Phosphorylated protein chip combined with artificial intelligence tools for precise drug screening.

We have developed a protein array system, named "Phospho-Totum", which reproduces the phosphorylation state of a sample on the array. The protein array contains 1471 proteins from 273 known signaling pathways. According to the activation degrees of tyrosine kinases in the sample, the corresponding groups of substrate proteins on the array are phosphorylated under the same conditions. In addition to measuring the phosphorylation levels of the 1471 substrates, we have developed and performed the artificial intelligence-assisted tools to further characterize the phosphorylation state and estimate pathway activation, tyrosine kinase activation, and a list of kinase inhibitors that produce phosphorylation states similar to that of the sample. The Phospho-Totum system, which seamlessly links and interrogates the measurements and analyses, has the potential to not only elucidate pathophysiological mechanisms in diseases by reproducing the phosphorylation state of samples, but also be useful for drug discovery, particularly for screening targeted kinases for potential drug kinase inhibitors.

Synthesis of 2,3-disubstituted indenones by cobalt-catalyzed [3+2] annulation of o-methoxycarbonylphenylboronic acid with alkynes.

Treatment of alkynes with o-methoxycarbonylphenylboronic acid in the presence of a cobalt catalyst resulted in the corresponding 2,3-disubstituted indenones in good yields. Excellent regioselectivities were observed, when silyl aryl alkynes were used. The intermediate 3-silyl-2-aryl-substituted indenones were converted to 2,3-diaryl indenones by a three-step protocol involving C-Si bromination and Suzuki-Miyaura coupling reaction.

[Complete Response in a Patient with HER2-Positive Gastric Cancer and Multiple Lung Metastases with Trastuzumab-Containing Chemotherapy].

We report the case ofa 79-year-old Japanese woman diagnosed with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer of the cardia with multiple lung metastases that showed complete response to trastuzumab-containing chemotherapy. First, we administered tegafur/gimeracil/oteracil (S-1) and cisplatin (CDDP) concurrently to the patient. Next, we switched to trastuzumab in combination with capecitabine and CDDP because gastric cancer tissue indicated HER2-positivity. Considering the patient's age and renal function, the dose of CDDP was decreased to 50% after starting the medication. Before the 2nd course of trastuzumab-containing chemotherapy, oral mucositis (Grade 3) and hand-foot syndrome (Grade 1) were observed. Therefore, a one-step dose reduction of capecitabine was necessary. After the 4th course, the primary gastric tumor was no longer visible endoscopically. After the 7th course, computed tomography (CT) showed the disappearance of all lung metastases. Accordingly, the patient was considered to be completely responsive to the medication. After the 12th course, recurrence of the tumor was not identified and at the request of the patient, the trastuzumab-containing chemotherapy was discontinued. Regular follow-up showed no evidence of recurrence 8 months after discontinuing treatment and the patient was in good condition 21 months after her initial diagnosis.

Heparin-induced thrombocytopenia and thrombosis in a patient with polycythemia vera.

A 75-year-old Japanese woman with polycythemia vera was admitted to our hospital in January 2003 with suspected pulmonary thromboembolism. After administration of heparin, platelet count decreased from 1,694 x 10(9)/l on admission to 60 x 10(9)/l on hospital day 14. The patient developed acute limb embolism and transient cerebral ischemic attack on days 17 and 25, respectively. Signs and symptoms mimicked those of disseminated intravascular coagulation. Antibodies against heparin and platelet factor 4 complexes were detected in serum, and a diagnosis of heparin-induced thrombocytopenia and thrombosis was made. Argatroban treatment improved thrombocytopenia and hypercoagulable state.