the 6-31G (d,p) basis set using Gaussian 09 (20) and then restrained electrostatic potential (RESP) charges were calculated using the B3LYP/cc-pVTZ quantum mechanical method. The Amber ff99SB force field (21) and general Amber force field (GAFF; ref. 22) were applied to proteins and ligands, respectively. All MD simulations were carried out using AMBER11 (23) on BlueBiou of the IBM cluster at Rice University using 32 cores with the same protocol. Each simulation system was put in a truncated octahedron periodic box of SPC water molecules with a margin of 10.0 Å along each dimension, and sodium ions were added to maintain charge neutrality. All covalent bonds to hydrogen atoms were constrained using the SHAKE algorithm (24). Electrostatic interactions were calculated using the particle-mesh Ewald (PME) algorithm. A cutoff of 10 Å was applied to Lennard–Jones interactions (25). A total of 500 steps steepest-descent minimization followed by 1,500 steps conjugated gradient minimization were applied to the system. Then it was heated up from 0 to 300 K gradually over 20 ps using the NVT (constant particles N, volume V, and temperature T) ensemble with the solutes restrained by a weak harmonic potential. Afterward, 160 ps equilibrations were carried out in the NPT (constant particles N, temperature T, and pressure P) ensemble via 3 steps: the solutes were restrained whereas the waters and counter ions were equilibrated in the first 60 ps, then protein were relaxed in the next 20 ps, and all of the restraints were removed in the last 80 ps. Finally, the production MD simulations were conducted at 1 atm and 300 K under the NPT ensemble for 4 ns. Temperature was controlled using Langevin dynamics (26). The last 2 ns trajectory from production simulation was used to obtain the snapshots for MMPBSA free energy calculation (methods were described in supplementary materials; refs. 27–29).
In vitro enzyme and cell-based assays
Amoxapine, 7-hydroxyamoxapine, and 8-hydroxyamoxapine were obtained from Sigma-Aldrich. E. coli DH5α (Zymo Research) was used for the cell-based assay. Purified E. coli GUS enzyme (Catalog No. G8420-25KU) was purchased from Sigma-Aldrich. All other reagents were obtained from Fisher Scientific. The assays were designed and performed as described in ref. 17. For detailed information, see Supplementary Method section.
In vivo animal studies
Irinotecan (CPT-11; Upjohn) was purchased from LC Laboratories (#I-4122) as a hydrochloride salt (>99% high-performance liquid chromatography purified grade). CPT-11 was dissolved in ddH20 to make a stock of 20 mg/mL and stored at room temperature for a maximum of 2 hours before use. As vehicle control, all animals received an equivalent volume (compared with experimental groups) of 1% DMSO (ddH2O) solution. Healthy 6- to 8-week-old female Balb/cJ mice (000651) were obtained from Jackson Laboratories. Mice were housed in conventional metabolic cages (N = 1/cage). All studies were conducted in accordance with the guidelines of the Animal Care and Use Committee of Houston Methodist Research Institute.
The well-described CT-26 cell line, derived from a murine Balb/c colon adenocarcinoma, was used to make the tumor-bearing mouse model by s.c. injection of 0.02 mL cells in PBS at 5 × 107 cells/mL into the posterior mid-dorsum of mice (30). Tumor volumes were estimated by the formula π/6 × a2 × b, where a is the short axis, and b is the long axis. When tumor size reached ∼500 mm3 (∼10 days after implantation, defined as day 1), mice were divided into 5 groups of 10 to 15 animals each: (i) vehicle group, vehicle controls received an equivalent volume of ddH2O intraperitoneally and 1% DMSO by oral gavage (∼100 μL twice per day); (ii) CPT-11 only group, CPT-11 was injected (50 mg/kg) intraperitoneally once daily in the morning with oral gavage of 1% DMSO (∼100 μL twice per day) for 12 days; (iii) Amox-1 mg group, amoxapine gavaged (0.5 mg/kg) twice per day (10 hours apart) for 12 days starting on day 1 with CPT-11 intraperitoneally once per day; (iv) Amox-5 mg group, amoxapine gavaged (2.5 mg/kg) twice per day (10 hours apart) for 12 days starting on day 1 with CPT-11 intraperitoneally once per day; (v) Inhibitor I group, inhibitor I gavaged (0.5 mg/kg) twice per day (10 hours apart) for 12 days starting on day 1 with CPT-11 intraperitoneally once per day. Inhibitor 1 was used as a control to compare the in vivo efficacy with amoxapine, and it is the closest analog to inhibitor 2 and has been tested in animals (ref. 13; Supplementary Fig. S1). Total injected volume for drugs or vehicles was identical for each animal.
Fifty mg/kg CPT-11 in mice is roughly equivalent to the typical 5 mg/kg human CPT-11 dose based on differences in body surface area (BSA; ref. 31, 32), and 1 and 5 mg/kg Amox in mice is approximately equivalent to 0.081 and 0.243 mg/kg human equivalent dose (HED), respectively (32). Body weight, stool consistency, and occult blood in stool were monitored daily using methods previously published (13). Mice were examined daily for signs of diarrhea (fecal staining of skin, lose watery stool) and bloody diarrhea (black sticky stool). After sacrifice, jejunum, ileum and colon samples were dissected. Tissues were formalin-fixed and paraffin embedded for histologic examination using 6-μm-thick, 200-μm step serial sections stained with hematoxylin and eosin (H&E), and a histologic score for each slide was calculated as described previously (13). For immunohistochemical staining, frozen slides at a thickness of 10 μm were stained with antibodies against Ki67 and β-catenin overnight at 4°C. Slides were then washed and stained with the appropriate secondary antibodies. Mounted slides were examined under Olympus laser scanning confocal microscopy (FV1000, TMHRI Advanced Cellular and Tissue Microscope Core Facility).
Statistical analysis
Statistical analysis was performed using SigmaPlot software (SigmaPlot for Windows, version 11.0). To determine the differences across multiple groups, one-way ANOVA was carried out. Independent 2-sample t test was conducted to detect difference in means between 2 groups. Data were summarized as means ± standard deviation (SD). P < 0.05 was considered statistically significant.
Analysis of binding modes obtained from docking
Similar to the inhibitor 2 in 3LPF (PDB code; ref. 13), all compounds bound at the entrance of the active site and make contacts with the residues from the primary monomer and F365′ from the bacterial loop of the adjacent monomer (Fig. 1). The side chain of F365′ is positioned parallel to the tricyclic aromatic ring of amoxapine and form a strong π–π interaction. L361 from the bacterial loop of the primary monomer, and F448/Y472 in the active site locate close to amoxapine and make strong hydrophobic contacts (Fig. 1A). The piperazine ring of amoxapine points into the active site with the amino moiety extending to within 2.7 Å of the catalytic E413 residue, forming strong hydrogen bond. The binding modes of the metabolites, 7-hydroxyamoxapine and 8-hydroxyamoxapine, are very similar to that of amoxapine (Fig. 1B). Additional hydrogen bonds are found between the hydroxyl substitutions and the main-chain oxygen atom of F365′. However, for loxapine, having the substitution of methyl on the piperazine ring, no hydrogen bond is formed with E413 (Fig. 1C). The orientation of loxapine is totally different from that of amoxapine, with the methyl-piperazine pointing outside from the active site, and the tri-cyclic aromatic ring lying in the active site instead.
To compare the modes of amoxapine and inhibitor 2, the docking pose of amoxapine and pose of inhibitor 2 from the crystal structure are shown simultaneously in the active site in Fig. 1E. The dihydroquinoline ring of inhibitor 2 almost overlaps with the tri-aromatic ring from amoxapine, forming contacts with F365′. The piperazine ring of amoxapine extends deeper inside the active site and has a closer hydrogen bond distance with E413 (2.7Å) compared with that of the hydroxyl group of inhibitor 2 (3.3 Å). Key characters were extracted based on the binding mode of amoxapine and inhibitor 2: 2 aromatic ring pharmacophore features located in a parallel manner with F365′ and hydrogen bond donor feature nearby E413 (Fig. 1F). Having both of the metabolites of amoxapine satisfying the pharmacophore model and even forming additional hydrogen bonds with main chain of F365′, it indicates that the activity of metabolites may be at a similar level as amoxapine or even more potent.
Molecular dynamics simulation and MMPBSA energy calculation
To refine the proposed binding modes from docking and evaluate the binding free energy, the complex structures of amoxapine, 7/8 hydroxyamoxapine, and loxapine were taken as initial structures for molecular dynamics simulation. The root mean square deviation (RMSD) of protein backbones are stable and around 2 Å in all the complex systems (Fig. 2). The average RMSD of amoxapine, 7-hydroxyamoxapine, 8-hydroxyamoxapine, and loxapine in 4 ns is 2.67, 2.64, 2.41, and 4.59 Å, respectively. Dissociation of ligand was not observed in all the systems, but the RMSD for loxapine system is much larger than the others, which indicates reorientation and relocation occurred during the simulation. AMOX and 7/8 hydroxy metabolites conducted almost the same binding poses before and after the simulation, whereas loxapine moved a lot during the process (Supplementary Fig. S2). The energetically unfavorable conformations usually result in a reorientation of the ligand or dissociation of the complex during the simulation. The high RMSD value and reorientation of loxapine implies unstable binding. Strong and stable hydrogen bonds were observed between amoxapine and the carboxyl side-chain of E413 during the simulation, as well as its metabolites (Supplementary Table S1). The occurrence time is more than 60% and average distance around 2.8 Å. The hydrogen bond observed in the initial docking poses of metabolites with main chain of F365′ was not maintained during the simulation.
Table 1 lists the energy items from the MMPBSA free energy calculation based on the MD simulation and the glide-docking score based on the initial poses. In both the MMPBSA free energy calculation (ΔGMMPBSA) and glide score, loxapine was ranked as the least potent compound in the table. It is consistent with our previous results from enzyme and cell-based assays that loxapine shows no inhibition of bacterial GUS, with IC50 values > 100 μmol/L. For loxapine, the desolvation cost (ΔGPB) is particularly higher than the other molecules. In its initial docking pose, the tri-aromatic ring was located inside the active site composed by side chains of several polar residues, E413, D163, and K562. The unfavorable hydrophobic ring in a polar environment may cause the highly increased electrostatic salvation energy, and finally the large increasing MMPBSA free energy for loxapine. 7/8-OHAMOX ranked as more potent than amoxapine in terms of glide score, however inversely via free energy. According to the computational results, we speculate that both of the metabolites may be active in the in vitro experiments.
Amoxapine and its metabolites are potent GUSis
Amoxapine and its metabolites were simultaneously tested in the GUS enzyme assay and cell-based GUS activity assay. AMOX, 7-OHAMOX, and 8-OHAMOX generated IC50 values and SDs of 796 ± 29 nmol/L, 981 ± 183 nmol/L, and 1,991 ± 275 nmol/L, respectively, in the GUS enzyme assay (Fig. 3A). The cell-based assay involves the measurement of GUS enzymatic activity in live, intact E. coli bacteria. AMOX, 7-OHAMOX, and 8-OHAMOX generated IC50 values and SDs of 58 ± 5 nmol/L, 41 ± 6 nmol/L, and 100 ± 1 nmol/L, respectively (Fig. 3B). A bacterial cytotoxicity assay using these same compounds indicated no toxicity to the bacterial cells at 2 and 20 μmol/L (Fig. 3C). Thus, the activity of the AMOX and metabolites in the GUS cell-based assay was not because of killing of the bacteria. AMOX, 7-OHAMOX, and 8-OHAMOX demonstrated 14-, 24-, and 20-fold, respectively, more potent activity in the cell-based GUS activity assay compared with the purified GUS enzyme assay. Although this trend is unusual, it has been repeatedly observed for other GUSi compounds, but varies depending on the compound, with some compounds shifting less potent in the cell-based assay whereas others becoming more potent (13, 17). The 8-OHAMOX metabolite is somewhat less potent than AMOX, with about 2.5-fold higher IC50 in enzyme assay and 2-fold higher in the cell-based assay. However, both of the metabolites are active, having relatively low IC50 values. In addition, we previously demonstrated that amoxapine had no measurable IC50 against mammalian GUS (>100 μmol/L IC50), thus resulting in a >100-fold selectivity for inhibiting bacterial GUS over mammalian GUS (17). With the 7 or 8 position substituted by hydroxyl, both of the metabolites retained the activity against bacterial GUS. The in vitro results are consistent with the computational modeling prediction and shows that not only AMOX, but also its major metabolites are potent GUSis.
Amoxapine successfully delayed or suppressed CPT-11–induced diarrhea in tumor-bearing mice
In our in silico and in vitro studies, both amoxapine and its metabolites show good potency against bacterial GUS. We thus conducted animal experiments to test the efficacy of amoxapine in vivo. Amoxapine was orally administered at 1 or 5 mg/kg/day along with daily intraperitoneal CPT-11 treatment (the Amox group) in tumor-bearing mice. Signs of diarrhea exhibited in mice were most apparent by residual staining around the anus. Diarrhea was first observed on day 7 of daily CPT-11 treatment with 50% of the mice from the CPT-11 group exhibiting diarrhea, whereas 10% of the Amox-1mg group had diarrhea (Fig. 4A). Peak efficacy was apparent on day 8 when 65% of the mice from the CPT-11 group exhibited diarrhea staining compared with only 10% of the mice in the Amox-1mg group. By day 9, 90% of the CPT-11 mice had diarrhea compared with 50% of Amox-1mg group. The Amox-5mg treatment totally prevented the appearance of diarrhea on day 7, and on days 8 and 9, only 20% and 30% of the mice, respectively, in the Amox-5mg group showed diarrhea. Thirty percent of the mice in both the amoxapine groups never showed diarrhea during the course of the entire study, and the body weight of the survived mice showed rapid recovery (about 50% of the lost weight) 4 days after the cessation of CPT-11. The previously published GUSi inhibitor 1 (13) was also included in this study as a positive control. Overall, amoxapine (1 or 5 mg/kg) had similar efficacy as inhibitor 1 in suppressing diarrhea (Fig. 4A). In addition, diarrhea staining in the CPT-11 group was much more severe than diarrhea staining in the Amox groups. Staining in mice from the CPT-11 group was darker (bloodier) and more liquid, and consequently, all mice in the CPT-11 group had to be euthanized before or on day 12. Mice in the Amox-5mg group had a significant delay on the euthanization survival plot (P = 0.004, log-rank test; Fig. 4B), even more of a delay than the inhibitor 1 control. Thus, in addition to the frequency of diarrhea being reduced, the euthanization data indicated that the severity of diarrhea was also attenuated by amoxapine.
Histologic examination of the jejunum, ileum, and colon indicated that all tissue samples from CPT-11–treated mice demonstrated moderate to severe damage, as shown in Fig. 5A. Tightly arrayed epithelial cells were displayed in the vehicle group samples, whereas obvious short villi and crypt loss, or even a complete abolishment of the top villi along with a large influx of inflammatory cells and significant fibrosis were observed in jejunum and ilenum in damaged intestines (Fig. 5A). In comparison with the damage in the small intestine, the morphology of colon tissues in CPT-11–treated mice showed similar changes (Fig. 5A). In contrast, oral administration of amoxapine protected the glandular structure of the intestinal and colon tissues (Fig. 5A and Supplementary Table S2). The protective effect of amoxapine was further studied by immufluorescence staining using the proliferative marker Ki67 and cell membrane marker β-catenin (Fig. 5B and C). Severe proliferative cell loss was observed in CPT-11–treated mice, implying a difficult recovery from the damage, in accordance with the loss of cell membrane integrity. However, cotreatment of amoxapine with CPT-11 facilitated a significant increase of proliferative cells and maintained the integrity of the top epithelial cell membrane (Fig. 5B and C and Supplementary Table S2). These results indicate convincing in vivo efficacy of amoxapine in suppressing diarrhea in CPT-11–treated mice.
Cotreatment of amoxapine and CPT-11 in reducing tumor growth
Cotreatment of amoxapine and CPT-11 yielded positive results in reducing average tumor growth (Fig. 4C). Throughout the experiment, the average tumor size of mice in the Amox-1mg group was as low as, if not lower than, the average tumor size of CPT-11 group mice. These data suggested that the 1 mg/kg dose of amoxapine, which possessed anti-diarrhea efficacy, had absolutely no effect on diminishing the tumor-killing ability of CPT-11. Furthermore, mice in the Amox-5mg group showed significantly lower tumor size than the average tumor size of CPT-11 group mice (P = 0.015, two-way ANOVA; Fig. 4C), suggesting possible enhanced efficacy for reducing tumor size by the combination of amoxapine and CPT-11.
For the first time, we report that the antidepressant drug amoxapine has the potential to be repositioned as a new potent and selective bacterial GUSi that alleviates irinotecan-associated diarrhea. The binding mode of AMOX is exhibited at the atomic level by using molecular docking and dynamics simulations. AMOX binds in the same active site of GUS as inhibitor 2 in crystal structure (17) and shares common pharmacophore features: 2 aromatic features near bacterial loop residue F365′ and one hydrogen bond donor feature toward E413, but with different chemical patterns. As a result of such binding with GUS, in vitro assays of amoxapine showed potent inhibition of GUS activity. Furthermore, the 2 metabolites with similar binding modes showed strong in vitro GUS inhibitory activity and likely contributed to in vivo efficacy.
Severe late-stage diarrhea, caused by intestinal SN-38, frequently occurs in patients treated with CPT-11. The current recommended treatment for this diarrhea is loperamide or antibiotics (33). However, loperamide only treats the symptoms while tissue damage still occurs, and it is not recommended for more than 48 hours because of the risk of paralytic ileus [Pfizer, Inc. (2012); CAMPTOSAR, New York]. Antibiotics kill the intestinal biota, which is important in carbohydrate metabolism, vitamin production, and the processing of bile acids, sterols, and xenobiotics; they are not optimal for the patients already challenged by tumor growth and chemotherapy (34, 35). There are active clinical trials in testing drugs to prevent or suppress such diarrhea, but no positive results have been published (clinicaltrials.gov identifier: NCT00037180, NCT01410955, NCT00255229, NCT00040391, NCT00006269, NCT00143533, and NCT00582426). GUSis are expected to fit the therapeutic need for several reasons. First, a GUSi would inhibit the intestinal regeneration of SN-38 from SN-38G to alleviate diarrhea via blocking the bacteria GUS. Concerns may arise that decreasing the SN-38 concentration in intestinal lumen may weaken the antitumor efficacy of CPT-11. However, SN-38 in feces of patient with cancer was only 2.45% ± 1.16% of the total administrated CPT-11 (11). Thus, re-absorption of SN-38 from intestines may not contribute significantly to plasma concentration. Moreover, blocking the SN-38 intestinal absorption in patients by using oral alkalization showed no decrease on the tumor response rates (36). To date, intestinal SN-38 has been reported to associate with only toxicity, not efficacy. Second, GUSis would not kill the commensal bacteria essential for human health and avoid potential complications of using antibiotics, including allergies. Third, reduction in the diarrhea side-effect may allow dose intensification of CPT-11 above what is currently used and thus enhance antitumor efficacy.
Amoxapine is identified as a potent and selective GUSi that may satisfy the aforementioned criteria. In addition, amoxapine has further advantages to strengthen the case for repositioning it for this new indication. Cotreatment of 5 mg/kg amoxapine with CPT-11 yielded enhanced effect in reducing tumor growth in mice, which was not found in mice treated with inhibitor 1 (Fig. 4C). We speculate that the observed enhanced antitumor efficacy may lie in the noncompetitive P-glycoprotein inhibitor property of amoxapine (37). P-glycoprotein is located on cell membrane and pumps foreign substances out of cells. Acquired tumor cell resistance to CPT-11 and SN-38 has been observed because of the drug transporter P-glycoprotein (38). Amoxapine may block the P-glycoprotein, lead to the accumulation of SN-38 in the cell, and thus increase the cell apoptosis and antitumor efficacy. However, the effect of amoxapine on tumor growth needs to be eventually confirmed in additional experiments with other xenograft models. Beside the enhanced antitumor efficacy, the dosages of amoxapine for preventing the diarrhea in mice was notably as low as 1 and 5 mg/kg/day, with the HED calculated as 0.081 to 0.243 mg/kg (32). It is roughly 6- to 8-fold lower than the minimal initial dose of amoxapine used for depression treatment in clinic. We expect low doses for patients to avoid new side effects or psychologic effects, and at the same time, achieve the diarrhea suppression. It should be noted that the extrapolation to an active human dose of amoxapine based on allometric scaling is imprecise. The dosage and resulting safety threshold would need to be determined in future work. Nevertheless, as an old drug, amoxapine has been carefully evaluated for side effects and toxicity in human body and its PK/PD properties have been comprehensively studied. It has the advantage to be translated to patients in a relatively short period compared with the de novo discovered compounds (e.g., inhibitor 1 or inhibitor 2).
Amoxapine is an FDA-approved drug and has been used in treatment of major depressive disorder since 1992 (39). The behavior of amoxapine in human subjects is clearly described in the literature (18, 40, 41). Amoxapine is rapidly absorbed and metabolized after oral administration, and maximum plasma concentration is achieved for AMOX, 7-OHAMOX, and 8-OHAMOX in 0.5, 1, and 3 hours, respectively. The level of 8-OHAMOX is significantly higher than that of AMOX or 7-OHAMOX in plasma. The area under the curve value for 8-OHAMOX was 3 to 5 times greater than that for AMOX. The mean elimination half-lives for AMOX, 7-OHAMOX, and 8-OHAMOX are 9.8, 5.1, and 30.8 hours, respectively. With the highest plasma concentration and longest half-life, 8-OHAMOX is the major existing form of AMOX in vivo by oral administration. The in silico and in vitro results showed that both 7-OHAMOX and 8-OHAMOX are potent GUSis, which likely contributed to the efficacy of AMOX against diarrhea in vivo. In both groups of AMOX, 1 and 5 mg/kg/day orally in combination with CPT-11(IP), significant suppression of severe diarrhea was observed starting on day 7 (Fig. 4C). About 30% of the mice receiving amoxapine never showed diarrhea during the course of the study.
Despite the observed efficacy, it is noted that the diarrhea could not be fully abrogated by amoxapine. The best anti-diarrhea effects of amoxapine were achieved on day 7 to 9, but at day 12, 70% of the mice still progressed to severe diarrhea. Interestingly, this phenomenon was the same for the mice receiving inhibitor 1 treatment (13). It should be noted that GUS is not the only factor leading to the diarrhea. The intestine in both humans and rodents is also rich in carboxylesterase (CES) and UGT enzymes. CES hydrolyzes the CPT-11 to SN-38, whereas the UGT enzyme undertakes the detoxification of SN-38 to SN-38G (4, 6, 7). The possible reason for accumulation of SN-38 in the presence of GUSi may lie in 2 aspects, the continuous conversion from CPT-11 to SN-38 by CES, and the incomplete transformation of SN-38 to SN-38G by UGT. GUSi is useless for the SN-38 that already exists in the GI other than the one regenerated from SN-38G by the bacterial GUS. These in vivo outcomes may be precisely controlled through the complicated manipulation of CES, UGT, and GUS. As the intestinal CES2 exhibits a higher affinity and velocity than hepatic CES1, it is suggested as a new clinical target to minimize CPT-11–induced diarrhea (42–44). The intestinal CES inhibitors working together with GUSi may achieve an improved therapeutic outcome for CPT-11 induced diarrhea. Moreover, the next step to strengthen the efficacy may be to reformulate AMOX as a slow-gut-release form to directly expose it to bacteria and improve the local compound concentration in intestine.
In conclusion, amoxapine and its metabolites are potent and selective GUSis binding in the active site near the bacterial loop. Significant suppression of diarrhea was obtained by combining the administration of amoxapine and CPT-11 in xenograft model mice, as well as improved efficacy in reducing tumor growth. As an old drug with known pharmaceutical properties and toxicity profile, amoxapine has great clinical potential to be transferred to human subjects in order to prevent CPT-11–induced diarrhea with minimal side effects and even strengthen the efficacy of this chemotherapy.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: R. Kong, X. Zhu, H. Zhao, J.E. Scott, L.-A. Yeh, S.T.C. Wong
Development of methodology: R. Kong, X. Zhu, S. Ahmad, H. Zhao, J.E. Scott, L.-A. Yeh, S.T.C. Wong
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): T. Liu, X. Zhu, S. Ahmad, H. Zhao, S.T.C. Wong
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): R. Kong, T. Liu, X. Zhu, S. Ahmad, A.T. Phan, H. Zhao, J.E. Scott, L.-A. Yeh, S.T.C. Wong
Writing, review, and/or revision of the manuscript: R. Kong, X. Zhu, S. Ahmad, A.T. Phan, H. Zhao, J.E. Scott, L.-A. Yeh, S.T.C. Wong
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): R. Kong, T. Liu, X. Zhu, H. Zhao, L.-A. Yeh, S.T.C. Wong
Study supervision: H. Zhao, J.E. Scott
Grant Support
This work was supported by John S. Dunn Research Foundation (S.T.C. Wong) in Houston Methodist Hospital and National Institutes of Health (NIH) grant U54CA156735 (J.E. Scott), as well as in part by a grant from the Golden LEAF Foundation (J.E. Scott) and funds from the State of North Carolina (J.E. Scott).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The authors thank J. Mancuso for proofreading the manuscript. The microscopic imaging experiments were performed at Houston Methodist Research Institute's Advanced Cellular and Tissue Microscope Core Facility. The authors are grateful for high performance computing resources provided by BlueBioU in Rice University. A patent application has been filed related to the use of amoxapine to treat CPT-11–induced diarrhea (US Patent Application 20130345196).
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
- Received February 15, 2014.
- Revision received April 7, 2014.
- Accepted April 10, 2014.
- ©2014 American Association for Cancer Research.


text:
It is said that not every victory is meaningful – we beg to differ. E-Club proudly brings to you Dota 2 – The Bounties. Contrary to the traditional game formats, every win on this tournament will be instantly gratified.
The name is apt to the format, as every win will let a team receive a 'bounty', and thus a progressive prize is developed as a team advances further into the tournament. Dota 2 – The Bounties is an online tournament, and it will be played on seven different SEA countries.
Tournament Bracket
Event Details
25th-26th May 2013
Will post team list once confirmed.
Competition Format:
16 teams Single Elimination (Best-of-1), Finals will be played Best-of-3
To be posted
Bounties will be collected as your teams win games and procced to the next round.
In-case of a walk-over win, bounty payment will be hold until your next game;
If you win your next round, you collect the current winning as well as walkover winnings.
However, if you lose the next match after a walkover win, you forfeit the bounty from that walkover match.
Bounties will be collected as your teams win games and proceed to the next round.
Team List
The invited teams are:
- Bagsik (confirmed)
- Bruh+4 (confirmed)
- Dreamz.Ledion.Steelseries (confirmed)
- Gangster.Blaque (confirmed)
- Happyfeet Reborn (confirmed)
- Inzomnia BG (confirmed)
- MI Cebu – It's Pro Time (confirmed)
- MILP – Speratus (confirmed)
- Mineski.Razer (confirmed)
- MSIEvoGT (confirmed)
- Pacific Badboys (confirmed)
- Pacific Badburn (confirmed)
- TnC Gaming (confirmed)
- Viggo.Ninjacool (confirmed)
- All in (confirmed)
- GK (confirmed)
Rules & Regulations
To be posted.
|Jointly Conducted By:
|Powered by:
The organiser reserve the rights to modify or change the content of this document without any prior notice


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A data is a information which is collected logically in an organized way so that it can be easily accessed, managed and updated. Data can be entered through input devices such as mouse, keyboard, touchscreen etc.
What's trending in BankExamsToday
Smart Prep Kit for Banking Exams by Ramandeep Singh - Download here


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Does Your Dog Freak Out Over Fireworks? Try CBD./
Fourth of July and New Year's Eve fireworks may make for a good time for humans, but usually not for our furry friends. For anxious pups who freak out during our celebrations, cannabidiol (CBD) has the potential to help them feel less anxious and more calm.


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MudStop sealing system was designed by VeloLab to ensure better protection for the vulnerable main motor bearing on the Bosch Active and Performance Line / CX motors.
Unlike the Bosch protection seal, MudStop compleatly covers the entire main motor bearing and outer casing. This stops water and contamination getting past the cover and entering the bearing.


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Understanding what Hospitality is and isn't may help us all truly capture that spirit of true Hospitality? (carry on reading or watch the video)
Often today most of us view hospitality as a luxury rather than a necessity. If we are out in a Hotel or Restaurant we pay for Hospitality?
Yet in earlier times in history, Hospitality was an underlying theme of our lives. Past generations would rush to prepare to feed their messengers. Perhaps we have a Confused understanding of Hospitality today?
For some, this type of hospitality comes naturally. As we all know, however, others must learn it. Surely, we all know a person who is perfectly Hospitable?
However, in much of our world, Hospitality is becoming a lost art. Real Hospitality is perhaps finished with for many people?
Remember; Hospitality implies care, shelter; entertainment, on the other hand, for most of us it means something entirely different – a paid for event?
Hospitality is not just entertaining, not just a planned-for event or performance in a Hotel? Hospitality is more than an attitude of service; perhaps conferring care and concern on others?
Recently I believe I have relearned my attitude towards Hospitality; I've come to realize that it's my care that people need. It says that I appreciate you and want to spend time with you. A walk in the park, a coffee, an email or telephone call of encouragement can be a simple extension of my hospitality that people really wish for?
It says, "I'm thinking of you. I care about you." Whoever we are and whatever our circumstances, we can all find ways to express care and show concern and show our Hospitality. Whether or not we are in a Hotel.
Go on – give it a go!
#hotelnews #hospitalitymanagement #hospitalitytraining #hospitalitytraining #hospitalitylife #hospitalityconsulting #hospitalityconsulting #hotelmanager #hotelbusiness #hotellerie


text: Jakuvious 1,776 Posted December 15, 2018 55 minutes ago, KC_Guy said: Matt VerderameVerifizierter Account @MattVerderame 41 Sek.Vor 41 Sekunden Mehr Source: The situation is fluid, but right now, the #Chiefs are not planning to re-sign Mitch Morse. They have major decisions coming including Justin Houston, Dee Ford, Chris Jones and Tyreek Hill. I kind of expected as much. The team's history has shown that we can pretty consistently replace interior linemen. And I'm sure he'll get more on the open market than he should. But Ford, Jones, and Hill are all far more essential pieces. Share this post Link to post Share on other sites


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Beautiful, completely renovated 1 bedroom, 1 bath, Brand new porcelain floors, custom open kitchen, quartz counter tops, new renovated bathroom. Bldg amenities include: 2 pools, gym, tennis court, 24 hrs. security, BBQ Area. Maint. includes: Basic Cable & Wi-fi.
Some Electric Appliances, Dishwasher, Range, Refrigerator
The data relating to real estate on this web site comes in part from the Internet Data Exchange program of the MLS of the Miami Association of REALTORS®, and is updated as of September 15th, 2019 at 6:00am EDT (date/time).
All information is deemed reliable but not guaranteed by the MLS and should be independently verified. All properties are subject to prior sale, change, or withdrawal. Neither listing broker(s) nor LANG REALTY shall be responsible for any typographical errors, misinformation, or misprints, and shall be held totally harmless from any damages arising from reliance upon these data. © 2019 MLS of MAR.
The information being provided is for consumers' personal, non-commercial use and may not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing
Listing information last updated on September 15th, 2019 at 6:00am EDT.


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Doireann Ní Ghríofa, Festival Artist in Residence
A Sunken Gallery
2.30pm & 4pm
- Regular Price €10
45 mins
2019 will see the tenth anniversary of the flooding of the Glucksman Gallery. To commemorate this important event in the contemporary history of Cork, festival artist-in-residence Doireann Ní Ghríofa will bring the river back to the gallery. Ten 'submerged texts' will lure the river back into once-flooded basement rooms, accompanied by live soundscapes performed by renowned composer Linda Buckley.


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Welcome to New Mexico History
Hello, my name is Melissa Garcia. I will be your child's 7th grade New Mexico History teacher this year. I am very excited! I love New Mexico History! This is my 13th year teaching for Rio Rancho Public Schools. I look forward to working with you and helping your child succeed! You're child can access what we are doing in class in our Google Classroom. The link is below. Thank you!
"Email to be used by those with Hearing Difficulties for Attendance and Emergency messages only. General inquiry messages will not be answered. Please call the school if you require further assistance or information. Thank you."


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This study focuses on the comparison of satisfaction level within different age groups in the core area of Ibadan, Oyo State, Nigeria. Based on the assumption that age of residents influences neighbourhood satisfaction and that this satisfaction is in varying degrees between different age groups, non-parametric test was used to examine the differences. Result showed that age of residents was significantly related to neighbourhood satisfaction. An analysis that focused on the differing age group satisfaction with the neighbourhood showed significant differences. However, the differences were more significant below 20 years age bracket and 61-70 years.
Keywords: Neighbouhood satisfaction, age of residents., core area housing, housing satisfaction
This work by European American Journals is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License


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Best Degree College Hyderabad|TMSS College Of Management
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Real-time 3D is changing everything for games, film, automotive, architecture and more. From genre-bending apps and Emmy-winning animations ... Leer más
Entradas de Community Team
Join us for Unite Copenhagen on September 23-26 to take part in one of the most highly anticipated tech conferences of the year. There'll be... Leer más
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Every year at GDC we make major announcements and debut our latest technologies. We can't wait to reveal our latest features, jaw-dropping d... Leer más
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Thousands of highly-rated assets will be discounted in the Unity Asset Store's May Madness sale, which started today and continues until May... Leer más
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Check this link for a taste of what might be for the Royal Oak – http://www.tallyhoinn.co.uk/
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Bigbury Golf Club
The Oyster Shack
The Pickwick Inn
Holywell Stores
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Did everyone have a good Fourth of July? Mine was surprisingly low-key, featuring a rousing balloon toss (Shane and I won!), grilled meat, cold beer and three different rooftop parties. I spent the rest of the weekend watching Wimbledon. This year's epic men's final between Andy Roddick and Roger Federer offered something for sports fans of both sexual orientations—women and gay men could admire handsome the Andy and Rog, while straight men and gay women clamored for more shots of Brooklyn Decker, wife of Andy, and Bridgette Wilson, wife of Pete Sampras. After the match I asked myself a crucial question: Is tennis the sexiest sport? Answer: No! Click through for my Top Four Sexiest Sports and vote for your own favorite.
Kerri Strug was at the party and I borrowed her coat.
When it comes to the balloon toss, it's all in the knees.
Ryan's Top Four Sexiest Sports
1) Beach Volleyball: Duh.
2) Soccer: I really like the shiny shorts, for some reason. And the toned legs that sport them.
- Tennis:__ Gratuitous Grunting. Tennis skirts. Statuesque Russians. More statuesque Rusians. Fripples. What more could a man ask for?__


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by DBS
Indomobil Sukses Internasional : BUY; Rp5,350;
Price Target : Rp7,500 (previous: Rp8,500); IMAS IJ
Primed for a rebound
· Management less sanguine on prospects for FY12
· Yet, despite cutting FY12/13F earnings to Rp1,121/1,387bn, share still offers compelling value. Growth to rebound from 2H12
· Maintain Buy with a revised TP of Rp7,500
Management's latest guidance paints less rosy outlook. Management has cut its FY12 target on Nissan car sales to 75-80K units from 90-100K units. A continued supply constraint (i.e. frame parts) for the production of 'Evalia' is a principal concern. Slower sales of 'Juke' (following the fire incident) and sales of 'March' (as a result of intensifying competition in the compact car segment) also contributed to the downward revision to management targets.
Cut FY12/13F earnings to Rp1,121/1,387bn. Still compelling value. Following management's new guidance, we have also lowered FY12/13F net profit estimates by 19/21% to Rp1,121/1,387bn, mainly on lingering supply concerns over 'Evalia', a moderate downward revision to 'March' sales, and lower OP margin assumptions. However, we still expect IMAS earnings to rebound in 2H12 and to sustain a solid growth in FY13, fuelled by growing unit sales of its new launch 'Evalia' and operating margin improvements.
Maintain BUY but TP lowered to Rp7,500. Even after our downward revisions, the share price is still attractively valued at 13.2/10.7 FY12/13F PE (vs. a 2 year net profit CAGR of 31%). In terms of FY13F earnings, we believe the counter offers compelling value as it is currently traded at a 25% discount to the broader market, in spite of its higher growth prospects. We believe most negatives have already been priced in relative to the earnings downgrade and have thus lowered our TP only moderately to Rp7,500, as we roll-over our valuation base to FY13F. Looking ahead, we expect stronger 2H12 and FY13 results to drive share price higher. Reiterate our BUY call.


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Ed: 36: August/2011
Arab Spring yields a Murky Summer
The acclaimed "Arab Spring" has given way to a murky summer, dominated by uncertainty, fog and danger as much as democratic hopes, according to academic experts. Some of the movements for reform which blossomed across the region earlier this year may take a long time to mature into democratic regimes resembling those in Eastern Europe which emerged after the fall of the Berlin Wall. Others may simply wilt and decay.
Bibi's Home Truths
It may be more Woodstock than Tahrir Square, but the energy springing from a protesters' tent city along Tel Aviv's fashionable Rothschild Boulevard represents economic, social and political realities that challenge Binyamin Netanyahu's leadership in a way he cannot ignore.
Some 300 tents sprang up almost overnight under the trees lining the road between the national theatre Habima and the glitzy skyscrapers housing Israel's major banks, all put there to protest spiralling housing prices.
If Assad Falls…
The US administration's policy toward Syria is shaping up to be potentially the greatest missed opportunity of Barack Obama's presidency. If Syria were to break the right way and the regime in Damascus were to fall, the most tenacious state-sponsor of terrorism in the Arab world - Teheran's strongest ally and the lifeline to the terrorism-loving Lebanese Hezbollah - would be taken out. Alas, an administration that came into office only a little less eager to engage Damascus than Teheran seems stuck in its stillborn Israeli-Palestinian peace process and the turmoil of the Great Arab Revolt.
The Biblio File: A Greek Tragedy in Persia
In 1977, Abbas Milani, then a US-educated lecturer at the National University of Iran was arrested by Iranian security forces loyal to the Shah as a result of his authorship of anti-regime pamphlets. He was given over to the far-from-tender mercies of the Komiteh ["the Committee to Fight Terrorism"], one of Iran's thuggish security services. In 1996, Milani wrote of his Komiteh interrogator, "In the past eighteen years, rarely has there been a day or night in which the memory of his threats, his punch, and the fierce look in his eyes has not haunted me." After a peremptory trial, Milani was jailed for one year, including three weeks in solitary confinement, at Teheran's infamous Evin Prison. (He would likely have received a harsher sentence if his case had not attracted attention in the West). He shared his imprisonment with such later luminaries of the subsequent 1979 Islamic Revolution as future President Ali Hashemi Rafsanjani and Grand Ayatollah Hussein-Ali Montazeri, who became Khomeini's designated successor in 1985 before falling out with him in 1989.
Editorial: Up A Tree
The Palestinian Authority's (PA) bid to unilaterally seek UN recognition of an independent Palestinian state on the pre-1967 lines in September appears to be losing momentum - not least among Palestnians...
The PA's plan to seek UN recognition of nominal statehood cannot lead to anything good for either Palestinians or Israelis, as even many Palestinians are now acknowledging. The US will likely veto any resolution on statehood in the Security Council, which alone has authority to grant UN entry, so the Palestinians will have to instead go directly to the UN General Assembly and seek recognition as a non-member observer state.
Essay: The Illusion of Return
Not far from Bethlehem's Church of the Nativity, the storied birthplace of Jesus Christ and the West Bank's most popular tourist site, there lies a landmark of a very different kind. Sitting horizontally on a gate in front of the al-Ayda Refugee Camp is a 10-metre long iron key, weighing nearly two tons. The seemingly innocuous monument actually represents the most controversial demand made by pro-Palestinian advocates: That Israel must permit up to 5 million Palestinians to immigrate across its borders, effectively ending any chance it will endure another generation as a homeland for the Jewish people.
Scribblings: The Significance of the Oslo Terrorist Attack
A horrific event, like the July 22 mass-murder of 76 people in Oslo, Norway by far-right terrorist Anders Behring Breivik, inevitably calls forth huge amounts of commentary attempting to explain how it could have happened and what it means. Some of what is said is insightful, useful, knowledgeable, comforting andor thought-provoking. But, inevitably, some is also questionable, misleading, self-serving, ill-informed, foolish, morally dubious and/or just plain ugly. Having read much of what is being said about this sickening crime, I wanted to call attention to some common themes I have seen - especially those exemplifying the latter kind of commentary.
The Last Word: Malice and analysis
A few days before this article was written, it is doubtful many, if any, readers were familiar with the name Anders Behring Breivik.
Perhaps some of my international colleagues who research and attempt to understand the various personalities that participate in the shadowy world of European extremism may have stumbled upon his rantings and rationalisations, but the dispassionate mass murderer had not been flagged as a person of any influence or likely impact, even though he had reportedly been on a Norwegian government watch list since March.
Now he is notorious - as a callous mass murderer.
Asia Watch: The Old Bogeyman
One of the most reliable indices of political heat in Malaysia is when the spectre of Jews or Israel is invoked to discredit domestic political enemies. That no instance seems too far-fetched is an interesting indicator of how Jews are perceived in a country with no Jewish population of its own - a fantasy notion of Jewish omnipotence, antisemitism or probably a combination of both.
State of Tension
The unilateral declaration of a Palestinian state, and its international recognition, would be a huge mistake.
A peace agreement between Israelis and Palestinians is essential, but can be achieved only through honest negotiations - not by one party imposing a unilateral decision.
Over the past two years, the Palestinian Authority has refused to sit at the negotiating table with the Israeli government, hiding behind the excuse of construction work on a few West Bank settlements. At the same time, it has been negotiating the creation of a national unity government with Hamas - a terrorist group whose stated aim is the elimination of Israel. A Palestinian "government" of a unilaterally established, self-declared "Palestinian state" in which Hamas is a member will make negotiations, to say nothing of a peace agreement, impossible.