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Abstract Background Corynebacterium striatum (C. striatum) is a gram-positive, anaerobic bacillus found both environmentally and in human skin and nasal mucosa flora. It is reportedly the etiologic agent of community-acquired and nosocomial diseases and is significantly associated with bacteremia and medical endovascular devices. This is the rare case of mitral valve native valve endocarditis (NVE) caused by C. striatum occurring in a young adult without underlying structural heart disease or indwelling cardiovascular medical devices successfully treated with multidisciplinary therapy. Case presentation The patient was a 28-year-old female with no medical history. She was transferred our hospital due to sudden onset of vertigo and vomit. A computed tomography on day 2 revealed the hydrocephalus due to the cerebellar infarction, and she underwent posterior fossa decompression for cerebellar infarction. An angiography on day 8 revealed a left vertebral artery dissection, which was suspected be the etiology. Afterwards, a sudden fever of 39 degrees developed on day 38. She was diagnosed with aspiration pneumonia and treated with ampicillin/sulbactam but was still febrile at the time of transfer for rehabilitation. Treatment continued with levofloxacin, the patient had no fever decline, and she was readmitted to our hospital. Readmission blood cultures (3/3 sets) revealed C. striatum, and an echocardiogram revealed an 11 mm long mitral valve vegetation, leading to NVE diagnosis. On the sixth illness day, cardiac failure symptoms manifested. Echocardiography revealed mitral valve rupture. She was transferred again on the 11th day of illness, during which time her mitral valve was replaced. C. striatum was detected in the vegetation. Following surgery, she returned to our hospital, and vancomycin administration continued. The patient was discharged after 31 total days of postoperative antimicrobial therapy. The patient experienced no exacerbations thereafter. Conclusions We report the rare case of C. striatum mitral valve NVE in a young adult without structural heart disease or indwelling cardiovascular devices. Clinical trial number Not applicable.

Abstract Background Laparoscopic rectopexy is an established treatment option for full-thickness rectal prolapse. Recently, reduced port surgery (RPS) has emerged as a novel concept, offering reduced postoperative pain and improved cosmetic outcomes compared with conventional multiport surgery (MPS). This study aimed to evaluate the feasibility and safety of RPS for full-thickness rectal prolapse. Methods From October 2012 to December 2018, 37 patients (MPS: 10 cases, RPS: 27 cases) underwent laparoscopic rectopexy for full-thickness rectal prolapse. Laparoscopic posterior mesh rectopexy (Wells procedure) is the standard technique for full-thickness rectal prolapse at our hospital. RPS was performed using a multi-channel access device, with an additional 12-mm right-hand port. Short-term outcomes were retrospectively compared between MPS and RPS. Results No significant differences were observed between MPS and RPS in the median operative time, the median blood loss volume, the postoperative complication rates, and median hospital stay duration after surgery. Conclusion Reduced port laparoscopic posterior mesh rectopexy may serve as an effective therapeutic option for full-thickness rectal prolapse. However, to establish the superiority of RPS over MPS, a prospective, randomized, controlled trial is warranted.

Introduction: We retrospectively analyzed convulsive patient outcomes transported by a physician-staffed Helicopter Emergency Medical Service (doctor helicopter [DH]) using the keyword-triggered dispatch with data from the Japan DH Registry System (JDRS). Upon receiving an emergency call containing critical keywords, such as an ongoing convulsion at the firefighting central command room, immediate dispatch of the DH is requested, in addition to dispatching an ambulance. The keyword-triggered dispatch relied on data obtained from the JDRS. Methods: Details from the JDRS database included patient age, sex, cardiac arrest presence upon DH contact, vital signs, DH dispatch timing (keyword-triggered dispatch/emergency medical technician [EMT]-triggered dispatch), medical intervention details, and 1-month outcomes (cerebral performance category [CPC]; CPC1, 2: Good; CPC 3–5: Poor). Subjects were divided into keyword (keyword-triggered dispatch) and control (EMT-triggered dispatch) groups for comparison. Results: Of 1201 patients, all evacuated from the scene, 617 were in the keyword group, and 584 in the control group. No significant differences existed between groups for cardiac arrest, respiratory and heart rates, CPC, or mortality. The keyword group had lower average age, systolic blood pressure, and medical intervention ratio but a higher median Glasgow Coma Scale and good outcome ratio. Conclusion: This first report on the keyword-triggered dispatch as a prognostic factor for convulsive patients evacuated by DH using the JDRS.

Abstract Human hematopoietic stem cell (HSC)-transferred humanized mice are valuable models for exploring human hematology and immunology. However, sufficient recapitulation of human hematopoiesis in mice requires large quantities of enriched human CD34+ HSCs and total-body irradiation for adequate engraftment. Recently, we generated a NOG mouse strain with a point mutation in the c-kit tyrosine kinase domain (W41 mutant; NOGW mice). In this study, we examined the ability of NOGW mice to reconstitute human hematopoietic cells. Irradiated NOGW mice exhibited high engraftment levels of human CD45+ cells in the peripheral blood, even when only 5,000–10,000 CD34+ HSCs were transferred. Efficient engraftment of human CD45+ cells was also observed in non-irradiated NOGW mice transferred with 20,000–40,000 HSCs. The bone marrow (BM) of NOGW mice exhibited significantly more engrafted human HSCs or progenitor cells (CD34+CD38− or CD34+CD38+ cells) than the BM of NOG mice. Furthermore, we generated a human cytokine (interleukin-3 and granulocyte-macrophage colony-stimulating factor) transgenic NOG-W41 (NOGW-EXL) mouse to achieve multilineage reconstitution with sufficient engraftment of human hematopoietic cells. Non-irradiated NOGW-EXL mice showed significantly higher engraftment levels of human CD45+ and myeloid lineage cells, particularly granulocytes and platelets/megakaryocytes, than non-irradiated NOGW or irradiated NOG-EXL mice after human CD34+ cell transplantation. Serial BM transplantation experiments revealed that NOGW mice exhibited the highest potential for long-term HSC compared with other strains. Consequently, c-kit mutant NOGW-EXL humanized mice represent an advanced model for HSC-transferred humanized mice and hold promise for widespread applications owing to their high versatility.

Spontaneous coronary artery dissection occurs predominantly in women and is associated with fibromuscular dysplasia. We illustrate a rare case of sudden coronary death as a result of cardiac rupture from spontaneous coronary artery dissection in a 54-year-old man without fibromuscular dysplasia. Cardiac rupture has been previously reported in 6 cases, mostly in women.

Abstract Chimeric TK-NOG mice with a humanized liver (normal Hu-liver) are a unique animal model for predicting drug metabolism in humans. However, residual mouse hepatocytes occasionally prevent the precise evaluation of human drug metabolism. Herein, we developed a novel humanized liver TK-NOG mouse with a conditional knockout of liver-specific cytochrome P450 oxidoreductase (POR cKO Hu-liver). Immunohistochemical analysis revealed only a few POR-expressing cells around the portal vein in POR cKO mouse livers. NADPH-cytochrome c reductase and cytochrome P450 (P450)-mediated drug oxidation activity in liver microsomes from POR cKO mice was negligible. After the intravenous administration of S-warfarin, high circulating and urinary levels of S-7-hydroxywarfarin (a major human metabolite) were observed in POR cKO Hu-liver mice. Notably, the circulating and urinary levels of S-4′-hydroxywarfarin (a major warfarin metabolite in mice) were much lower in POR cKO Hu-liver mice than in normal Hu-liver mice. POR cKO Hu-liver mice with minimal interference from mouse hepatic P450 oxidation activity are a valuable model for predicting human drug metabolism.

Plaque rupture, plaque erosion, and COVID-19 infection can cause acute coronary syndromes (ACS). We illustrate case examples demonstrating the distinctive and characteristic pathologic findings underlying each of these various causes of acute myocardial infarction. A deeper understanding of the pathophysiology of ACS is necessary for the development of newer agents and techniques to improve outcomes after ACS. (Level of Difficulty: Advanced.)

The purpose of this study is to quantitatively evaluate the effects of steam curing and internal curing on contribution of fly ash to strength development of mortar by using cementing efficiency factor (k-value) that represents strength development performance as a binder of fly ash. In addition, the pozzolanic reaction of fly ash was evaluated from the viewpoint of calcium hydroxide consumption by using thermogravimetry and differential thermal analysis as well as the degree of fly ash reaction by using selective dissolution method. The result indicated that steam curing improved early compressive strength and internal curing improved compressive strength and k-value at all ages. Also, a linearrelationship between the degree of fly ash reaction and the k-value was shown regardless of the age and the replacement ratio of fly ash.

Vascular calcification (VC) is concomitant with atherosclerosis, yet it remains uncertain why rupture-prone high-risk plaques do not typically show extensive calcification. Intraplaque hemorrhage (IPH) deposits erythrocyte-derived cholesterol, enlarging the necrotic core and promoting high-risk plaque development. Pro-atherogenic CD163+ alternative macrophages engulf hemoglobin:haptoglobin (HH) complexes at IPH sites. However, their role in VC has never been examined to our knowledge. Here we show, in human arteries, the distribution of CD163+ macrophages correlated inversely with VC. In vitro experiments using vascular smooth muscle cells (VSMCs) cultured with HH-exposed human macrophage — M(Hb) — supernatant reduced calcification, while arteries from ApoE–/– CD163–/– mice showed greater VC. M(Hb) supernatant–exposed VSMCs showed activated NF-κB, while blocking NF-κB attenuated the anticalcific effect of M(Hb) on VSMCs. CD163+ macrophages altered VC through NF-κB–induced transcription of hyaluronan synthase (HAS), an enzyme that catalyzes the formation of the extracellular matrix glycosaminoglycan, hyaluronan, within VSMCs. M(Hb) supernatants enhanced HAS production in VSMCs, while knocking down HAS attenuated its anticalcific effect. NF-κB blockade in ApoE–/– mice reduced hyaluronan and increased VC. In human arteries, hyaluronan and HAS were increased in areas of CD163+ macrophage presence. Our findings highlight an important mechanism by which CD163+ macrophages inhibit VC through NF-κB–induced HAS augmentation and thus promote the high-risk plaque development.

BackgroundA deeper understanding of coronary medial thickness is important for coronary intervention because media thickness can limit the safety and effectiveness of interventional techniques. However, there is a paucity of detailed data on human coronary medial thickness so far.Materials and methodsWe investigated the thickness of the media by histologic analysis. A total of 230 sections from 10 individuals from the CVPath autopsy registry who died from non-coronary deaths were evaluated. We performed pathological analysis on 13 segments of the following primary vessels from coronary arteries: the left main trunk, proximal left anterior descending artery (LAD), mid LAD, distal LAD, proximal left circumflex artery (LCX), mid LCX, distal LCX, proximal right coronary artery (RCA), mid RCA, and the distal RCA. The following side branches were also evaluated: diagonal, obtuse margin, and posterior descending artery branches.ResultsThe average age of the studied individuals was 60.4±12.3 years. The median medial thickness for all sections was 0.202 (0.149-0.263) mm. The median medial thickness of the main branches was significantly higher compared to that of the side branches (pConclusionsThe human coronary arteries demonstrate variation in medial thickness which tends to vary depending upon an epicardial coronary artery itself, as well as its segments and branches. Understanding these variations in medial thickness can be useful for both the interventionalists and interventional product development teams.

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer in the clinic. Further discovery of novel drugs or therapeutic protocols that enhance efficacy requires reliable animal models that recapitulate human immune responses to ICI treatment in vivo. In this study, we utilized an immunodeficient NOG mouse substrain deficient for mouse FcγR genes, NOG-FcγR−/− mice, to evaluate the anti-cancer effects of nivolumab, an anti-programmed cell death-1 (PD-1) antibody. After reconstitution of human immune systems by human hematopoietic stem cell transplantation (huNOG-FcγR−/− mice), four different programmed death-ligand 1 (PD-L1)-positive human cancer cell lines were tested. Among them, the growth of three cell lines was strongly suppressed by nivolumab in huNOG-FcγR−/− mice, but not in conventional huNOG mice. Accordingly, immunohistochemistry demonstrated the enhanced infiltration of human T cells into tumor parenchyma in only nivolumab-treated huNOG-FcγR−/− mice. Consistently, the number of human T cells was increased in the spleen in huNOG-FcγR−/− mice by nivolumab but not in huNOG mice. Furthermore, human PD-L1 expression was strongly induced in the spleen of huNOG-FcγR−/− mice. Collectively, our results suggest that the anti-cancer effects of anti-PD-1 antibodies can be detected more clearly in NOG-FcγR−/− mice than in NOG mice.

Abstract Background The robotic system has been applied in the treatment of gastric cancer (GC), and the procedure has been found to be safe and feasible. Situs inversus totalis (SIT) is a relatively rare autosomal recessive congenital anomaly. We successfully performed robot-assisted proximal gastrectomy (RAPG) and handsewn double-flap esophagogastrostomy for GC in a patient with SIT. Case presentation A 71-year-old woman was referred to us with an asymptomatic ulcerative lesion in the upper body of the stomach. Computed tomography revealed that she had SIT. She was diagnosed with cT1bN0M0, cStageIA gastric cancer. RAPG with lymph node dissection and handsewn double-flap esophagogastrostomy was performed. Robotic surgery enabled the surgeon to perform the surgery without changing his position and experiencing any confusion resulting from the patient’s reversed anatomy. It took 448 min, and no intraoperative complications occurred. Her postoperative course was uneventful; she was discharged on postoperative day 10. The final pathologic report showed pT1b1N0M0, pStage IA. Conclusions This is the first case describing RAPG with handsewn double-flap esophagogastrostomy for a SIT patient with early GC.

Abstract Background Ligation clips are used for vessel or tissue ligation in surgery. Although previous reports have described the migration of metallic clips after hepato-biliary-pancreatic surgery, very few reports have described the migration of non-absorbable polymer clips (NAPCs: Hem-o-Lok). Case presentation We present 4 cases of NAPC migration that occurred after laparoscopic surgery. Case 1 was an 81-year-old woman that had undergone a laparoscopic right hemihepatectomy for an intrahepatic bile duct cyst adenocarcinoma at the age of 79 years. Two years after the operation, she underwent an upper gastrointestinal endoscopy to investigate epigastric pain. The endoscopy showed NAPCs lodged at the anterior side of the duodenal bulb. Case 2 was an 80-year-old man that had undergone a laparoscopic cholecystectomy for choledocholithiasis at the age of 77 years. Three years after the operation, follow-up computed tomography and magnetic resonance cholangiopancreatography (MRCP) imaging indicated a mass in the upper bile duct. After a laparoscopic bile duct resection and reconstruction, an NAPC was found inside the inflammatory pseudotumor. Case 3 was a 63-year-old man that had undergone laparoscopic liver S4b and S5 resections and lymph node dissection for gallbladder cancer. Three months after the operation, follow-up MRCP imaging suggested a bile duct stenosis. An endoscopic retrograde cholangiopancreatography (ERCP) was performed, and an NAPC was found inside the bile duct. Case 4 was a 74-year-old man that had undergone a laparoscopic S5 segmentectomy, S7 partial liver resection, and cholecystectomy for liver metastasis of lung cancer and cholelithiasis. A trans-cystic drainage tube was inserted, and it was ligated and fixed with NAPCs. Three months after the operation, follow-up MRCP imaging showed common bile duct stones (CBDS). An ERCP was performed, and two NAPCs were found with the CBDS. Conclusions Few previous reports have described complications due to NAPC migration after hepato-biliary-pancreatic surgery. However, with the widespread use of NAPC, postoperative complications due to NAPC migration are expected to increase in the near future. The differential diagnosis of complications should include potential NAPC migration in patients that have undergone laparoscopic surgery.

IntroductionDentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease with various neurological manifestations. Corneal endothelial degeneration and optic atrophy have been reported separately; however, there are no reports of corneal endothelial degeneration with optic atrophy.CasesHerein, we present four related patients with DRPLA: two patients (69-year-old woman and 80-year-old man) who exhibited both corneal endothelial degeneration and optic atrophy and another two (49- and 51-year-old women, respectively) who exhibited only corneal endothelial degeneration. We quantified the reduction in corneal endothelial cell density (ECD) and hexagonality using specular microscopy and thinning of the circumpapillary retinal nerve fiber layer (RNFL) using optical coherence tomography (OCT).ConclusionThis is the first report of DRPLA accompanied by corneal endothelial degeneration and/or optic atrophy, which were both quantified based on the corneal ECD and the circumpapillary RNFL thickness using specular micrography and OCT, respectively. The pathophysiological mechanism is unclear; however, the involvement of the nuclear receptor TLX interacting with atrophin-1 may be implicated in ophthalmic manifestations of DRPLA. Therefore, we recommend performing specular micrography and/or OCT when patients with DRPLA experience visual disturbances.

Abstract Laparoscopic liver resection (LLR) has been reported as a safe, minimally invasive, and effective surgery for the management of liver tumor. However, the efficacy and safety of laparoscopic repeat liver resection (LRLR) for recurrent liver tumor are unclear. Here, we analyzed the surgical results of LRLR. From June 2010 to May 2019, we performed 575 LLR surgeries in our department, and 454 of them underwent pure LLR for the single tumor. We classified the patients who received pure LLR for the single tumor into three groups: LRLR (n = 80), laparoscopic re-operation after previous abdominal surgery (LReOp; n = 136), and laparoscopic primary liver resection (LPLR; n = 238). We compared patient characteristics and surgical results between patients undergoing LRLR, LReOp and LPLR. We found no significant differences between LRLR and LPLR in the conversion rate to laparotomy (p = 0.8033), intraoperative bleeding (63.0 vs. 152.4 ml; p = 0.0911), or postoperative bile leakage rate (2.50 vs. 3.78%; p = 0.7367). We also found no significant difference in the surgical results between LReOp and LPLR. However, the number of patients undergoing the Pringle maneuver was lower in the LRLR group than the LPLR group (61.3 vs. 81.5%; p = 0.0004). This finding was more pronounced after open liver resection than laparoscopic liver resection (38.9 vs. 67.7%; p = 0.0270). The operative time was significantly longer in patients with proximity to previous cut surface than patients with no proximity to previous cut surface (307.4 vs. 235.7 min; p = 0.0201). LRLR can safely be performed with useful surgical results compared to LPLR.

Vascular and valvular calcification are commonly encountered in clinical medicine and a greater understanding of their significance and pathophysiology remain a subject of immense importance. In the coronary arteries, vascular calcification burden correlates with the severity of luminal stenosis and atherosclerotic plaque burden. While in progressive lesions, the presence of coronary calcification is not binary but rather depends on the type of calcification. Racial and gender differences, and comorbidities like diabetes mellitus and chronic kidney disease, all affect the presence and severity of calcification. The peripheral arteries of the lower extremities are affected by both medial calcification and intimal calcification, and the former barely contributes to luminal stenosis. The character of atherosclerosis differs between above-knee and below-knee lesions. Valvular calcification generally occurs on the aortic valve leaflets, and pathologic findings range from minimal fibrocalcific changes in early disease to end-stage lesions characterized by fibrotic thickening and nodular calcification. Valvular calcification is similar to atherosclerotic changes, in terms of lipid deposition, inflammation, osteogenic differentiation of valvular interstitial cells, and oxidative stress. However, the mechanisms of vascular and valvular calcification are still not well understood. A deeper understanding of vascular and valvular calcification is needed in order to develop effective anti-calcification therapies and to improve outcomes in these patients.

Abstract Aquaporin-4 (AQP4) has been suggested to be involved in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD), which may be due to the modulation of neuroinflammation or the impairment of interstitial fluid bulk flow system in the central nervous system. Here, we show an age-dependent impairment of several behavioral outcomes in 5xFAD AQP4 null mice. Twenty-four-hour video recordings and computational analyses of their movement revealed that the nighttime motion of AQP4-deficient 5xFAD mice was progressively reduced between 20 and 36 weeks of age, with a sharp deterioration occurring between 30 and 32 weeks. This reduction in nighttime motion was accompanied by motor dysfunction and epileptiform neuronal activities, demonstrated by increased abnormal spikes by electroencephalography. In addition, all AQP4-deficient 5xFAD mice exhibited convulsions at least once during the period of the analysis. Interestingly, despite such obvious phenotypes, parenchymal amyloid β (Aβ) deposition, reactive astrocytosis, and activated microgliosis surrounding amyloid plaques were unchanged in the AQP4-deficient 5xFAD mice relative to 5xFAD mice. Taken together, our data indicate that AQP4 deficiency greatly accelerates an age-dependent deterioration of neuronal function in 5xFAD mice associated with epileptiform neuronal activity without significantly altering Aβ deposition or neuroinflammation in this mouse model. We therefore propose that there exists another pathophysiological phase in AD which follows amyloid plaque deposition and neuroinflammation and is sensitive to AQP4 deficiency.

MI is a leading cause of morbidity and mortality worldwide. Coronary artery thrombosis is the final pathologic feature of the most cases of acute MI primarily caused by atherosclerotic coronary artery disease. The concept of vulnerable plaque has evolved over the years but originated from early pioneering work unveiling the crucial role of plaque rupture and subsequent coronary thrombosis as the dominant cause of MI. Along with systemic cardiovascular risk factors, developments of intravascular and non-invasive imaging modalities have allowed us to identify coronary plaques thought to be at high risk for rupture. However, morphological features alone may only be one of many factors which promote plaque progression. The current vulnerable-plaque-oriented approaches to accomplish personalized risk assessment and treatment have significant room for improvement. In this review, the authors discuss recent advances in the understanding of vulnerable plaque and its management strategy from pathology and clinical perspectives.

Upwelling mantle plumes often instigate extensional stress within the continental crust of Earth. When stress exceeds crustal strength, extensional structures develop, reducing the effective stress and trigger magmatic processes at the crust–mantle boundary. However, such processes and their relationship to the formation of many surface structures remain poorly characterized on Mars. We identified a series of extensional structures in the southern highlands of Mars which collectively resemble continental rift zones on Earth. We further characterized these extensional structures and their surrounding region (area of ~1.8 M km2) by determining the surface mineralogy and bulk regional geochemistry of the terrain. In turn, this constrains their formation and yields a framework for their comparison with extensional structures on Earth. These terrains are notable for olivine and high-Ca pyroxene with a high abundance of potassium and calcium akin to alkali basalts. In the case of Mars, this Earth-like proto-plate tectonic scenario may be related to the plume-induced crustal stretching and considering their distribution and temporal relationship with the Hellas basin, we conclude that the plume is impact-induced. Overall, the findings of this work support the presence of mantle plume activity in the Noachian, as suggested by thermal evolution models of Mars.

Pluripotent stem cells (PSCs), embryonic stem cells (ESCs), and induced PSCs (iPSCs) are excellent tools for studying embryonic development in organisms and classified into naïve and primed states. ESC-derived germline chimera individuals can be produced by injecting naïve ESCs/iPSCs into preimplantation embryos, and conversion of primed human ESCs/iPSCs into a naïve state provides insights into epiblast cell features. Non-human ESCs/iPSCs are alternatives to human naïve ESCs/iPSCs, which elicit ethical issues. In this study, we used the common marmoset (Callithrix jacchus) as an animal model. Since 1996, 16 marmoset ESC lines have been established. Because most of these ESC lines are female and were derived >10 years ago, new ESCs, particularly male marmoset ESC lines, are needed. Here, we successfully established 17 novel marmoset ESC lines, including six male ESC lines from in vitro-fertilized (IVF) embryos and 12 ESC lines under feeder-free conditions. This report is the first to establish ESC lines using feeder-free conditions and IVF preimplantation blastocysts in marmosets, and these novel ESC lines could potentially facilitate future non-human primate ESC studies.

We generated an NOD/Shi-scid-IL2Rγnull (NOG) mouse deficient for the Fcer1g and Fcgr2b genes (NOG-FcγR−/− mice), in which monocytes/macrophages do not express activating (FcγRI, III, and IV) or inhibitory (FcγRIIB) Fcγ receptors. Antibody-dependent cellular cytotoxicity (ADCC) by innate immune cells was strongly reduced in this strain. Thus, while the growth of xenogeneic human tumors engrafted in conventional NOG mice was suppressed by innate cells upon specific antibody treatment, such growth inhibition was abrogated in NOG-FcγR−/− mice. Using this novel strain, we further produced NOG-FcγR−/−-mice expressing human IL-15 (NOG-FcγR−/−-hIL-15 Tg). The mice inherited unique features from each strain, i.e., the long-term sustenance of human natural killer (NK) cells, and the elimination of mouse innate cell-mediated ADCC. As a result, segregation of human NK cell-mediated ADCC from mouse cell-mediated ADCC was possible in the NOG-FcγR−/−-hIL-15 Tg mice. Our results suggest that NOG-FcγR−/−-hIL-15 Tg mice are useful for validating the in vivo function of antibody drug candidates.

Purpose: The purpose of this study is to elucidate the impact of out-stent plaque characteristics on vascular response after implantation of second generation drug-eluting stent (G2-DES). Methods: Enrolled were 37 patients with 39 coronary artery lesions into which three types of G2-DES were successfully implanted (9 Nobori biolimus-, BES; 15 Xience everolimus-, EES; 15 Resolute zotarolimus-eluting stents; R-ZES). Immediately after (baseline) and one year after the implantation (follow-up), iMAP-intravascular ultrasound (IVUS) was performed to measure out-stent plaque volume (OSPV) and its components. Percent OSPV and vulnerable plaque index (VPI) were defined as percentile of OSPV to vessel volume and as percentile of lipidic plus necrotic volume to OSPV. Coronary angioscopy at follow-up rated the degree of arterial repair by neointimal stent coverage (NSC). Results: Poor NSC was found in approximately 60% of each G2-DES. In BES, % OSPV at baseline was significantly greater in poor NSC than in good NSC (36.2 ± 3.9 vs. 27.3 ± 4.0%, P = 0.01). In EES, %OSPV was significantly greater in poor NSC than in good NSC (41.0 ± 4.1 vs. 32.6 ± 2.7%, P

Summary: Several groups have reported the existence of a form of pluripotency that resembles that of mouse embryonic stem cells (mESCs), i.e., a naive state, in human pluripotent stem cells; however, the characteristics vary between reports. The nuclear receptor ESRRB is expressed in mESCs and plays a significant role in their self-renewal, but its expression has not been observed in most naive-like human induced pluripotent stem cells (hiPSCs). In this study, we modified several methods for converting hiPSCs into a naive state through the transgenic expression of several reprogramming factors. The resulting cells express the components of the core transcriptional network of mESCs, including ESRRB, at high levels, which suggests the existence of naive-state hiPSCs that are similar to mESCs. We also demonstrate that these cells differentiate more readily into neural cells than do conventional hiPSCs. These features may be beneficial for their use in disease modeling and regenerative medicine. : Kisa et al. modified several methods for converting human induced pluripotent stem cells (hiPSCs) into a naive state, a form of pluripotency that exists in mouse embryonic stem cells (ESCs). Converted cells express components of the core transcriptional network upregulated in mouse ESCs, including ESRRB. They also show that these cells differentiate more readily into neural cells than do conventional hiPSCs. Keywords: naive pluripotency, human iPSC, reprogramming, neural differentiation

Mouse is the most widely used animal model in biomedical research, but it remains unknown what causes the large number of differentially regulated genes between human and mouse livers identified in recent years. In this report, we aim to determine whether these divergent gene regulations are primarily caused by environmental factors or some of them are the result of cell-autonomous differences in gene regulation in human and mouse liver cells. The latter scenario would suggest that many human genes are subject to human-specific regulation and can only be adequately studied in a human or humanized system. To understand the similarity and divergence of gene regulation between human and mouse livers, we performed stepwise comparative analyses in human, mouse, and humanized livers with increased stringency to gradually remove the impact of factors external to liver cells, and used bioinformatics approaches to retrieve gene networks to ascertain the regulated biological processes. We first compared liver gene regulation by fatty liver disease in human and mouse under the condition where the impact of genetic and gender biases was minimized, and identified over 50% of all commonly regulated genes, that exhibit opposite regulation by fatty liver disease in human and mouse. We subsequently performed more stringent comparisons when a single specific transcriptional or post-transcriptional event was modulated in vitro or vivo or in liver-specific humanized mice in which human and mouse hepatocytes colocalize and share a common circulation. Intriguingly and strikingly, the pattern of a high percentage of oppositely regulated genes persists under well-matched conditions, even in the liver of the humanized mouse model, which represents the most closely matched in vivo condition for human and mouse liver cells that is experimentally achievable. Gene network analyses further corroborated the results of oppositely regulated genes and revealed substantial differences in regulated biological processes in human and mouse cells. We also identified a list of regulated lncRNAs that exhibit very limited conservation and could contribute to these differential gene regulations. Our data support that cell-autonomous differences in gene regulation might contribute substantially to the divergent gene regulation between human and mouse livers and there are a significant number of biological processes that are subject to human-specific regulation and need to be carefully considered in the process of mouse to human translation.

The tumor microenvironment contains unique immune cells, termed myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) that suppress host anti-tumor immunity and promote tumor angiogenesis and metastasis. Although these cells are considered a key target of cancer immune therapy, in vivo animal models allowing differentiation of human immunosuppressive myeloid cells have yet to be established, hampering the development of novel cancer therapies. In this study, we established a novel humanized transgenic (Tg) mouse strain, human interleukin (hIL)-6-expressing NOG mice (NOG-hIL-6 transgenic mice). After transplantation of human hematopoietic stem cells (HSCs), the HSC-transplanted NOG-hIL-6 Tg mice (HSC-NOG-hIL-6 Tg mice) showed enhanced human monocyte/macrophage differentiation. A significant number of human monocytes were negative for HLA-DR expression and resembled immature myeloid cells in the spleen and peripheral blood from HSC-NOG-hIL-6 Tg mice, but not from HSC-NOG non-Tg mice. Engraftment of HSC4 cells, a human head and neck squamous cell carcinoma-derived cell line producing various factors including IL-6, IL-1β, macrophage colony-stimulating factor (M-CSF), and vascular endothelial growth factor (VEGF), into HSC-NOG-hIL-6 Tg mice induced a significant number of TAM-like cells, but few were induced in HSC-NOG non-Tg mice. The tumor-infiltrating macrophages in HSC-NOG-hIL-6 Tg mice expressed a high level of CD163, a marker of immunoregulatory myeloid cells, and produced immunosuppressive molecules such as arginase-1 (Arg-1), IL-10, and VEGF. Such cells from HSC-NOG-hIL-6 Tg mice, but not HSC-NOG non-Tg mice, suppressed human T cell proliferation in response to antigen stimulation in in vitro cultures. These results suggest that functional human TAMs can be developed in NOG-hIL-6 Tg mice. This mouse model will contribute to the development of novel cancer immune therapies targeting immunoregulatory/immunosuppressive myeloid cells.

Lymph nodes (LNs) are at the center of adaptive immune responses. Various exogenous substances are transported into LNs and a series of immune responses ensue after recognition by antigen–specific lymphocytes. Although humanized mice have been used to reconstitute the human immune system, most lack LNs due to deficiency of the interleukin (IL)-2Rγ gene (cytokine common γ chain, γc). In this study, we established a transgenic strain, NOG-pRORγt-γc, in the NOD/shi-scid-IL-2Rγnull (NOG) background, in which the γc gene was expressed in a lymph-tissue inducer (LTi) lineage by the endogenous promoter of RORγt. In this strain, LN organogenesis was normalized and the number of human T cells substantially increased in the periphery after reconstitution of the human immune system by human hematopoietic stem cell transplantation. The distribution of human T cells differed between NOG-pRORγt-γc Tg and NOG-non Tg mice. About 40% of human T cells resided in LNs, primarily the mesenteric LNs. The LN-complemented humanized mice exhibited antigen-specific immunoglobulin G responses together and an increased number of IL-21+–producing CD4+ T cells in LNs. This novel mouse strain will facilitate recapitulation of human immune responses.

Common marmosets (Callithrix jacchus) are frequently used for biomedical research but can be afflicted with diarrhea-a serious and potentially lethal health problem. Enteropathogenic Escherichia coli (EPEC) is thought to be the causative pathogen of hemorrhagic typhlocolitis in common marmosets, but the actual incidence of the disease and the relationship between EPEC and hematochezia are unknown. This study investigated the prevalence of EPEC infection in common marmosets and the association between EPEC and hematochezia. A total of 230 stool or rectal swab samples were collected from 230 common marmosets (98 clinically healthy, 85 diarrhea, and 47 bloody stool samples) and tested by culture-based detection and PCR amplification of VT1, VT2, LT, ST, eae, and bfp genes. Healthy animals were divided into three groups (n = 4 each for high and low concentration groups and n = 2 as negative control), and those in the experimental groups were perorally inoculated with a 2-ml of suspension of EPEC R811 strain adjusted to 5 × 108 (high concentration) and 5 × 104 (low concentration) CFU/ ml. Two animals in each group were examined 3 and 14 days post-inoculation (DPI). EPEC was detected in 10 of 98 clinically healthy samples (10.2%), 17 of 85 diarrhea samples (20%), and all 47 bloody stool samples (100%), with a significant difference detected between presence of EPEC and sample status (P < 0.01). Acute hematochezia was observed in all animals of the high-concentration group but not in other groups at 1 or 2 DPI. A histopathological examination revealed the attachment of gram-negative bacilli to epithelial apical membranes and desquamated epithelial cells in the cecum of animals in the high-concentration group at 3 DPI. These findings suggest that EPEC is a causative agent of hemorrhagic typhlocolitis in common marmosets.

Here, we present a versatile method for detecting human tumor xenografts in vivo, based on the enhanced permeability and retention (EPR) effect, using near-infrared (NIR) fluorochrome-conjugated macromolecule probes. Bovine serum albumin (BSA) and two immunoglobulins-an anti-human leukocyte antigen (HLA) monoclonal antibody and isotype control IgG2a-were labeled with XenoLight CF770 fluorochrome and used as NIR-conjugated macromolecule probes to study whole-body imaging in a variety of xenotransplantation mouse models. NIR fluorescent signals were observed in subcutaneously transplanted BxPC-3 (human pancreatic cancer) cells and HCT 116 (colorectal cancer) cells within 24 h of NIR-macromolecule probe injection, but the signal from the fluorochrome itself or from the NIR-conjugated small molecule (glycine) injection was not observed. The accuracy of tumor targeting was confirmed by the localization of the NIR-conjugated immunoglobulin within the T-HCT 116 xenograft (in which the orange-red fluorescent protein tdTomato was stably expressed by HCT 116 cells) in the subcutaneous transplantation model. However, there was no significant difference in the NIR signal intensity of the region of interest between the anti-HLA antibody group and the isotype control group in the subcutaneous transplantation model. Therefore, the antibody accumulation within the tumor in vivo is based on the EPR effect. The liver metastasis generated by an intrasplenic injection of T-HCT 116 cells was clearly visualized by the NIR-conjugated anti-HLA probe but not by the orange-red fluorescent signal derived from the tdTomato reporter. This result demonstrated the superiority of the NIR probes over the tdTomato reporter protein at enhancing tissue penetration. In another xenograft model, patient-derived xenografts (PDX) of LC11-JCK (human non-small cell lung cancer) were successfully visualized using the NIR-conjugated macromolecule probe without any genetic modification. These results suggested that NIR-conjugated macromolecule, preferably, anti-HLA antibody probe is a valuable tool for the detection of human tumors in experimental metastasis models using whole-body imaging.

Objective: To evaluate the optical performance of plate-haptic rotationally asymmetric refractive multifocal intraocular lenses (IOLs) with + 1.5 D addition power by reproducing calcium deposition using rabbit eyes. Methods: Five IOLs (LS-313 MF15 [Santen/Teleon], W-60R [Santen], NS1 [KOWA], SY60WF [Alcon], and NS-60YS [NIDEK]) with varying water content were randomly implanted in rabbit eyes. Cell proliferation in the lens capsule and deposits on the IOL surface were confirmed with a slit lamp. The surface deposits were stained with alizarin red, and IOL transmittance was measured with a spectrophotometer. IOL storage solutions were analyzed using inductively coupled plasma mass spectrometry to confirm the presence of calcium. Results: Slit-lamp observations revealed abundant cellular proliferation on all IOLs. Granular deposits, unlike proliferating cells, were observed on LS-313 MF15 lenses two months after surgery, increasing over time, and stained red. The transmittance of LS-313 MF15 decreased in correlation with the stained area. Calcium was detected in all IOL storage solutions; however, deposits were confirmed only on the LS-313 MF15 surface, indicating decreased transmittance. Conclusion: These findings can facilitate predicting deposition on IOLs in clinical settings and selecting IOL materials for long-term stability. The long-term use of LS-313 MF15 IOLs requires further verification to avoid post-surgical extraction. [ABSTRACT FROM AUTHOR]

A persistent descending mesocolon is defined as a congenital fixation anomaly caused by the defective membrane fusion of the descending colon and the lateral abdominal wall. Anatomically, in persistent descending mesocolon, the left colonic artery is often shortened, and joins the marginal artery soon after its bifurcation from the inferior mesenteric artery, while the colonic mesentery often adheres firmly to the mesentery of the small intestine. As a result of these characteristics, anatomical knowledge of the persistent descending mesocolon and preservation of bowel blood flow are important during surgery for left-sided colorectal cancer to avoid adverse events. Moreover, indocyanine green based blood flow assessment is useful for the detailed evaluation of bowel ischemia at the anastomotic site. Here we report the usefulness of blood flow evaluation using indocyanine green fluorescence in laparoscopic or robot-assisted surgery for three patients with colorectal cancer and persistent descending mesocolons. [ABSTRACT FROM AUTHOR]