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Viral proteases, the key enzymes that regulate viral replication and assembly, are promising targets for antiviral drug discovery. Herpesvirus proteases are enzymes with no crystallographically confirmed noncovalent active-site binders, owing to their shallow and polar substrate-binding pockets. Here, we applied our previously reported "Peptide-to-Small Molecule" strategy to generate novel inhibitors of β-herpesvirus proteases. Rapid selection with a display technology was used to identify macrocyclic peptide 1 bound to the active site of human cytomegalovirus protease (HCMV Pro ) with high affinity, and pharmacophore queries were defined based on the results of subsequent intermolecular interaction analyses. Membrane-permeable small molecule 19 , designed de novo according to this hypothesis, exhibited enzyme inhibitory activity (IC 50 = 10 -6 to 10 -7 M) against β-herpesvirus proteases, and the design concept was proved by X-ray cocrystal analysis., Competing Interests: The authors declare the following competing financial interest(s): S.Y., Y.S., E.N., T.U., I.K., Y.I., A.N., M.O., Y.Y., T.K., and Y.T. are employees of SHIONOGI & Co., Ltd. J.N. is an employee of PeptiDream Inc. S.Y., E.N., T.U., Y.I., and T.K. are shareholders in SHIONOGI & Co., Ltd. J.N. is a shareholder of PeptiDream Inc., (© 2023 American Chemical Society.)

A 53-year-old man presented to the emergency department with chest and back pain. Contrast-enhanced computed tomography( CT) revealed a Stanford type A acute aortic dissection with a pseudo-lumen occlusion. On the same day, the patient underwent emergent aortic arch replacement with frozen elephant trunk. When introducing cardiopulmonary bypass, arterial cannula was inserted into the right femoral artery. The day after surgery, swelling of the right lower leg appeared with CK and intramuscular compartment pressure elevation. Thus, the patient was diagnosed with compartment syndrome and decompressive fasciotomy was performed. Although there was no preoperative blood flow disturbance in the lower extremities on preoperative CT, lower limbs ischemia happened. Necrotic muscles in his right leg required debridement, but amputation was not needed. The patient was discharged unaided utilising orthotics on the day 120. In muscular, young male patients, care should be taken in the method of blood delivery.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622 , the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.

Purpose: Sarcopenia is characterized by depletion of skeletal muscle mass (SMM) and can cause increased postoperative complication in free flap procedure. One of the most important considerations while deciding the indication of the procedure is patients' survival. This study aimed to verify the relationship between low SMM and survival in patients who undergo oral cancer resection using free flap., Methods: SMM was evaluated using the skeletal muscle index (SMI cm 2 /m 2 ), which was defined using cross-sectional areas of skeletal muscles on computed tomography at the level of the third lumbar vertebrae normalized for height. Overall, 111 patients who underwent primary oral cancer resection and free flaps were included. Multivariate Cox regression analyses were used to evaluate the prognostic factors for survival., Results: A total of 25 patients (22.5%) were diagnosed with low SMM. The mean SMI was 42.2 cm 2 /m 2 . Multivariable analyses showed that increased age (hazard ratio [HR]; 4.98, p = .004), infiltrative growth pattern INF-c (HR; 3.83, p = .037), and low SMM (HR; 2.59, p = .034) were significant negative prognostic factors for overall survival. Increased age (HR; 3.18, p = .005), extra-nodal extension (HR; 3.30, p = .001), and low SMM (HR; 2.42, p = .017) were significant negative prognostic factors for disease-free survival., Conclusions: Low SMM is a significant negative prognostic factor for overall and disease-free survival in oral cancer patients undergoing free flap. Future prospective studies are warranted to identify effective preoperative exercise and nutrition programs to improve low skeletal muscle and survival rate in patients undergoing free flap procedures., (© 2020 Wiley Periodicals LLC.)

Hyperbaric oxygen (HBO) therapy promotes wound healing in patients with ischemic disease; however, HBO-induced changes in skin peripheral circulation have not been evaluated in clinical practice. Here, we investigated these changes in patients with critical limb ischemia (CLI), with a focus on the angiosome of crural blood vessels with blood flow improved by endovascular therapy (EVT). Six patients with CLI and ulcers who were treated with HBO after EVT (7 limbs; 1 patient had ulcers in the bilateral limbs) and 3 healthy subjects (6 limbs) were enrolled. HBO therapy was performed at 2 atm under 100% oxygen for 90 min per session. Skin perfusion pressure (SPP) was measured in the dorsum and sole of the foot 1 hour before (pre-SPP) and after (post-SPP) HBO therapy. ΔSPP was calculated as post-SPP minus pre-SPP. SPP measurement regions were divided into those that did (direct region) and did not (indirect region) correspond to the vascular angiosome in which angiography findings of the crus were improved after EVT; i.e., when the anterior tibial artery was effectively treated with EVT, the dorsum was the direct region and the sole was the indirect region, and vice versa when the posterior tibial artery was treated. In the direct, indirect, and healthy subject groups, the ΔSPPs were 20.5±8.7 (p=0.002), -6.4±10.9, and -15.1±18.1 (p=0.014), respectively; that of the direct group was significantly greater than that of the other groups. These results suggest that short-term improvement of the peripheral circulation by HBO therapy was significant in patients with successful revascularization.

The most suitable management of recurrent abdominal desmoid tumor is still unclear. A case of recurrent huge abdominal desmoid tumor successfully treated by hyperthermia therapy is described. A 63-year-old man was operated upon for desmoid tumor in the retroperitoneum involving pancreas, posterior wall of the stomach and transverse mesocolon in 2007. In 2008, the tumor recurred and could not be resected because of the patient refused the operation. Several therapies using tamoxifen, anastrozole, imatinib mesylate and radiotherapy were all ineffective. The tumor grew bigger and bigger during a treatment period. Finally, hyperthermia treatment was applied to the tumor. The size of the recurrent desmoid tumor reduced 75% by hyperthermia treatment for 46-month. Base on this experience, we recommend hyperthermia as the treatment for patients with recurrent abdominal desmoid tumor that several therapeutic strategies did not achieve a remarkable response.

In the chicken, the cranial and caudal parathyroid glands (parathyroid gland III and IV), which are connected to each other, are located adjacent to the carotid body. In the present study, we found that a mass of glomus cells surrounded by a thick layer of connective tissue was frequently distributed within the parathyroid gland III. The glomus cells in the parathyroid III, as well as those of the carotid body, expressed intense immunoreactivity for serotonin, chromogranin A, and tyrosine hydroxylase but no immunoreactivity for neuropeptide Y. The cells possessed long cytoplasmic processes containing dense-cored vesicles of 70-220 nm in diameter, and were in close association with sustentacular cells. In and around the glomus cell clusters of the parathyroid III, dense networks of varicose fibers showed immunostaining with the monoclonal antibody TuJ1 to a neuron-specific class III beta-tubulin isotype, c beta 4. Furthermore, the distribution was also detected of numerous galanin-, vasoactive intestinal peptide (VIP)-, substance P-, and calcitonin gene-related peptide (CGRP)-immunoreactive fibers.

Development of the carotid body and the glomus cell groups in the wall of the common carotid artery and its branches was examined in chickens at various developmental stages by immunohistochemistry using three different monoclonal antibodies, i.e., anti-neuron-specific class III beta-tubulin isotype (TuJ1), anti-rat brain beta-tubulin, and anti-Leu-7 (HNK-1) antibodies. All the antibodies reacted with neurons. The carotid body anlage was first discerned at 6 days of incubation at the lateral portion of the third branchial artery. The cells and nerve fibers immunoreactive for TuJ1, brain beta-tubulin and Leu-7, which were connected with the distal ganglion of the vagus nerve, were found around the carotid body anlage at this stage. Within the carotid body anlage, no immunoreactivity yet appeared. The immunoreactive cells were accumulated around the carotid body anlage until 8 days of incubation. From 9 days of incubation, the immunoreactive cells continuing with the distal vagal ganglion began to enter into the carotid body anlage and also dispersed widely along the common carotid artery and its branches, giving rise to the glomus cells. At 12 days of incubation, a large portion of the carotid body was occupied by the immunoreactive cells. Thus, the present study evidences that the glomus cells in the carotid body and around the arteries are emigrés that arrive in each residential place from the distal vagal ganglion. Immunoreactivity for TuJ1, brain beta-tubulin, and Leu-7 in the glomus cells started to decrease at late stages of embryonic development. After hatching, no TuJ1-immunoreactive cells were detected in the carotid body region.