新しいカルパイン阻害剤はラット生体位心における緩和な虚血再灌流による左心室機能障害を保護する

We have previously indicated that a new soluble calpain inhibitor, SNJ-1945 (SNJ), attenuates cardiac dysfunction after cardioplegia arrest-reperfusion by inhibiting the proteolysis of α-fodrin in in vitro study. Nevertheless, the in vivo study design is indispensable to explore realistic therapeutic approaches for clinical use. The aim of the present in situ study was to investigate whether SNJ attenuated left ventricular (LV) dysfunction (stunning) after mild ischemic-reperfusion (mI-R) in rat hearts. SNJ (60 μmol/l, 5 ml i.p.) was injected 30 min before gradual and partial coronary occlusion at proximal left anterior descending artery. To investigate LV function, we obtained curvilinear end-systolic pressure–volume relationship by increasing afterload 60 min after reperfusion. In the mI-R group, specific LV functional indices at midrange LV volume (mLVV), end-systolic pressure (ESPmLVV), and pressure–volume area (PVAmLVV: a total mechanical energy per beat, linearly related to oxygen consumption) significantly decreased, but SNJ reversed these decreases to time control level. Furthermore, SNJ prevented the α-fodrin degradation and attenuated degradation of Ca2+ handling proteins after mI-R. Our results indicate that improvements in LV function following mI-R injury are associated with inhibition of the proteolysis of α-fodrin in in situ rat hearts. In conclusion, SNJ should be a promising tool to protect the heart from the stunning.博士（医学）・甲617号・平成26年3月17

Using NU-KNIT® for hemostasis around recurrent laryngeal nerve during transthoracic esophagectomy with lymphadenectomy for esophageal cancer

BACKGROUND: We thought that using electrocautery for hemostasis caused recurrent laryngeal nerve palsy. We reflected the prolonged use of electrocautery and employed NU-KNIT® to achieve hemostasis nearby the recurrent laryngeal nerve. We assessed that using NU-KNIT® hemostasis prevented or not postoperative recurrent laryngeal nerve palsy, retrospectively. The present study was evaluated to compare using electrocautery hemostasis with using NU-KNIT® hemostasis during lymphadenectomy along recurrent laryngeal nerve. The variables compared were morbidity rate of recurrent laryngeal nerve palsy, operation time, and blood loss. RESULTS: We use NU-KNIT® to achieve hemostasis without strong compression. This group is named group N. On the other hand, we use electrocautery to achieve hemostasis. This group is named group E. Complication rate of recurrent laryngeal nerve palsy was higher in group E (55.6%) than group N (5.3%) (p = 0.007). CONCLUSIONS: Even hemostasis using NU-KNIT® was slightly more time-consuming than using electrocautery, we concluded that it would be useful to prevent recurrent laryngeal nerve palsy

NMR and mutational identification of the collagen-binding site of the chaperone Hsp47.

Heat shock protein 47 (Hsp47) acts as a client-specific chaperone for collagen and plays a vital role in collagen maturation and the consequent embryonic development. In addition, this protein can be a potential target for the treatment of fibrosis. Despite its physiological and pathological importance, little is currently known about the collagen-binding mode of Hsp47 from a structural aspect. Here, we describe an NMR study that was conducted to identify the collagen-binding site of Hsp47. We used chicken Hsp47, which has higher solubility than its human counterpart, and applied a selective (15)N-labeling method targeting its tryptophan and histidine residues. Spectral assignments were made based on site-directed mutagenesis of the individual residues. By inspecting the spectral changes that were observed upon interaction with a trimeric collagen peptide and the mutational data, we successfully mapped the collagen-binding site in the B/C β-barrel domain and a nearby loop in a 3D-homology model based upon a serpin fold. This conclusion was confirmed by mutational analysis. Our findings provide a molecular basis for the design of compounds that target the interaction between Hsp47 and procollagen as therapeutics for fibrotic diseases

Short-term outcomes of preoperative chemotherapy with docetaxel, oxaliplatin, and S-1 for gastric cancer with extensive lymph node metastasis (JCOG1704)

The version of record of this article, first published in Gastric Cancer, is available online at Publisher’s website: https://doi.org/10.1007/s10120-023-01453-7.Background: The prognosis for marginally resectable gastric cancer with extensive lymph node metastasis (ELM) remains unfavorable, even after R0 resection. To assess the safety and efficacy of preoperative docetaxel, oxaliplatin, and S-1 (DOS), we conducted a multicenter phase II trial. Methods: Eligibility criteria included histologically proven HER2-negative gastric adenocarcinoma with bulky nodal (bulky N) involvement around major branched arteries or para-aortic node (PAN) metastases. Patients received three cycles of docetaxel (40 mg/m², day 1), oxaliplatin (100 mg/m², day 1), and S-1 (80–120 mg/body, days 1–14), followed by gastrectomy with D2 plus PAN dissection. Subsequently, patients underwent postoperative chemotherapy with S-1 for 1 year. The primary endpoint was major (grade ≥ 2a) pathological response rate (pRR) according to the Japanese Classification of Gastric Carcinoma criteria. Results: Between October 2018 and March 2022, 47 patients (bulky N, 20; PAN, 17; both, 10) were enrolled in the trial. One patient was ineligible. Another declined any protocol treatments before initiation. Among the 45 eligible patients who initiated DOS chemotherapy, 44 (98%) completed 3 cycles and 42 (93%) underwent R0 resection. Major pRR and pathological complete response rates among the 46 eligible patients, including the patient who declined treatment, were 57% (26/46) and 24% (11/46), respectively. Common grade 3 or 4 toxicities were neutropenia (24%), anorexia (16%), febrile neutropenia (9%), and diarrhea (9%). No treatment-related deaths occurred. Conclusions: Preoperative chemotherapy with DOS yielded favorable pathological responses with an acceptable toxicity profile. This multimodal approach is highly promising for treating gastric cancer with ELM

Sample collection from asteroid (162173) Ryugu by Hayabusa2: Implications for surface evolution

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