温馨一刻
留住孩子们成长的快乐时光。
穷在乡下有远亲
听说我家的桃子熟了，城里的朋友周末抽空来品尝采摘。怕我们破费，拉我们一家出门吃午饭。看着日日上升的疫情，不敢。朋友说他们会外卖带过来。。。
给领导说，他们太客气了。我们就按自己的方式待客吧：今天要去农贸市场买做酸豆角的原料，就给他们准备点带回家的土特产。谁想小菜摊的绿色豇豆（试下来，绿色的豇豆比紫色的好）还不够我上周预定的30斤呢。拿了十五斤，加两把紫色的新鲜吃。
我自己做酸豆角用的：
让朋友带回家的：
自家的黄瓜不错，一根藤上就有三条可摘，城里人就喜欢新鲜的，留着他们自己摘：
新鲜玉米不错，来一打：
来个walleye鱼汤。头尾钓回来的当天就被我和领导做了汤，剩下的就是肉了：
梯子准备好，桃子在树上：
白桃（今年真不错，摘了两个礼拜了，还有这么多。估计一颗树今年不少于200斤的产量）：
蟠桃（还没完全熟，可看到成群结队的Japanese beetles，不敢等了）：
礼拜一给女儿寄点蟠桃过去。和她娘一样的City girl，也喜欢农家新鲜蔬果。。。
（二0二一年七月十七日）
回答网友有关我家桃子的问题
我家桃树种了三四年了。网上买来的。白桃不是一般店里卖的4401的白桃。我家的小一些，酸一些。4401更象水蜜桃。蟠桃是一起买来的，也是白桃（有黄蟠桃的）。蟠桃熟了比较甜，没有酸味，好吃一些。可惜虫害太厉害，日本甲壳虫等好几种上来了，周末摘的时候还没完全熟。家里放几天应该就好了。另外，我喜欢吃硬桃，领导喜欢软的。
除了虫害，就是霉菌。以往颗粒无收，就是霉菌，长着长着就蔫了，尤其蟠桃厉害。桃子开花后容易赶上冰冻和冰雹，所以，前几年都是看花，没吃到过。去年开始学习对付霉菌，用波尔多液，买来的，今年赶上好年成，加霉菌控制得不错（没有卷叶）。波尔多液一年处理两次----叶长出来之前或叶落之后，喷树干树枝。所以，树不能长太高，我去年修理了一下，但往高处长的趋势很难控制。。。这是我家领导买回来的波尔多液（fungicide）：
果树是领导的功劳。我小时候水蜜桃吃得多，喜欢甜的桃子，这种酸甜的白桃一般，但有朋友喜欢。蟠桃正合我的胃口。
下一个目标是枣树。据酒友说是枣七年。买回来两颗，冻死了又发芽，去年开始离主树一米远，从根上发芽。我怕和去年一样割草时把它们割了，就围了两颗。今天发现今年发出来的一颗居然小苗上开花结果了，才一尺高呢，主树上有花，还没见到果。但叶子也卷起来，我怀疑也有霉菌，需要处理。今秋明春和桃树一起处理吧。
种果树，最麻烦的事烂水果，引苍蝇。需要勤快，经常埋。
（二0二一年七月十八日）
爹妈的爱哪能用钱来度量呢
周末邀请城里的朋友来摘桃，来我家过一个农家乐周末。没想到已经摘了两个礼拜的白桃树上还有那么多；还没完全熟的蟠桃树大约是桃子比较甜，更吸引虫害，每天五个十个地掉下来，剩下的不足早春的十分之一了。看着成群结队的Japanese beetles于是也决定一起摘了。过磅一下，大约有60多斤白桃，30多斤蟠桃呢。
朋友带走一些，分给城里没来的朋友，剩下几十斤，左右邻居同城的朋友分点, 办公室的同事也分享一些。。当然，最重要的是远在波士顿快两年没见面的女儿了。老妈说第一次收这么多，得给女儿寄点过去，不能只给她看照片解馋。桃子容易烂，只能走快递服务，包装好30个没完全熟的蟠桃，加上六个差不多熟了的白桃。一个包装6磅，今早就drop到邮局，70块，比超市贵多了呢。连邮局工作人员都说priceless peaches！ I will do whatever I can to make sure it get there on time。。。
老妈感叹说：当年她们小的时候，吃顿麦当劳都得想想，五块钱是我一个小时的工资啊。。。
后记
第二天下午三点女儿来短信说：好贵哦，不过蛮好吃的。。。
不错不错，今天大丰收，桃子到了芝加哥，DC，还有波士顿。。。等我退休了，多钓点鱼，油炸好了就可以寄更多地方了。。。
（二0二一年七月十九日）
穷人家煮“猪食”
昨天酒友从DC回来了。树上还有一些给他留着的桃子，就让他全摘了，不然就让日本甲壳虫全报销了。正好周末他要去看外地的儿女，就捎带上邻居叔叔阿姨的祝福。不想一摘又是30斤，还有十几斤烂的。穷人家吃不完的桃子舍不得扔，和领导连夜猛削清理出一大锅好的部分，然后就煮一锅猪食。煮的时候加点糖，第二天早上凉了，再打成果酱。吃不完可以冻起来，4度冰箱放点随时喝。估计够两老吃两三个礼拜了。。。
（二0二一年七月二十一日）
再拿一个grant, 我又可以玩五年？
学校和Science Translational Medicine的news release昨天出来了，老板今天一进办公室，就来找我说：电话里一大堆病人留言呢。。。
这是昨天的News Release中一个：
Bayer's drug that turns a cancer-protective pathway toxic eradicates breast tumors in mice
Bayer's drug that turns a cancer-protective pathway toxic eradicates breast tumors in mice
by Angus Liu | Jul 21, 2021 2:00pm
Bayer's ErSO, recently licensed from Systems Oncology, eradicated tumors in mouse models of ER-positive breast cancers and reduced metastasis. (Bayer)
An investigational breast cancer drug Bayer recently licensed from Systems Oncology has shown strong antitumor responses in mice, offering early clues as to why the German pharma shelled out $25 million for the preclinical asset last September.
The drug, dubbed ErSO, works by over-activating a normally tumor-protective pathway to make it toxic for cancer cells. It eradicated both primary and metastatic tumors in mouse models of estrogen receptor-positive breast cancers, according to results published in Science Translational Medicine.
The pathway ErSO targets is called the anticipatory Unfolded Protein Response (aUPR). Through mild and transient activation, aUPR prepares ER-positive cancer cells for growth and protects them from stress such as anticancer treatment.
But in a PNAS study in 2015, a research team from the University of Illinois at Urbana-Champaign led by biochemistry professor David Shapiro, Ph.D., showed that massive and sustained activation of aUPR with a drug could instead inhibit protein synthesis, depriving ER-positive breast cancer cells key building blocks necessary for survival.
For the new research, Shapiro and colleagues identified ErSO as a more potent aUPR hyper-activator that could selectively kill ER-positive breast cancer cells.
In multiple mouse models of ER-positive breast cancer, ErSO quickly killed off tumor cells in high numbers just days after treatment. Combined data from four mouse models showed that 38 of 39 tumors regressed by over 95%, with about half of cases reduced to undetectable levels, the team reported. Even tumors that didn’t completely disappear and regrew after stopping treatment still remained fully sensitive to another cycle of ErSO, the team found.
In another mouse model bearing mutant, patient-derived breast tumors with low expression of ER, oral ErSO treatment outperformed standard-of-care therapies tamoxifen and AstraZeneca’s Faslodex (fulvestrant) at blocking tumor growth, the team found.
“Many of these breast cancers shrink by more than 99% in just three days,” Shapiro said in a statement. “ErSO is fast-acting and its effects on breast cancers in mice are large and dramatic.”
What’s more, the Bayer drug also significantly reduced cancer metastases at multiple locations, including the lung, bone and brain, the researchers showed.
The success of Faslodex has prompted several biopharma companies to develop next-generation selective ER downregulators (SERDs). They include Sanofi, which is moving its drug, amcenestrant, into a phase 3 trial against tamoxifen after showing promising early results in combination with Pfizer’s CDK4/6 inhibitor Ibrance.
Roche is pairing its SERD drug, giredestrant, with Ibrance in the phase 3 persevERA trial. And Radius Health is working with Menarini on an oral SERD dubbed elacestrant. It expects phase 3 data from the EMERALD trial later this year.
The UIUC team noted that in mouse models, second-generation SERDs typically induced moderate regression of primary tumors. Those that were tested against metastases showed limited efficacy. And resistance is still a risk with CDK4/6 inhibitors.
Compared with the common inhibitory modes of action against ER, ErSO could offer “a turn-on approach to convert a tumor-selective protective pathway into a lethal, targeted anticancer response,” the researchers wrote in the study. The drug’s ability to target metastatic tumors and its activity in ER-low tumors that are traditionally considered ER-negative could broaden its potential therapeutic range, the researchers said.
Bayer picked up global rights to ErSO in September for $25 million upfront, and Systems Oncology is eligible to receive milestone payments of up to $345 million.
While the current study found the drug was well tolerated in mice and dogs, further safety analyses are needed before it can be tested in humans, the UIUC team said. The researchers also plan to explore ErSO’s use against other types of ER-positive cancers.
至今还没拿到过Bayer对我们研究的资助。这些合同的钱没我的份。。。据说学校已经把patent卖了。以后我们就成了啦啦队，希望自己的研究结果能造福百姓。。。
Pfizer也试着重复过我们的结果。关键在ER-negative乳腺癌细胞这个定义上，也是领域里专家们让我们为STM文章做很多revision的原因。我们的compound是一个和Tamoxifen作用原理完全不一样的思路，我2008年的文章就开始了这个序幕--找一个estrogen binding pocket之外的compound来达到抑制estrogen receptor的功能。但当时的那个compound和drug要求的potency差太远，一直到2015年才有了突破。目前这个是2015年找到的那个compound的第二代。。。但ER- negative是按Tamoxifen的作用原理来定义的，我们的作用原理是不是还能沿用那个定义，就成了争论的焦点。。。最后Pfizer放弃，认为我们的compound可能不仅仅target estrogen receptor。。。
Bayer据说重复了我们的大多数试验，但STM的文章是我们的，和Bayer没有关系。PDX是小公司做的，他们有自己的一套体系，有contract实验室，也知道如何推销。Bayer不会发文章的，他们只会往临床方向推进。我们现在的研究方向还是走理论，临床我们插不上手，包括病人分型，哪些基因表达是这个药物杀死癌细胞必须的（文章接近完成），方便临床挑选病人，当然还有别含estrogen receptor的癌症。。。小公司还是给我们的研究一些资助，不知道会维持多久，所以一个政府部门的grant还是很有必要的。
我随时可以退休。领导知道我能干到60岁，也不催我找工作了。我现在就挣点旅游的钱，带领导到处跑跑。。。
（二0二一年七月二十二日）
很欢喜地看你的Blog，忽然想到“真正让人轻松的是心态，而不是状态”。