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Silent Treatment Emotional Abuse in Relationships–SPECIFIC EXAMPLES to help Counteract Passive Aggressive Conduct.
Breaking the Cycle of Passive Aggressive Silent Treatment
Do not reward a passive aggressive Silent Treatment perpetrator for their abusive tactics as it will lead to them doing it even more since they derive a sense of satisfaction, if not "guilty" pleasure, at seeing the negative effect they can have upon you. From their perspective, it proves to them that they matter to you.
Your objective should be to have husband, wife, boyfriend or girlfriend realise that you have become immune to their Silent Treatment so that they will eventually stop doing it. They need to realise this by themselves, by way of observing your changed reactions to their giving you the cold shoulder.
NB: When considering the coping strategies in this series of articles, it is also wise to undertake careful self-reflection to assess and ensure that you are approachable, fair and reasonable when communicating with your partner. In other words, be sure to give your partner no genuine pretext to give you the Silent Treatment.
LOVE & RESPECT - Amazon reviewers have rated this 4.3 out of 5 stars (and there are over 700+ customer reviews!).
It is felt to be of benefit whether the relationship/marriage be solid or floundering.
- In addition to the book, there is a CD version available - great if your partner is reluctant to read self help books!
Examples of how to change your response
Building on the strategies detailed in Part 1 and Part 2 of this series of articles, here are some situations which may be familiar to you in your marriage or union, and how you might react in a way that does not encourage or reward your tormentor.
Mealtimes –
If the passive aggressive abuser ignores you when you call them to come eat the meal you've prepared, the next time you prepare a meal instead of calling them simply tell them their meal is in the oven for when they are ready for it. In this way you save yourself the stress of calling over and over or wondering when/if they will come etc. Now go straight ahead and enjoy your own meal. This will take away the power from the silent treatment manipulator who wants to see you waiting and wondering when he/she will grace you with their presence or indeed do you the honour of eating the meal at all! If the Abuser eventually does eat the meal at some point, continue with telling them that their meal is in the oven for when they want it, as opposed to calling them for dinner. However, if you find that the food is still in the oven the next day, without any satisfactory explanation from the Abuser, don't rise to the bait by getting visibly put out or upset. In these circumstances you might want to consider stopping making meals for them until you are back on good terms. Why waste good food!
Isolation –
If you feel sure that your partner is deliberately staying out of the room you are in, whereas normally you would have been present together, pointedly ignore the behaviour and take the opportunity to amuse yourself with a favourite CD, comedy show or the like. Make yourself comfortable and stress free and actually enjoy the "space" they have given you. Whatever you do, don't openly mope. This is easier said than done as such tactics on the part of the silent treatment abuser can leave you feeling despised and unworthy. Please know that you are not deserving of such treatment and resolve to rise above it. Take some comfort in the fact that you are not the only person to feel this way at the hands of a practised passive aggressive emotional abuser. Keep your chin up and never let them see the hurt that they cause, because if you do the cycle will go on and on.
Tearfulness and feeling overwhelmed with misery –
When you feel weighed down or weepy, silently in your head repeat to yourself, over and over and over, "I am handling this situation without tears" and/or "I am peaceful and content". Repeat this to yourself as if you REALLY do mean it and REALLY do believe it. In point of fact, you do need to start believing it because you CAN handle the situation without tears and you CAN be peaceful and content, and what's more you owe it to yourself. This kind of repetitive thinking on your part might feel very strange to begin with but just do keep repeating because it will help you shorten the length of time you feel overwhelmed or miserable and help you not to wallow in your sorrows. (The same basic principle can be used for other negative emotions such as irritability or anger.)
Passive Aggressive Silent Treatment - What to actually do if your partner won't answer you! - see the video
Decide how you will respond to passive aggressive Silent Treatment and be consistent.
Rather than continuing to react in a way that rewards your partner, actually choose to make yourself more jovial and content. Initially you might be pretending to be happy and content but if you are persistent in applying the strategies recommended in this series of hubs, before you know it you will actually begin to be more happy and content. Placing a small handwritten note or a visual reminder such as a fridge magnet where you will see it often, may help you to maintain your efforts to become stronger, wiser, and happier despite the tactics employed by a passive aggressive or narcissistic partner.
Don't let your happiness be solely dependent on what mood your partner is in! Get out that list of things you can do to distract yourself from falling victim to your partner's Silent Treatment methods and keep yourself usefully occupied. Above all, make your own happiness your own responsibility.
In all likelihood your manipulator will tire of not getting their desired response (i.e. you being upset, anxious to converse, sulking, and/or arguing). If you are persistent in applying these techniques EVERY TIME the silent treatment emotional abuse rears its ugly head, over a period of time, it should occur less frequently and get shorter in duration as and when it does occur.
NB – If the passive aggressive silent treatment emanates from a partner who is verbally abusive and/or physically abuse, do not proceed with the advice given above. Seek help from an appropriately trained professional in the field.
Please click here for PART 4 of How to cope with Silent Treatment. When/How to Discuss/Confront Silent Treatment - The above link gives advice on how you can go about putting in place a time limited cooling off period/time out with your partner; emphasising your new boundaries plus the importance of having realistic expectations of your partner. Also see this link if you would like information on how you might overcome some of the "awkwardness" of moving on from a "not speaking" episode.
THANK YOU for sharing, voting and/or commenting on these articles. You may wish to bookmark and return to catch up on comments etc.
Love Poem: The Silent Treatment
And once you are back on "good" speaking terms .....
- The Five Love Languages in Silent Treatment Relation...
If you are dreading the next seemingly inevitable segment of silent treatment from your partner, you may be wondering if there is anything you can do now, whilst you are indeed on speaking terms, to help avert it. Rather than rely on walking on...
- Silent Treatment Relationships and Speaking your Partner's Love Language
Recommended Reading
Why does he do that?: Inside the Minds of Angry and Controlling Men by Lundy Bancroft. Rated 4.7 stars out of 5 as at March 2014 (pictured below)
Emotional Assault: Recognizing an Abusive Partner's Bag of Tricks by Lisa Kroulik - rated 4.8 stars out of 5 as at March 2014 (pictured below)
See below for further articles relating to Silent Treatment
Silent Treatment in Marriage - The Marriage Restoration Project
What should I do when my wife ignores me? - The Marriage Restoration Project
© 2012 Ebonny
Comments - Specific Examples - How to cope with Silent Treatment Emotional Abuse in Relationships - Part 3:
I have looked back and many of my comments and my episodes with my husband have gotten much less extreme. However there is still the basic issue of what feels to me like such utter disrespect. I don't understand how the silent treatment abuser does not realize how disrespectful they are to the ones they love. Why did they not snap out of it at some point and apologize? This morning I had a small argument with my husband and when he came home this evening I thought it was water under the bridge but he ignored me all night again and left me to put the three children to bed by myself again and went to bed without speaking to me. He is not only punishing me, he is ignoring the children. I realize that my coping techniques from your hub have helped me to survive in this marriage. However I am to the point now where I just don't expect very much. When you give me the silent treatment I go on with my day but really inside I'm not as happy as I used to be with my marriage. It's slowly wearing me down and sapping my joy. Also, at this point I feel like I'm just hanging in here for the sake of the kids. I keep thinking maybe I can just make it until the kids graduate high school because I don't want to put them through divorce and I don't have the means to survive on my own with them and I just feel like every man is going to have his flaws. Does life have to be so bleak? I am just starting feel depressed and trapped but I don't want my children to suffer.
Also, I wanted to thank you for the articles you have written. Very helpful information. My relationship with my boyfriend is usually very good and only this has happened when I have caused it. He is still trying to punish and control me I feel which is working because I'm so afraid he is going to break up with me. I cried all last night but reading about this is helping me stay a bit sane. Do the men who give silent treatment usually stay, if they can, with their partners or do you think in my case he will given my indiscretions in the past? I really don't want to lose him and I think if I do better in the future that there will be no more episodes of silent treatment under reasonable circumstances. Thanks again
Hi Ebonny,
I have been dating an older man since January 2015 and we have gotten on very well until October when I drove under the influence. Admittedly this was very wrong and unsafe and he didn't speak to me for 3 days. We usually text and he would not respond until then and he ended up coming over and we talked about it and he was very sweet and wanted to know if he had done anything and I said no. He plays guitar and I left the bar he had been playing. This was a truthful answer that he not done anything.
A couple of weeks ago he was caught in a lie and would not explain about it. It made me a bit suspicious but I let it go and everything was going along fine until some weird girls showed up at his gig this past saturday night after the bar was closed. That coupled with the lie and me drinking caused me to confront him. I'm not sure what was said and it's possible I may have been mean to him and stormed out and left with a girlfriend of mine who drove me home. He actually sent her outside to stay with me. Again I know my part in this (well somewhat except for the conversation but there was no yelling because no one around heard anything), but he has not responded to texts since then. I apologized and left him alone Monday morning. Last night I once again apologized via text and said let's talk. No response and so I saw he was on facebook and sent him an instant message that he did not respond to just reiterating when could we talk. This situation is not as bad as some of the others and I've read the articles and sounds like I messed up but form here on out I would like to do better and have a plan about my role as well. Since we don't live together and usually text every day and make plans to see each other via text should I just refrain from communication? He has a gig this weekend and I usually go when I don't have my daughter on Saturday nights. There is a facebook event that I was invited by his drummer the other day. I usually don't respond to those until I know for sure I am going. If I don't hear from him should I not go which is what I'm leaning toward or should I go and act like everything is hunky dory?
Thanks for any insight!
I have been with my boyfriend for a few years now. Things were going great, and then (again) a little thing made him very angry, which made me very upset. And it all went downhill, as usual.
When this happens he doesn't want to talk about things, but the only way I can feel better is talking. I do realise now insisting on talking doesn't help, and will try the advise, but I can't help feeling it's not fair. He is much stronger emotionally than I am, and he knows it. The rest of the time things are great, he is caring, supportive, does his bit around the house, etc. but this arguments even if they only happen every few months bring me down so much. I just can't cope when he doesn't talk to me, even for a very short period of time.
I can't decide if I need to "fix myself" (anxiety, stress...) so the relationship can work out, or if it's a relationship problem. I'm happy to do my bit, and will from now on work on my own happiness but I feel he should work on his anger. But I'm afraid if I bring that up, it will make him angry and the cycle will start again.
So basically, I'm lost and there's so much more good than bad in the relationship, but I don't think that justifies him giving me the ST, shouting at me or name calling (which has happened very, very few times but hurt so much). I guess because it's something I'd never do, I can't understand why he does it to me. But then, how can I expect him to understand my anxiety/insecurities when he's not going through them?
I never know if I'm being fair or not any more.
Any advise?
it's been 5 months since the last bad episode. Yesterday Hyde was frustrated and swearing after bonking his head on something in the garage, scaring my 2 year old. Then throughout the day he was agitated and prone to snap at every tiny thing. I used the strategies to completely ignore and stay away from the bad behavior and stay upbeat. I believe that is why he snapped out of it so quickly and we watched a movie together lastnight. But during the movie I stopped and asked him: "if something ever happens to me, will you please try to be nicer for our kids' sake?" That comment was made sincerely, and with heart. He flew off the handle, screaming that he's been really good for a long time, went and slept in the couch, went to work, came home, ignores me, and literally went to bed at 5pm laying across the bed face first with all his clothes on, and wouldn't eat dinner or anything. Of course, I was also on my own getting our 3 children to bed. I just don't understand how someone can snap like that, and to such an extreme!! Thanks for listening.
I've applied all of those rules, it's my mother always giving the silent treatment. I go about my day (we work together), still chat and to be honest you're right, eventually you will feel happy or less anxious than you used to. The thing is, she retaliates, she does not like it when we treat her the same way, or it seems like the silent treatment isn't working. There is no way she'll seek help, in her mind she's doing nothing wrong and is the victim.
3 months of much better behavior and then mothers day of all days. The morning started well in church and then it seemed like the tension was building and my 4 year old son made him upset and after that he shut himself off. He ignored me and my 3 children for the next 2 hours until my parents came. Then he was civil but we aren't speaking (mutually ) since they went home. I just don't understand why when things we so nice for 3 months how he could have gotten out of control and made me and my 4 year old feel so sad on mothers day
I saw the comments of Jen and wanted to follow up. My husband has improved since my last post although I am writing now because after about 6 months of mostly Jekyll he had a hyde episode again the last 2 days. He acted like a 2 year old yesterday* ignoring me and slamming things. I used ebony strategies and was upbeat, etc. He was remorseful this morning and kissed me goodbye etc but when he got home today he acted like nothing happened. Since the silence was over, I tried to calmly discuss what happened and he totally flipped out, knocked over the garbage can, swore at me and stormed out of the room for the night* commenting that I just HAD to ruin the evening. I read what Jen wrote. And I agree - when does the personal responsibility for the crappie behavior ever come into play? My husband is content to drop things when he's over them, but God forbid I bring up that his behavior hurt me or the kids and we are back to square one. If I never say anything, I am consumed with resentment. If I speak my peace, I get silent treatment and abuse. What an I supposed to do?
I have noticed that each time my husband is unhappy about something in our marriage he gives me silent treatment until i ask him what the matter is. This has happened even while we were still dating, (e.g. he was refusing to let go of a female friend he confessed they once kissed; the girl was also disrespectful towards me). He once told me he blames me for all problems we are experiencing, i am always blamed. According to him i have been giving him problems since we were dating up-to-date.
We have 1 year old son together and he tells me to stop church activities, always be home, leave my friends but at the same time at home he ignores me by being on his phone/laptop chatting until i go to bed. He has been giving me silent treatment for about 5 weeks now, and even when he travels i have to ask him to communicate. I have wept so much because i feel like we no longer married we just two people staying together.I am glad to have found this site i am so encouraged to follow the strategies.
Being upbeat and cheerful confuses them! They realize their silent 'tactic' is not having any impact. I tried it, and loved hearing him ask me why I was so happy! Truly, when you can let them choose their behavior, and you choose your own and 'let them be', it is remarkable what it does for your own inner peace, and how it confounds them!
Just a question - by being upbeat and cheerful despite the treatment, isn't that just allowing him to get away with it? Isn't that kind of saying, 'it's ok if you treat me like crap, because I'll just be positive and friendly anyway'? There are no consequences for his behaviour, so why would he change?
Another question - my husband's way of dealing with conflict and disagreements is the silent treatment. While I quickly reach a point of wanting to talk things through, as soon as he is annoyed he either loses his temper or shuts down or both - and then he doesn't want to talk through the issue anymore. Apologising or giving him space and then asking if we can talk does nothing. You say that this approach doesn't work (which I agree with), but if I was part of the argument, shouldn't it be my responsibility at least some of the time to apologise and ask if we can talk? Even if I know it won't work? And if the silent treatment originates from an argument, surely we need to talk through it eventually, but I know that the only chance of that happening is if I say 'can we talk'. In other words - if I stop being the one apologising and trying to talk through things, then I'm worried we will never resolve anything!
I suspect that this destructive pattern is learned and repeated down through generations. I'm learning that my husband's family have similar episodes of silent treatment, grudges over minor perceived "wrongs," etc. how can these perpetrators unlearn these destructive patterns, or even realize how destructive and abnormal these methods are?
Quick update - after 4 days of silent treatment and thank God employing your brilliant strategies, today he was great and acted like nothing happened. Dr. Jekyll is back again. Problem is, in the past when I want to resolve things, if I even mention the Mr. Hyde episode he either blames me for it or becomes Mr. Hyde again. I want to seek professional help, but have had such bad luck with counseling in the past, with therapists whose attitude seems to be to divorce if he won't attend, and that is not what I want to do. I start building up do much resentment when issue after issue is unresolved. Any ideas?
I faced silent treatment on a regular basis for the last 14 yrs of married life to a husband with NPD. The longest session went on for 6months....in which he didn't talk to me, didn't eat the food I cook and would sleep in a diff room. It hurt like crazy and every night I used to go begging him....but nothing worked! It ultimately ended after 6 months of torture. I sometimes feel did my begging help him break his silence faster or else may be it would have continued for another 6 months??? What do u think??...I am a very weak person emotionally and feel like committing suicide....why me?? How do I make myself strong??......if I don't beg and plead him.... May be he will never talk to me at all??? How do I get out of this mindset?
Hi there. I am going to try to employ these tactics as of right now. Here are my thoughts and please understand that I am at a low from being the recipient of this type passive- aggressive behavior. By using your advice, I am unclear on when or how these tactics will
resolve or at least open a dialogue regarding the actual conflict that caused the silence to manifest in the first place. The whole hint pains me deeply, but I keep asking myself why I don't get a backbone and leave? As of now I am in a relationship where my thoughts, feelings and needs are not addressed. It has taken me a while to realize that this is not a different personality type or argument ste, but a true disorder. Any advice or encouragement is appreciated from those of you who are more seasoned at this than me.
Some great comments - Two weeks ago I experienced the cold treatment this was not an isolated event. It had occurred many times before. The same patterns every time. I always reacted to the silent treatment, by trying to convince, communicate with no positive outcome for change I was always left feeling very overwelmed by the whole experience. Recently, before christmas the (friend?) a man and I went away camping, for Christmas, I did not feel altogether comfortable with this as I would be missing out on seeing my family, he does not have any living in this part of the world. I was told to buy the food and organise the camping location as he was too busy at work, even though I had been extremely busy at work myself, I organised the food paid for by me, we took separate cars - I was not going to be stuck in the middle of nowhere by myself. We arrived at the camping area. I asked for some money for purchasing the food he made excuses not to I cooked the meals, then came the insults, I ignored them to some degree. I evently had enough by the next day I asked him to discuss if I should continue to stay on or leave, he ignored me and said nothing at all. I decided in my very upset state to pack my gear including all the food I had purchased and returned home to spend christmas with my friends and family, I was however extremely distressed over several days, He texted me the other day with what a low life person I was and that he would never trust being with someone who would stoop so low... as to not leave him any food for him to eat. I responded by letting him know that he had previously refused to communicate at all, that he had supplies, a car, and a supermarket 15 mins down the road from the campsite to purchase food for himself and guess what I have not heard a word from him since ... but I am not going to someone's doormat
To those going through this - Ebonny's amazing advice CAN work! My husband emailed me early November telling me he wanted me to move out - I had stopped being his narcissistic supply, and was no longer showing him any 'upset' for his hostile silence. As far as I was concerned, he could be as angry and silent as he wanted to be - I was getting on with doing things that gave me peace. I did decide not to move out until Thanksgiving / Christmas was done, as we have adult children who come visit then. I DID take advantage of friends offering for me to house/ pet sit for them while they were out of town. This was a huge relief as I could get out of the hostile environment. I had initial consultations with lawyers and let my husband know - in a very matter of fact way - what they had said, and what I planned to do. He was surprised! New Years Eve day he came to me and informed me, humbly, that he doesn't feel he can stand before our kids and family and say he has done all he can for the marriage, that the emotional 'toll is too high', and would I reconsider. MUCH has to change, and he knows his pattern of retreating into hostile silence will NOT be tolerated. We are taking to heart the teaching of 'Love and Respect' by Dr. Eggerich. As a narcissist, my husband believes that I do things (or don't do things) because I am trying to get back at him, to 'attack', and he assigns malicious intent when there ISN'T any! The first DVD of Love and Respect actually addresses the fact that people get on the 'crazy cycle' because they believe the other person did or did not do something due to being malicious. It talks about believing in the 'good will' of your partner, and not getting sucked into the crazy cycle. The light is turning on in my husband's mind that he hasn't given me the benefit of the doubt, has not seen me as a 'goodwilled' person. There is still much that has to change, foremost are his assumptions of why I do or don't do something. His pattern of retreating into hostile silence to punish me HAS to end. His excuse of saying that he does that so he can 'process' is FALSE. He has had to admit that his silences are meant to punish me. These realizations can help us move forward. I am hopeful... While 2011 and 2012 just about 'kicked my butt' (if I can use that term), I am taking the initiative and will do whatever I need to do, to ensure that we stay on track - or will leave if need be. I will NOT get to the end of another full year, just grateful for the year prior to be over. I plan to make the year a good one. He has been informed he can't play me for a 'fool'. I am NO longer passively accepting others behaviour. I am stronger within myself, and thank you Ebonny for your articles. They were exactly what I needed to hear / learn. That is why I have continued to follow the comments. Bless you and yours this year.
Fantastic hub.I know people going through this who don't really see it as emotional abuse.Just him being moody.But you are so right.
Great comment, Ebonny. I don't know what your own decision was ultimately in terms of choosing to help change the dynamics from within, or move on if change was not happening. With this being a 2nd marriage and all our kids out of the house, I am choosing to move on. Being that I have chosen not to engage him in conversation these past 2 months, and have thus taken myself out of being his 'narcissistic supply', he has asked (demanded) me to leave. Gives me room to do just that. The silent treatment is a 30+year pattern that I have finally, after 6+ years of trying, realized I can not change. Only he can change it and he chooses not to.
I am going,thru this kind of abuse from a guy i have dating for 3 years. When i met him he was the perfect person and after 6 months he started to change. One night he said the game is over, and he said and did things that,put me in a tailspin.Then he calls back and says it was me that started it that he loved,me beyond and he needed me, so we got back together, and for 3 years this has,been the pattern, breakup, it was my fault, he needs space, he wants to get back together,etc.
He belittles me and then will not talk for days, then he tells me i have to change, stay away from friends, family, etc.
I feel like i am going ,crazy.
Great help! I have found my ability to create my own happiness, but realized that just this Sunday, I went to him and asked forcefully 'Are you speaking to me now?'... thereby reinforcing his bad behaviour. I will continue to speak to him normally on typical things and not focus on re-engaging overall or showing any distress. Thank you for this great insight. It is refreshing to see this written by someone who has been there.


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Family Trick Brother Into Thinking He's Invisible, He Completely Loses It
After a video went viral recently of a family convincing a 13-year-old he was invisible, many other people have attempted the prank sharing their efforts online.
While the majority failed, some were successful. Meanwhile the efforts of the Camacho family may well be the best we have seen so far.
It is safe to say the poor kid who was being pranked was not impressed by his family's joke.
You can watch a video of it here:
While 13-year-old Jocelyn, from El Centro, California, was browsing through social media one day, she noticed there were plenty of these 'disappearing' videos around and so decided to give it a try.
Joining forces with her 17-year-old sister Julissa, the pair got the support of their parents to play a prank on their younger brother.
Poor eight-year-old Ezequiel never saw it coming, as is made clear by his rather shocked and upset reaction.
Jocelyn could barely keep a straight face as she started the prank yelling 'abracadabra', waving her hands over a blanket covering Ezequiel.
Whipping the blanket off to revealing he was very much in the room, looking bored and unconvinced, Jocelyn and Julissa can be heard screaming 'no way, he is not here, he is not here' showing off their acting skills.
It clearly worked as Ezequiel is now beginning to look more interested.
Julissa can then be heard telling Jocelyn to sit down so they can take a picture and prove to Ezequiel he is invisible.
By this point it is clear he is fully convinced, giving Jocelyn the middle finger as she took a picture next to him.
However, his attitude soon changes as they show him the photographic 'evidence' which 'proves' he is indeed invisible.
First not knowing what to do, Ezequiel suddenly starts screaming before breaking down into floods of tears.
Clearly upset, he then pushes his sister Jocelyn who is still hilariously playing along saying to her sister 'OMG something just hit me'.
Speaking exclusively to UNILAD, Julissa said she couldn't believe how her brother reacted:
We always get him so good but his reaction was hilarious. I wanted to laugh so bad but I just couldn't as I would have spoiled it.
Even this morning, he has barely got over it. It is amazing how viral it has gone. I would never have expected that.
He is happy the video has gone viral as he always wanted to be a YouTuber.
So every cloud hey Ezequiel!
If you have a story you want to tell send it to UNILAD via [email protected] To license this article contact [email protected]
Topics: Featured, Licensed, Viral Video

subset: commoncrawl


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Condo developers. In a city like Toronto, those two words can strike fear into the hearts of the diverse and close-knit communities we're famous for. They're like the bogeyman, moving stealthily through a neighbourhood, chiselling away at its foundations, scattering long-term residents and families in the wake of mammoth glass and steel boxes. In a way, it's almost admirable, their efficiency in finding pockets of greed to exploit, smoothing their way with money and influence until the path is clear.
Su Friedrich knows only too well the tactics employed by developers in their quest for profits beyond what most of us can imagine. Recently, she and her partner watched helplessly as their historic Brooklyn neighbourhood was chipped away by condo developers, determined to demolish buildings that have stood for generations. Knowing the end was nigh, Friedrich grabbed a movie camera and began filming the experience. The result is Gut Renovation, a searing and illuminating documentary on condo development left largely unchecked.
"The rezoning was handed down in May of 2005," Friedrich says. "By that fall things had started happening. I knew I had to start quickly because of what I saw in the East Village in the late '70s. At the time I was young and I just thought, 'Oh, how sad, we're losing this charming bakery or a great family store.' I registered the changes and thought I would remember the way it was, but even a year later it had all become erased."
As the surrounding century buildings fell, Friedrich realized that the venerable historic loft she lived in was next on the chopping block. When she and her fellow tenants – many of whom were artists living and working in loft spaces – finally got their marching orders, it was clear that the neighbourhood they had all loved had been eradicated. They were all forced out using various tricks of the trade: no hot water, no heating, threatening notices. The building was then demolished to make room for upscale condos.
The film documents this process in heartrending detail, chronicling the stories of people losing their homes, reduced to a category: undesirable renter or potential purchaser. Friedrich records community meetings, conversations with old and new residents, and even takes her camera along for a clandestine meeting with a condo sales agent. It's real, raw, angry and sad. It's also riveting, like watching a car accident, knowing you could be next if your neighbourhood is targeted for destruction.
Despite losing her home and watching her beloved Williamsburg irrevocably changed, Friedrich doesn't uniformly vilify the company responsible for her home's destruction.
"My impression is that some tell themselves that they're doing a good thing, because they have a way of looking at the area they're developing and seeing it as something that needs developing," she says. "Along with city officials, they declare the neighbourhood as a blighted area, but they come up with this really special criteria of what is blighted. An auto-body shop that's been there since the 1960s may look run down, so they're going to make it all nice and new. They also make all sorts of promises of what they're going to replace it with, and who's going to benefit.
"And of course, some of them are assholes and they really dislike the people living in those older buildings and don't care about who they're displacing. All they care about is money."
Gut Renovation


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Hans Jakob "Jack" Steinberger (born May 25, 1921) is a physicist currently residing near Geneva, Switzerland. He co-discovered the muon neutrino, along with Leon Lederman and Melvin Schwartz, for which they were given the 1988 Nobel Prize in Physics.
Steinberger was born in the city of Bad Kissingen in Bavaria, Germany, on 1921. The rise of the Nazi party in Germany, with its open anti-Semitism, prompted his parents, Berta and Ludwig Steinberger, who was a cantor and religious teacher,[1] to send him out of the country.
Steinberger emigrated to the United States at the age of 13, making the trans-Atlantic trip with his brother Herbert. Barnett Farroll cared for him as a foster child, the connection was made by Jewish charities in the United States. During this period, Steinberger attended New Trier Township High School, in Winnetka, Illinois.
Steinberger studied chemical engineering at Armour Institute of Technology (now Illinois Institute of Technology) but left after his scholarship ended to help supplement his family's income. He obtained a bachelor's degree in Chemistry from the University of Chicago, in 1942. Shortly thereafter, he joined the Signal Corps at MIT. With the help of the G.I. Bill, he returned to graduate studies at the University of Chicago in 1946, where he studied under Edward Teller and Enrico Fermi. His Ph.D. thesis concerned the energy spectrum of electrons emitted in muon decay; his results showed that this was a three-body decay, and implied the participation of two neutral particle in the decay (later identified as the electron (ν
e) and muon (ν
μ) neutrinos) rather than one.
As an atheist and a humanist, Steinberger is a Humanist Laureate in the International Academy of Humanism.[2][3]
He is the father of Ned Steinberger, founder of the eponymous company for headless guitars and basses.
After receiving his doctorate, Steinberger attended the Institute for Advanced Study in Princeton for a year. In 1949 he published a calculation of the lifetime of the neutral pion,[4] which anticipated the study of anomalies in quantum field theory.
Following Princeton, Steinberger went to the Radiation Lab at the University of California at Berkeley, where he performed an experiment which demonstrated the production of neutral pions and their decay to photon pairs. This experiment utilized the 330 MeV synchrotron and the newly invented scintillation counters.[5] Despite this and other achievements, he was asked to leave the Radiation Lab at Berkeley due to his refusal to sign the so-called Non-Communist Oath.
Steinberger accepted a faculty position at Columbia in 1950. The newly commissioned meson beam at Nevis Labs provided the tool for several important experiments. Measurements of the production cross section of pions on various nuclear targets showed that the pion has odd parity.[6] A direct measurement of the production of pions on a liquid hydrogen target, then not a common tool, provided the data needed to show that the pion has spin zero. The same target was used to observe the relative rare decay of neutral pions to a photon, an electron and a positron. A related experiment measured the mass difference between the charged and neutral pions based on the angular correlation between the neutral pions produced when the negative pion is captured by the proton in the hydrogen nucleus.[7] Other important experiments studied the angular correlation between electron-positron pairs in neutral pion decays, and established the rare decay of a charged pion to an electron and neutrino; the latter required use of a liquid-hydrogen bubble chamber.[8]
During 1954–1955, Steinberger contributed to the development of the bubble chamber with the construction of a 15 cm device for use with the Cosmotron at Brookhaven National Laboratory. The experiment used a pion beam to produce pairs of hadrons with strange quarks in order to elucidate the puzzling production and decay properties of these particles.[9] Somewhat later, in 1956, a 30 cm chamber outfitted with three cameras was used in the discovery of the neutral Sigma hyperon and a measurement of its mass.[10] This observation was important for confirming the existence of the SU(3) flavor symmetry which hypothesizes the existence of the strange quark.
An important characteristic of the weak interaction is its violation of parity symmetry. This characteristic was established through the measurement of the spins and parities of many hyperons. Steinberger and his collaborators contributed several such measurements using large (75 cm) liquid-hydrogen bubble chambers and separated hadron beams at Brookhaven. One example is the measurement of the invariant mass distribution of electron-positron pairs produced in the decay of Sigma-zero hyperons to Lambda-zero hyperons.[11]
In the 1960s, the emphasis in the study of the weak interaction shifted from strange particles to neutrinos. Leon Lederman, Steinberger and Schwartz built large spark chambers at Nevis Lab and exposed them in 1961 to neutrinos produced in association with muons in the decays of charged pions and kaons. They used the Alternating Gradient Synchrotron (AGS) at Brookhaven, and obtained a number of convincing events in which muons were produced, but no electrons.[12] This result, for which they received the Nobel Prize in 1988, proved the existence of a type of neutrino associated with the muon, distinct from the neutrino produced in beta decay.
The CP violation (charge conjugation and parity) was established in the neutral kaon system in 1964. Steinberger recognized that the phenomenological parameter epsilon (ε) which quantifies the degree of CP violation could be measured in interference phenomena (See CP violation). In collaboration with Carlo Rubbia, he performed an experiment while on sabbatical at CERN during 1965 which demonstrated robustly the expected interference effect, and also measured precisely the difference in mass of the short-lived and long-lived neutral kaon masses.[13][14]
Back in the United States, Steinberger conducted an experiment at Brookhaven to observe CP violation in the semi-leptonic decays of neutral kaons. The charge asymmetry relates directly to the epsilon parameter, which was thereby measured precisely.[15] This experiment also allowed the deduction of the phase of epsilon, and confirmed that CPT is a good symmetry of nature.
In 1968, Steinberger left Columbia University and accepted a position as a department director at CP-violation. The NA31 experiment at CERN was built in the early 1980s using the CERN SPS 400 GeV proton synchrotron. Aside from banks of MWPC's and a hadron calorimeter, it featured a liquid argon electromagnetic calorimeter with exceptional spatial and energy resolution. NA31 showed that direct CP violation is real.[16]
Jack Steinberger was awarded the Nobel Prize in Physics in the year 1988, "for the neutrino beam method and the demonstration of the doublet structure of the leptons through the discovery of the muon neutrino".[17] He shares this prize with Leon M. Lederman and Melvin Schwartz. At the time, all three experimenters were at Columbia University.
The experiment used charged pion beams generated with the Alternating Gradient Synchrotron (AGS) at Brookhaven National Laboratory. The pions decayed to muons which were detected in front of a steel wall; the neutrinos were detected in spark chambers installed behind the wall. The coincidence of muons and neutrinos demonstrated that a second kind of neutrino was created in association with muons. Subsequent experiments proved this neutrino to be distinct from the first kind (electron-type). Steinberger, Lederman and Schwartz published their work in Physical Review Letters in 1962.[12]
He gave his Nobel medal to New Trier High School in Winnetka, Illinois (USA), of which he is an alumnus.
$puc, Los Alamos National Laboratory, Barack Obama, Energy, United States Secretary of Energy
Nobel Prize in Literature, Physics, Nobel Prize, Nobel Prize in Chemistry, Nobel Peace Prize
Berlin, North Rhine-Westphalia, Hamburg, France, United Kingdom
Harry S. Truman, Richard Nixon, Manhattan Project, Dwight D. Eisenhower, World War II
New York City, United States, American Civil War, Hawaii, Western United States
Albert Einstein, Amartya Sen, T. S. Eliot, Milton Friedman, Mario Vargas Llosa
Proton, Kaon, Lead, Pion, Omega (cern)
Nobel Prize in Physics, Electric charge, Proton, Physics, Elementary particle
Wolf Prize in Physics, New York, Physics, Columbia University, Illinois Institute of Technology
Italian language, Uranium, Nobel Prize in Physics, Manhattan Project, University of Göttingen


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text: When companies first form, they need a lot of powerhouses in management to drive the right investments and help form the right attitudes about the company's future. Looking back on some of the top companies, Hexagon, Inc. comes to mind. This was the brainchild of Scott Reiman, a young student who graduated with a B.S. in Business Administration and Finance. He later became the president of Hexagon, Inc, a private investment firm that worked with securities in real estate, venture capital, private equity, gas and oil. Continue reading "Driving Financial Investment Management"


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This time of year I get excited about corn. Corn on the cob. I can eat a dozen in one sitting! But as wonderful as it is, I am not going to write about it this month. Just know that you should eat as much of it as you can, preferably dripping in real butter and liberally salted. Fancy it up if you must with some parmesan cheese, then cut it off the cob and freeze it for January. Much better than buying it on the cob from the grocery store!
I'm going to write about the other market staple I get excited about, and that is stone fruits. I do enjoy them all, but I especially love peaches.
They are in full force now. We are especially glad to see the ones from Snowy Mountain Organics. Lauren and her family on high alert as the Cawston fires are burning perilously close to their property. We are so thankful that they are safe and able to bring their amazing Champagne peaches to us. Find them at Close to Home Organics. Okanagan Fresh Fruit have delicious peaches too.
Did you know peaches are native to China? And that more than half the world's peach production comes from China? Aren't we fortunate to have the Okanagan and the Niagara Peninsula? Both freestone (the pit pops out) and clingstone ( the pit sticks to the peach flesh) are grown in Canada. Here is another interesting fact. Peaches are actually a member of the rose family! And like a rose, smell is everything. Peaches are ready to eat when there is a little "give" to the flesh and the fragrance is peachy.
Peaches are a moderate source of both Vitamin A and C, and they are super low in calories. Surprisingly, they also provide a decent amount of Vitamin E, Iron, Copper, Niacin, potassium and b-carotene.
Peaches are best when eaten out of hand with all those lovely juices dripping down your chin and onto your shirt! The added laundry is well worth it. However, if you would like a tidier peach snack, a fresh peach salsa is super easy. Dice a peach, toss in a bit of diced red onion and diced red pepper, perhaps a bit of tomato, definitely some fresh basil, season with a bit of salt and pepper and grab a spoon! Or serve it over grilled chicken. Either way, all that lovely fresh peach flavour shines through. That is one of the great things about peaches. They can be used for sweet or savoury dishes. Here are two more quick ideas. Peach crisp is as simple as peeling ( place peaches in a pot of boiling water for 1 minute and the skins will slide right off ) and pitting 6 peaches, roughly chopping them and tossing them with 3 tbsp honey, 1 tbsp flour and a squeeze of lemon juice ( or KICS of course!) and placing the fruit in a buttered baking dish. Sprinkle your favourite granola from Gaby and Jules over the top and bake in a 350 degree oven for 30 mins or so. Top it with a scoop of Dolce Amore gelato just to take it over the top! A green salad topped with peach slices, basil, slivered almonds and fresh mozzarella is so good, and even better if it's drizzled with a balsamic vinegar from Amazing Foods.
As much as I love peaches, the other stone fruits are wonderful too. Nectarines, apricot and plums all shine this time of year and are just as easy to work with as peaches.
Peaches are also rather tasty with alcohol! Here is one last recipe in case you don't want to eat your peaches !
Peach Raspberry White Wine Sangria
1 750 ml bottle Viognier (try the one from Blackwood Lane)
½ bottle of Fraser Valley Cider House Cider
2 peeled and sliced peaches
1 C fresh raspberries
½ c KICS Raspberry Lemonade Syrup
Combine all the ingredients and let sit for an hour or so.
Serve chilled
Written by: Karen Curtis
Head Lemon Lady
Kics Lemonade – Website


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Mike Conley is heading to Utah.
The former Ohio State guard will be traded from Memphis – where he's played his entire 12-season NBA career – to the Utah Jazz, according to multiple reports, first reported by Stadium's Shams Charania.
In return for Conley, Memphis will receive Grayson Allen, Kyle Korver, Jae Crowder, the 23rd pick in Thursday's NBA draft and a future first-round pick, according to ESPN's Adrian Wojnarowski.
Memphis has traded guard Mike Conley to the Utah Jazz for Grayson Allen, Kyle Korver and Jae Crowder, the 23rd pick in Thursday's Draft and a future first-round pick, league sources tell ESPN.— Adrian Wojnarowski (@wojespn) June 19, 2019
The move comes as the Grizzlies are expected to select Murray State guard Ja Morant with the No. 2 overall pick in Thursday's NBA draft.
In 12 seasons with the Grizzlies, Conley has averaged 14.9 points, 5.7 assists and 1.5 steals per game. The 31-year-old former Buckeye is coming off a career-high 21.1 points per game last season.
What more can I say about my city! You guys made me the man I am today! Memphis is home. Always! ..Time for another chapter! Excited to give all I have to The Jazz and the city of Utah! #LetsGetIt #GodsPlan #takenote— Mike Conley (@mconley11) June 19, 2019
The trade is expected to become official on July 6, when the league's moratorium on trades and free-agent signings ends.


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Lessons: Has your wife ever mentioned an activity or hobby she desires to take up but has never gotten around to mission? How about signing her up for some lessons? Maybe it's something sports-related like golf or tennis lessons, or, something more educational like photography or painting classes. Ask your wife what she likes immediately after which check your phone book or web search engine to discover what classes are located in your setting.
For the more serious types, they are available tickets in copious details. These tickets will have to relax in every form and genre possible to receive constant sales all year. If they sell tickets just for the winter season, what could become analysts during summer? Will their funds get dehydrated, too?
A good leather jacket is critical have for anyone and makes a person of the highest 10 best Christmas gifts 2010. This bomber jacket is made of the softest lamb nappa leather creating this one of the highest quality holiday gifts 2010 for him. The manufacture this leather jacket adheres towards same standards as the authentic A-2 military version making is made up of of most desirable Christmas presents for men and women.
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The Back-To-School Bash featuring Make the Scene comes from 2-4p.m featuring games and prizes, together with a chance to win Selena Gomez and The Scene concert tickets.


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How about exporting a Tab Delimited Log? Perhaps the Submit answer command has a Log option pop up, or perhaps there's a Submit w/Log command/option. The data would include just about "everything", but most importantly the User, Date, Time of Day, Level, Time to Solve, Success??, # Retries, Hint status & number of hints -- etc.
Basically, this allows one to generate useful spreadsheets to track performance. There are many articles on using Sudoku to treat/ward-off Alzheimers, etc. (Personally I'm using it along with Chess to track recovery from an illness). The inherent facility of a Spreadsheet handles all sorts of history desires. Useful Spreadsheets could be shared here in the user community.
It's sort of embarassing posting a wish against such a really well thought out and cleanly implemented program - I do so with great humility.


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A radio show for clients? How these advisers do pro bono planning
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A clinic that serves the surrounding community by integrating free holistic financial planning with therapy sessions. A program that enables students to prepare 500 to 1,000 tax returns annually without charge. Planning seminars offered gratis to sororities, fraternities and other groups. A radio show that teaches the basics of smart financial management.
A hive of these and other pro bono financial planning activities is humming at the University of Georgia.
For their dedication and creativity across so many fronts, the 2017 Pro Bono Runner-Up Award goes to the professors and students at the University of Georgia who volunteer their time offering services to people who could not otherwise afford them.
One of the university's older initiatives, the Aspire Clinic, has provided free one-on-one planning sessions to hundreds of students and others in the community since 2009. "We target low-income families because they are priced out of fiduciary advice," Associate Professor Joseph Goetz says of the program, which he co-founded to give planning students the chance to work directly with nonpaying clients. "We've had clients who have had 20 sessions."
While the clinic provides stand-alone planning sessions, the most effective ones integrate the financial component with traditional therapy.
"We are probably one of the first [academic] entities in the country to provide financial therapy," says Goetz, who believes that all good advisers, whether they have trained to do so or not, "are practicing financial therapy."
With a new $1 million infusion from a corporate donor and the university, the clinic is on the verge of a significant expansion to become "a world class training facility," says Sheri Worthy, head of the department of financial planning, housing and consumer economics in the College of Family and Consumer Sciences.
Through another outreach program, founded by Associate Professor Lance Palmer, planning students also earn advanced certifications from the IRS to provide tax preparation services for free — which can shield people in the community from predatory tax preparers selling them "inappropriate products," Goetz says.
Two other university figures have teamed up to launch a radio show, "Nothing Funny About Money," which airs on a local NPR station. Matt Goren, a newly hired adjunct assistant professor of financial planning, and planning doctoral student Michael Thomas co-host the program. Thomas also runs a for-profit practice, Modom Financial Services, which serves mass-affluent clients.


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Romania selects representative for 2019 Eurovision contest
Ester Peony will represent Romania at the 2019 Eurovision contest, set to take place in May, in Tel Aviv, Israel. She will perform the song On a Sunday.
The winning song received 65 points from the jury, in a tight competition with Bella Santiago's Army of Love, which received 50 points, and Laura Bretan's Dear Father, which got 48 points.
Ester Peony, the stage name of Ester Alexandra Creţu, has Romanian origins. She discovered her passion for music while living in Montreal, Canada, with her family. She closed her first contract with a recording label in Romania after becoming known online for the recordings she self-published. She made her debut with the song Sub aripa ta (Under your wing), performed together with Romanian hip-hop artist Vescan. She launched her first EP, named Dig It, in 2018.
Ester Peony wrote On a Sunday together with Alexandru Şerbu. The lyrics belong to Ioana Victoria Badea.
Romania's representative at the 2019 Eurovision contest was selected by a jury made up of Tali Eshkoli, head of event & content Eurovision Song Contest 2019, Emmelie de Forest, a winner of the 2013 edition, journalists Deban Aderemi and William Lee Adams, Şerban Cazan, head of production HaHaHa Production, and Moldovan artist Alex Calancea. At the last stage of the national selection, the points cast by the public through televoting weighed as much as the points granted by a jury member.
This year's edition of Eurovision takes place under the slogan Dare to Dream. The semifinals are scheduled for May 14 and May 16, and the final for May 18. Israel's representative, Netta, won the 2018 edition of the contest, with the song Toy.
Romania's best performances at the contest include the third spot on two occasions (Luminiţa Anghel & Sistem in Kiev, 2005; Paula Seling and Ovi in Oslo, 2010) and the fourth spot once (Mihai Trăistariu in Athens, 2006).
(Photo: Eurovision Romania Facebook Page)


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Well it is the calm before the storm as it were. It's Tuesday afternoon and Chris is dropping my parents at the airport and picking up Uncle Rob, sort of like a human relay! I have turned the house into a hostel to accommodate all the bodies that will be turning up tonight and tomorrow.
We have 3 beds in the front bedroom; 2 doubles a single and even a child's bed/sofa! Shows you how large these rooms are as there is still plenty of room to walk around. The main bathroom has turned into a deluxe en-suite for Rob. Well at least he won't have to go far to pee in the night! I must remember to get him to lock the door in case he gets unexpected company!!!!!!
I have stocked up on essentials and am ready to feed 6 very hungry men. It is going to be 3 full-on days of hard work, chaos and mess but I am excited to see the finish.


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Purpose: BMS-275291 is a novel broad-spectrum inhibitor of matrix metalloproteinase (MMPs) rationally designed to spare a class of closely related metalloproteinases known as sheddases. Inadvertent sheddase inhibition is hypothesized to play a role in the dose-limiting joint toxicities occurring with hydroxamate-based MMP inhibitors. This trial was conducted to establish the recommended phase II dose; determine safety, toxicity, and pharmacokinetics of BMS-275291; and to assess potential markers of sheddase activity [tumor necrosis factor-α (TNFα) release and TNFα-RII shedding].
Experimental Design: This was an open label, single arm, phase I study conducted at two centers. Patients with advanced or metastatic cancer were treated with once-daily oral BMS-275291 at doses escalating from 600 to 2400 mg/day. Six to eight patients/dose level were to be studied with the recommended phase II dose level expanded to a total of 15 patients. Pharmacokinetic sampling was performed on days 1, 15, and 29 at 0, 0.5, 1, 2, 4, 6, 8, and 24 h after dosing. Radiological tumor assessment was performed every 8 weeks.
Results: Forty-four evaluable patients were enrolled in this study with the most frequent tumor types being colorectal cancer and non-small cell lung cancer. Dose limiting toxicities were observed at 600 mg/day (one of eight patients with grade 3 transaminitis) and at 1200 mg/day (1 of 15 patients with grade 3 rash and grade 4 shortness of breath), both in the context of predisposing conditions. No dose-limiting toxicities occurred at 900, 1800, or 2400 mg/day. The most frequent adverse events considered possibly, probably, or definitely drug-related were joint toxicity (myalgia/arthralgia), rash, fatigue, headache, nausea, and taste change, all of which were mild, grade 1, grade 2, and not dose-limiting. No objective tumor responses were observed. Twelve of forty-four patients received treatment for 4+ months, six for 8+ months, three for >1 year. Desired trough levels of parent BMS-275291 were maintained with once daily dosing. The mean plasma concentration of parent BMS-275291 at trough exceeded the calculated in vitro IC80 value for MMP-2 and IC90 value for MMP-9 at the recommended phase II dose of 1200 mg/day. No major changes in serum concentrations of sheddase enzymatic products, TNFα or TNFα-RII, were observed.
Conclusions: BMS-275291 is a nonhydroxamate MMP inhibitor with a novel mercaptoacyl zinc-binding group. In this study, plasma concentrations of BMS-275291 continuously exceeded in vitro MMP IC50 values without dose-limiting joint toxicity. In this refractory patient population, a suggestion of disease stabilization was observed in 12 patients. On the basis of preclinical, clinical, and pharmacokinetic data, the recommended phase II dose for future study is 1200 mg/day.
Matrix metalloproteinases (MMPs) are involved in normal wound healing, ovulation, and embryogenesis (1 , 2) as well as in tumor growth, tumor metastasis, and tumor angiogenesis (3, 4, 5) . MMPs are proteolytic enzymes that are thought to facilitate growth and angiogenesis of tumors at primary and metastatic sites (2) . There are >20 enzymes classified as MMPs, and MMP-2 and MMP-9 have been shown to be consistently overexpressed in human cancer; however, the precise pattern of overexpressed MMPs varies by tumor type. Elevated expression of various MMPs in serum or biopsy samples has been correlated with increased local invasiveness or shorter survival in several malignancies including non-small cell lung cancer (6, 7, 8, 9) , colorectal cancer (10 , 11) , and others (11, 12, 13, 14, 15) .
Peptidic and nonpeptidic inhibitors have been rationally designed and selected based on the molecular structure of MMPs determined by X-ray crystallographic studies (16) . Matrix metalloproteinase inhibitors (MMPIs) have been designed to inhibit a broad range of MMPs or to target specific MMPs selectively. Initial clinical trials with marimastat showed that this agent caused musculoskeletal toxicity that was dose limiting (17 , 18) . The mechanism of this toxicity has not been completely elucidated; however, MMP-1 inhibition has been thought to play a role (19) . Subsequently, more selective MMPIs targeting MMP-2 and -9 with reduced inhibition of MMP-1, -7, and -11 were developed in an attempt to create more effective compounds with reduced toxicity. However, musculoskeletal toxicity was not completely abrogated (20) . Recently, inhibition of "sheddase" activity attributed to non-MMP metalloproteinases [such as those of the "Adamalysin" (ADAM and ADAM-TS) family] has been postulated as a mechanism of MMPI-mediated musculoskeletal toxicity (21) .
BMS-275291 is a p.o. bioavailable, rationally designed peptidomimetic MMPI that contains a novel mercaptoacyl zinc-binding group (Ref. 22 ; Fig. 1A⇓ ; BMS-275291). Apart from the novel zinc-binding group, BMS-275291 is very similar in structure to marimastat (Fig. 1B⇓ ; marimastat) and inhibits a similar broad spectrum of MMPs including, like marimastat, MMP-1 (22) . However, unlike marimastat, BMS-275291 is designed to potently inhibit MMP activity although minimally affecting those of other metalloproteinases (e.g., sheddases) involved in the release of cell-associated molecules such as tumor necrosis factor-α, tumor necrosis factor-α receptor, interleukin-6 receptor, or l-selectin. In vitro, BMS-275291 is a potent inhibitor (nm) of the activities of MMP-1, -2, -7, -9, and -14. BMS-275291 inhibits tumor growth in a B16BL6 model of experimental metastases and in this model, BMS-275291 treatment results in a dose-dependent reduction in the number of lung metastases compared with vehicle controls. BMS-275291 also inhibits angiogenesis in a murine angiogenesis model, where once daily treatment with BMS-275291 results in a dose-dependent inhibition of endothelial cell migration into s.c. implanted Matrigel plugs. Pharmacokinetic studies demonstrated that the plasma concentrations of parent BMS-275291 in mice exceeds the in vitro IC50 values for MMP-1, -2, -7, -9, and -14 for at least 4 h after the administration of a therapeutic dose of BMS-275291. BMS-275291 has been administered at doses of 100 mg/kg/day daily for 3 months to marmoset monkeys with no clinical or histological changes of weight-bearing joints (23) .
In prior studies in healthy subjects, BMS-275291 was administered for up to 14 days at escalating doses of 150 mg/day to 1200 mg/day (24) . No dose-limiting adverse events were observed and at all doses, average steady-state trough plasma concentrations of parent BMS-275291 exceeded the in vitro IC50 values for MMP-2 and MMP-9.
On the basis of these encouraging data, a phase I clinical trial of BMS-275291 was initiated to determine the maximum-tolerated dose, safety, toxicity, pharmacokinetic profile, and recommended phase II dose of this agent in advanced cancer patients.
Patient Selection.
The protocol was approved by George-town and Duke University Institutional Review Boards. Inclusion criteria included the following: (a) histologically confirmed advanced cancer having failed standard therapy; (b) 18 years of age or older; (c) Karnofsky performance status ≥70%; (d) adequate hematological funtion (neutrophil count ≥1500/mm3, platelet count ≥100,000/mm3, hemoglobin ≥8 g/dl), hepatic function [aspartate aminotransferase, alanine aminotransferase <2 times upper limit of normal, total bilirubin <1.5 times upper limit of normal, alkaline phosphatase <2 times upper limit of normal], and renal function (serum creatinine <1.5 times upper limit of normal; and (e) if applicable, negative pregnancy test and effective means of contraception. Exclusion criteria included the following: (a) chemotherapy, immunotherapy, or radiotherapy within 4 weeks of the study; (b) investigational drug or major surgery within 2 weeks of the study; (c) known brain metastases (in the absence of neurological symptoms, baseline CNS imaging was not required for study entry); (d) prior history of inflammatory arthritis treated with systemic steroids or inflammatory arthritis within 6 months of the study; and (e) any condition that did not permit compliance with the protocol. All patients provided signed informed consent.
Treatment Plan.
This study was a dose escalation phase I study of oral BMS-275291 in patients with advanced cancer. Drug was supplied as 150 mg of gelatin capsules and as 300 mg of tablets. Patients received a single oral daily dose and were assessed weekly for the first 4 weeks and every 2 weeks thereafter. Patients underwent radiographic disease assessment at week 9 of treatment and then every 8 weeks thereafter. In the absence of progressive disease, patients were allowed to continue on treatment. Five dose levels were evaluated (600, 900, 1200, 1800, and 2400 mg). Intra-patient dose escalation was not permitted. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria. Six to eight patients were enrolled to each dose level, and if dose-limiting toxicity (DLT) was observed in ≤1 patient, the dose was escalated to the next dose level. Escalation to the next dose level occurred only after the last patient on the previous dose level was observed for 4 weeks, and <1 patient experienced a DLT at that dose level. Further dose level escalation would be discontinued if DLT was observed in ≥two of six patients. A recommended phase II dose was chosen based on clinical, pharmacokinetic, and surrogate marker data rather than based on maximum-tolerated dose; this dose level would be expanded to 15 patients according to the protocol to further characterize the recommended phase II dose level. Complete blood counts and chemistry (creatinine, total bilirubin, alkaline phosphatase, alanine aminotransferase/aspartate aminotransferase) were performed weekly for 4 weeks and every 2 weeks thereafter; prothrombin time and partial thromboplastin time were performed every 2 weeks, and platelet aggregation studies were performed on day 29. Chest radiograph or chest computed tomography scan and electrocardiogram were performed at baseline. Imaging studies to evaluate possible tumor response were performed every 8 weeks.
Twenty patients had pretreatment and on-study punch biopsies of skin from the forearm as part of a study of the effect of BMS-275291 on wound angiogenesis. This was an ancillary study conducted only at Duke University and is reported separately (25) .
Sample Collection and Analysis.
Blood samples for pharmacokinetics were obtained on days 1, 15, and 29 at predose and at 0.5, 1, 2, 4, 6, 8, and 24 h after dosing, as well as predose on days 8 and 22. BMS-275291 contains a free sulfhydryl group and forms disulfide dimers with other sulfhydryl-containing molecules in vivo. Therefore, analytical methods were developed to quantitate both BMS-275291 and "total" BMS-275291 (BMS-275291 plus any BMS-275291 recovered from reducible disulfides containing BMS-275291). Because a free sulfhydryl group is required for activity, disulfides of BMS-275291 are inactive. To quantitate monomeric BMS-275291, blood samples were collected into tubes containing methyl acrylate to react with free sulfhydryl groups of monomeric BMS-275291. The resulting BMS-275291-methyl acrylate derivative was quantitated to provide monomeric BMS-275291 concentrations. For the quantitation of total BMS-275291, blood samples were treated with tris 2-carboxyethyl phosphine to reduce disulfide linkages before quantitation of BMS-275291.
An on-line extraction liquid chromatography-tandem mass spectrometry method was developed for the quantitation of unchanged BMS-275291. Chromatography was carried out using a Shimadzu LC-10AD VP pump and a Waters 2690 high-performance liquid chromatography system. Plasma samples containing methyl acrylate and internal standard (CH-3335) were subjected to an on-line purification that was achieved on an Oasis (1 × 50 mm × 30 μm) column with a 100% aqueous mobile phase containing 0.5% formic acid, at a flow rate of 3 ml/min. Chromatographic separation was achieved on a Waters Symmetry, C18, 3.9 × 50 mm, 5 μm column maintained at room temperature using an isocratic mobile phase containing acetonitrile, water, and formic acid. Detection was by positive electrospray tandem mass spectrometry. The standard curve ranged from 10 to 1000 ng/ml, the intra-assay precision was within 8.5% relative standard deviation, and the inter-assay precision was within 9.7% relative standard deviation. The assay accuracy was within 5.6% of the nominal values.
A liquid chromatography mass spectrometry method was developed and validated for the quantitation of total BMS-275291. Plasma samples containing tris 2-carboxyethyl phosphine and internal standard (CH3921) were processed using an automated 96-well solid-phase extraction. Chromatographic separation was achieved isocratically on a YMC Basic, 2 × 50 mm, 5 μm column maintained at 35°C using an isocratic mobile phase containing water, acetonitrile, methanol, and ammonium acetate. Detection was by positive ion electrospray mass spectrometry in the selected ion-monitoring mode. The standard curve ranged from 20 to 5000 ng/ml, the intra-assay precision was within 6.1% relative standard deviation and the inter-assay precision was within 5.5% relative standard deviation. The assay accuracy was within 5.2% of the nominal values.
Pharmacokinetic Analysis.
The plasma concentration-time data for parent and total BMS-275291 were analyzed by noncompartmental methods using the program MENU/PKMENU (SAS, Cary, NC). There was insufficient data (sampling only up to 24 h after dosing), for terminal elimination half-life determination for both parent and total BMS-275291. Compartmental analysis was performed using WinNonlin (v1.5, Pharsight Corp.).
Surrogate End Point Biomarker Studies and Analysis.
Samples for quantitation of serum tumor necrosis factor-α (TNF-α) and soluble TNF receptor were collected immediately before dosing (predose) on days 1, 15, and 29. TNF-α and TNF-α receptor II extra cellular domain were assayed in patient plasma using commercially available ELISA kits (HSTA50 and DRT200, respectively; R&D Systems) using the manufacturer's recommended method. ELISA plates were analyzed using a Molecular Devices Vmax Kinetic Microplate reader (Menlo Park, CA) at the recommended wavelengths.
Patient Characteristics.
A total of 44 patients were treated with BMS-275291 at escalating dose levels of 600 to 2400 mg/day. Patient characteristics are shown in Table 1⇓ .
Adverse Events.
Toxicities thought to be related to the study drug observed are listed by Common Toxicity Criteria grade and dose level in Table 2⇓ . Two dose-limiting toxicities occurred. One patient treated at 600 mg/day had an asymptomatic grade 3 elevation in aspartate aminotransferase that resolved after 7 days off drug. This patient had grade 1 aspartate aminotransferase elevation, a history of alcoholism and fatty liver infiltration by CT scan at baseline. One patient at 1200 mg/day had a grade 3 rash and a grade 4 dose-limiting dyspnea that was possibly related to study drug. This patient had progressive non-small cell lung cancer and a history of rheumatoid arthritis, scleroderma, and drug allergy. No dose-limiting toxicities occurred at the 900 mg/day (n = 9), 1800 mg/day (n = 6), or 2400 mg/day (n = 6) dose levels. One patient, a 62-year-old woman with a 22-year history of prior hormonal therapy and chemotherapy for breast cancer was discovered after 7 months on study to have bilateral, posterior, subcapsular cataracts.
The most frequent adverse events reported were generalized myalgia and specific arthralgias. These adverse events were reported in 26 of 44 (59%) patients. They were mild in the majority of patients, with grade 1 toxicity observed in 17 of 44 and grade 2 toxicity observed in 9 of 44 patients. No patient experienced grade 3 or 4 arthralgia or myalgia, and no arthritis was reported for any patient. Grade 1/2 arthralgia was often unifocal and resolved during continued dug administration or after discontinuation of study drug. One patient experienced a slowly progressive grade 2 tenosynovitis of both hands (left > right) that was associated with a weakly positive antinuclear antibody after 7 months of therapy. The antinuclear antibody resolved, and the tenosynovitis gradually improved over several months after discontinuation of study drug.
Ten patients developed drug-related rash within the first three weeks of BMS-275291 administration. In nine patients, rash was grade 1 or 2 in severity and resolved despite continued BMS-275291 administration. Pruritis accompanied rash in three patients; arthralgias of knees or ankles accompanied rash in two patients. In four patients, the rash was characterized as "flushing" and occurred in the first week. One patient with non-small cell lung cancer, described previously, developed dose-limiting rash. This patient developed grade 2 rash, which did not resolve during a one-week drug holiday. The patient was rechallenged with rapid return of the rash, which worsened to grade 3 and was associated with fever and worsening shortness of breath. The rash was typically a patchy erythematous rash without elevation. It was not localized to one region of the body. There were no acneiform changes or skin desquamation observed. Other commonly reported adverse events considered possibly drug-related included the following: fatigue in 14 of 44 (32%) patients; dry mouth or taste alteration in 9 of 44 (20%) patients; nausea in 10 of 44 (23%) patients; and headache in 7 of 44 (16%) patients. For each of these adverse event categories, the severity of these events was grade 2 or less and frequently resolved during continued study drug administration. There was no relationship between dose level and the incidence or severity of adverse events. These toxicities were typically mild and were not clearly temporally related to study drug administration. These toxicities often presented and abated with ongoing dosing of BMS-275291 and did not appear to alter the patient's activities of daily living.
The maximum tolerated dose was not reached in this study. Only 1 of 6 patients at 600 mg/day and 1 of 15 patients at 1200 mg/day experienced a DLT. None of 33 patients treated at dose levels of 900, 1800, or 2400 mg/day experienced DLT.
No alterations in hematology, chemistry, coagulation, or platelet aggregation studies were observed with BMS-275291 (data not shown).
Surrogate End Points.
Given the premise that inhibition of sheddases (such as TNF-α converting enzyme) is at least partially responsible for joint toxicity (18) observed with hydroxamate-based MMPIs, patients were sampled at pretreatment baseline, days 15 and day 29 for TNFα and TNFα-RII by ELISA assay. In 44 patients sampled, no major alterations in TNFα and TNFα-RII levels were observed during study drug administration compared with pretreatment baseline, consistent with the sheddase-sparing design of BMS-275291. The shed TNF-α RII levels in patient plasma typically ranged between 200 and 500 pg/ml with little intrapatient variability. The TNF-α similarly had little intrapatient variability with plasma levels in the 1–10 ng/ml range (data not shown).
Of 44 patients, 12 patients received treatment for 4+ months, 6 patients for 8+ months, and 3 patients for >1 year. The median number of days on study was 8 weeks. Of the three patients treated for >1 year, two patients were enrolled at the 1200 mg/day dose level, and one patient at the 2400 mg/day dose level. The patient at the 2400 mg/day dose level was dose-reduced twice for mild myalgias and tolerated treatment well at 1200 mg/day dose level. No partial or complete tumor responses were observed in this study. A 51 year-old male diagnosed with mucinous cystadenocarcinoma pseudomyxoma peritoneum had previously experienced three treatment failures and remained stable for 15 months of treatment with BMS-275291.
At the phase II dose of 1200 mg/day, plasma concentrations of parent BMS-275291 peaked at about 0.5–4 h after dosing. The accumulation index was about 1 based on data from both days 15 and 29, suggesting that steady state had been achieved by day 15 (Table 3)⇓ . At the 1200 mg/day dose level, the mean Cmin value was 158 ng/ml based on trough concentrations values obtained predose on days 15, 16, 22, 28, and 29. This value was greater than the calculated in vitro IC80 value for MMP-2 and greater than the calculated in vitro IC90 value for MMP-9 (Fig. 2)⇓ . Assessment of individual plasma concentration versus time profiles indicated that trough concentrations of all patients exceeded the in vitro IC50 values for MMP-2 and MMP. The IC values were determined in vitro under reduced conditions, using purified human MMP-2 and MMP-9 and quenched fluorescent peptide substrate (22 , 26) . On the basis of Akaike Information Criterion indicating superiority of a two-compartment model compared with a one- or three-compartment model, the mean plasma concentration versus time data were modeled using an extravascular two-compartment model with first-order input, no lag time, and an iterative re-weighting scheme of [calculated concentration]−2 was used. Correlation coefficient exceeding 0.98 between the observed and predicted mean data (Fig. 3)⇓ , and coefficients of variation of <30% (data not shown) for the parameter estimates indicated that a reasonable fit of the data was achieved. Thus steady state was predictable from single dose data.
Comparison of plasma concentration versus time data of BMS-275291 and total BMS-275291 at 1200 mg/day indicated that BMS-275291 constituted about 25% of total BMS-275291 (e.g., BMS-275291 and BMS-275291 recoverable from reducible disulfides) in the plasma at Cmax and constituted <10% at Cmin. The accumulation index of the total form was about 2.0 (Table 3)⇓ .
Because PK samples at the other dose levels were not evaluable or not available, dose proportionality assessment could not be performed. This assessment will be conducted in other ongoing phase I studies.
MMPIs have been evaluated extensively in the clinic; however, they have shown little clinical benefit when used as monotherapy in patients with advanced disease (24) . Studies with MMPIs such as marimastat may have shown modest clinical efficacy and dose-proportional benefit but have been limited by musculoskeletal side effects including joint pain and stiffness. Musculoskeletal toxicity limits both the dose delivered and the duration of therapy (27, 28, 29, 30) . This toxicity has limited dose escalation or maintenance type treatment approaches for most MMPIs, particularly marimastat. BMS-275291 is similar to marimastat; it is a broad spectrum, peptidomimetic MMP inhibitor. However, unlike marimastat, BMS-275291 has a novel zinc-binding group that was selected to spare sheddases using high-throughput screening of a rationally designed, combinatorial chemical library. Sheddases are enzymes containing zinc that mediate the shedding of proinflammatory cytokines and cytokine receptors (including TNFα, TNF α-RII, interleukin 1-RII, l-selectin, and interleukin-6R) from the cell surface.
The initial daily starting dose of BMS-275291 was 600 mg in this phase 1 dose escalation study. This dose was 33% less than a dose (900 mg or 350 mg/m2) that was safe and well tolerated when given daily for 14 days to healthy normal males (24) . This dose was also well below a dose (900 mg/m2) tolerated daily for 3 months in marmosets without toxicity and is one-third the dose of 1200 mg/m2 tolerated daily for 3 months in cynomologous monkeys without clinically evident drug-related toxicity (23) . The initial dose level (600 mg/day) was chosen as the starting dose for this study because this dose has the potential to inhibit MMP activity in vivo as inferred from a comparison of achievable plasma concentrations of BMS-275291 in normal subjects to the measured in vitro IC50 values of MMP-2 and MMP-9. Therefore, six to eight patients were accrued to each dose level (rather than the traditional three patients per dose level) to better characterize safety and permit more precise calculation of pharmacokinetic parameters. A range of patients (6, 7, 8) to be accrued per dose level was stipulated to provide flexibility of enrollment for this multicenter trial. Five dose levels were evaluated (600, 900, 1200, 1800, and 2400 mg) in this study. Specific dose levels (rather than escalation to DLT) were tested to identify a dose that is well tolerated with effective MMP inhibition. On the basis of the preclinical and clinical data described above, it was expected that escalation beyond 2400 mg/day would not provide additional benefit but might lead to unnecessary and unacceptable toxicity particularly with long-term administration. A pattern of late-occurring study drug-related toxicities has been observed with other broad spectrum MMPIs in development, and given the potential application of BMS-275291 as a long-term daily treatment (31) , a traditional dose-escalation until the maximum-tolerated dose has been exceeded study design was not used in this study.
BMS-275291 toxicity was mild overall. The most frequent adverse events considered possibly drug-related were grade 1 or 2 joint toxicity, fatigue, rash, taste change, nausea, and headache, all of which often resolved during and despite continued study drug administration. The forestated toxicities were not clearly attributable to study drug administration, and as mentioned these toxicities did not consistently occur when starting or restarting study drug and frequently abated when treatment was continued under close observation. The majority of these patients had been extensively pretreated as shown in Table 4⇓ , and it is likely that patients may have had residual or intermittent symptoms related to their advanced cancer or prior treatments. There was no relationship between dose and incidence or severity for any adverse event. This lack of a dose-toxicity relationship may reflect the preselection of high-dose levels, which were known to result in continuously high-plasma concentrations, based on previous studies in healthy subjects. In particular, arthralgia was mild or moderate, mostly transient, and not dose-limiting. Grade 3 and 4 joint toxicity did not occur with BMS-275291. No patients discontinued BMS-275291 treatment because of joint toxicity. For patients that came off of study because of other reasons and had joint toxicity at the time of study drug discontinuation, these joint symptoms usually resolved rapidly, within 1–2 weeks. Rash or flushing occurred in several patients within the first three weeks of therapy. In 9 of 10 cases, rash resolved despite continued BMS-275291 administration. In one case, extensive rash, drug-fever, and shortness of breath (in the setting of advancing non-small cell lung cancer) resulted in discontinuation of the patient from the study for toxicity.
In a previous study evaluating the disposition of BMS-275291 and total BMS-275291 in healthy volunteers,24 the half-life of parent BMS-275291 after 14 days of administration ranged from 23 to 53 h, suggesting that steady state could be achieved by about 11 days of dosing. Although the lack of substantial accumulation of unchanged BMS-275291 is not in complete agreement with the long terminal elimination half-life values, mean effective terminal elimination half-life estimates, ranging from 4 to 16 h, support the attainment of steady state by day 7 accompanied by minimal accumulation over the 14-day dosing period. These findings were in agreement with the observations in this trial. The half-life of total BMS-275291 (representing predominantly inactive disulfides of the drug) in healthy volunteers was assessed to be >100 h with accumulation; these observations were also similar to observations made in this trial.
Ultrafiltration experiments were conducted to evaluate the overall binding of radioactivity in human serum samples added to [14C]BMS-275291 (32) . The extent of protein binding (inclusive of disulfide linkages) was moderate and concentration dependent (77.2% at 100 ng/ml to 46.0% at 20,000 ng/ml). Therefore, chronic administration of 1200 mg/day BMS-275291 may result in plasma concentrations of BMS-275291 sufficient to inhibit MMP-2 and MMP-9 in cancer patients (33) .
The rationale for recommending a 1200 mg/day dose is based on a number of considerations. Because MMPs are implicated in embryogenesis, ovulation, wound healing, wound angiogenesis, and cancer, a biologically active dose of an MMPI may have few readily observable adverse effects in the adult human. Preclinically, there is a dose-efficacy relationship for in vitro MMP inhibition, in vivo antiangiogenesis, and in vivo efficacy in the preinitiation B16BL6 tumor model. In vitro MMP inhibition is maximal at the IC90, and concentrations above the IC90 added very little to in vivo antitumor activity in preclinical models. This would suggest a therapeutic ceiling with dose escalation of MMPIs. Additionally, in long-term monkey toxicology studies, the chronic toxicity (drug-induced lupus) appeared to be dose related, and this was one of the factors in the decision to study an intermediate dose of 1200 mg/day for subsequent phase II studies. In the phase I study of doses ranging from 600 mg/day to 2400 mg/day there was no relationship between dose and incidence or severity of adverse event of any kind. The dose of 1200 mg/day was the lowest dose at which the steady-state mean Cmin exceeded the in vitro IC90 of key MMPs, suggesting that this may be the lowest dose that maximizes MMP inhibition. At 1200 mg/day, the area under the curve and Cmin exceeded the area under the curve and Cmin seen at efficacious doses in mice. At 1200 mg/day, the Cmax was less than the IC50 for inhibition of sheddases, TNFα levels were not perturbed, and no patients experienced arthritis.
As the role of MMPs in cancer becomes more established, rational design becomes an important factor in MMPI development. Positive and negative experiences with earlier-generation MMP inhibitors must be considered when designing agents to optimize clinical activity and therapeutic index. BMS-275291 represents a novel, rationally designed MMPI that may realize the full potential of MMPIs by targeting a broad range of MMPs, similar to marimastat, without dose-limiting arthritis such that biologically relevant doses can be delivered with continuous inhibition of MMPs over a long term basis. Further clinical testing is under way to evaluate this potential.
We thank Delina Conway, Michael Huang, Yan Mao, Michelle Raphael, Carolanne Tarby, and Roxanne Truax for invaluable contributions to this study.
Grant support: MO1-RR-30 and MO1-RR13297 grants from the General Clinical Research Center Programs of the National Center for Research Resources, NIH. H. Hurwitz is supported in part by NIH CDA 5K23-CA-85582.
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.
Requests for reprints: Naiyer Rizvi, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-3204; Fax: (212) 794-4357; E-mail: rizvin{at}mskcc.org
- Received October 3, 2002.
- Revision received December 11, 2003.
- Accepted December 12, 2003.


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