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1.
PLoS Genet ; 18(5): e1009846, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35551519

RESUMO

Mammalian germ cells stem from primordial germ cells (PGCs). Although the gene regulatory network controlling the development of germ cells such as PGCs is critical for ensuring gamete integrity, substantial differences exist in this network among mammalian species, suggesting that this network has been modified during mammalian evolution. Here, we show that a hominoid-specific group of endogenous retroviruses, LTR5_Hs, discloses enhancer-like signatures in human in vitro-induced PGCs, PGC-like cells (PGCLCs). Human PGCLCs exhibit a transcriptome signature similar to that of naïve-state pluripotent cells. LTR5_Hs are epigenetically activated in both PGCLCs and naïve pluripotent cells, and the expression of genes in the vicinity of LTR5_Hs is coordinately upregulated in these cell types, contributing to the establishment of the transcriptome similarity between these cell types. LTR5_Hs are preferentially bound by transcription factors that are highly expressed in both PGCLCs and naïve pluripotent cells (KLF4, TFAP2C, NANOG, and CBFA2T2), suggesting that these transcription factors contribute to the epigenetic activation of LTR5_Hs in these cells. Comparative transcriptome analysis between humans and macaques suggests that the expression of many genes in PGCLCs and naïve pluripotent cells is upregulated by LTR5_Hs insertions in the hominoid lineage. Together, this study suggests that LTR5_Hs insertions may have finetuned the gene regulatory network shared between PGCLCs and naïve pluripotent cells and coordinately altered the gene expression in these cells during hominoid evolution.

2.
Cureus ; 14(3): e23591, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35505744

RESUMO

Background and purpose Internal carotid artery intima-media thickness (IMT) and pulse wave velocity (PWV) are risk factors of cerebrovascular disease and coronary artery disease. They are known as independent predictors of arteriosclerotic disease. It has been reported that IMT and PWV are useful factors for predicting stroke subtype and/or outcome. Coronary artery disease onset is proportional to atherosclerosis progression, and the Framingham Risk Score (FRS) and Suita score (SS) are standard risk predictors. This study examined whether FRS and SS can be useful for patient outcomes with acute infarction in the lenticulostriate artery (LSA) region without special tests or invasive procedures while using IMT or PWV as predictive factors. Methods We screened 629 consecutive patients with ischemic stroke and reviewed 84 patients with acute infarction in the LSA region who were admitted between January 2018 and December 2020. An early deterioration (ED) group was defined. In addition, the clinical characteristics, FRS, SS, treatment therapy, and neurovascular findings were evaluated. Results FRS and SS (FRS: 11.6 vs. 8.3, p < 0.01, SS: 58.2 vs. 53.7, p = 0.01, respectively), pre-symptomatic modified Rankin Scale (mRS) (p = 0.03), mRS at discharge (p < 0.01), and deterioration of manual muscle test (MMT) (<0.01) were significantly higher in patients in the ED (34 patients) group than in the no-ED group (54 patients). FRS and SS were correlated with mRS deterioration (FRS: r = 0.47; p < 0.01, SS: r = 0.23; p = 0.03). Among the laboratory parameters, total cholesterol (TC) (p < 0.01) and low-density lipoprotein cholesterol (LDL-C) (p < 0.01) were significantly higher in the ED group, and no significant differences in any acute therapeutic interventions. Conclusion Atherosclerosis risk scores, such as FRS and SS, may be useful for predicting outcomes in patients with acute LSA-region infarctions within 48 hours of onset.

3.
Int J Cardiol Heart Vasc ; 40: 101045, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35514877

RESUMO

Background: Malignancy is common in older adults undergoing transcatheter aortic valve implantation (TAVI), and may affect prognosis. The present study aimed to examine whether active cancer affects all-cause mortality rates among patients undergoing TAVI. Methods: This retrospective study examined data from 1,114 consecutive patients treated between April 2010 and June 2019. Patients with life expectancy of <1 year due to non-cardiac causes were excluded. Results: Active cancer was defined as cancer under treatment or cured within 1 year, and was recognized in 62 patients (5.6%) with (n = 17) and without (n = 45) metastases. In multivariate analysis, being female (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.39-0.77, p < 0.001), body mass index (BMI) (HR = 0.92 per 1 kg/m2 increase, 95% CI 0.87-0.97, p = 0.001), New York Heart Association (NYHA) class III/IV (HR = 1.53, 95% CI 1.06-2.20, p = 0.022), atrial fibrillation (HR = 2.40, 95% CI 1.70-3.38, p < 0.001), albumin levels (HR = 0.41 per 1-g/dl, 95% CI 0.30-0.57, p < 0.001), and cancer metastasis (HR = 5.28, 95% CI 1.86-14.9, p = 0.001) were associated with all-cause mortality after TAVI. Conclusion: In patients undergoing TAVI, being female, high BMI, NYHA class III/IV, atrial fibrillation, albumin levels, and cancer metastasis were factors associated with mortality. Meanwhile, active cancer without metastasis was not associated with increased mortality rates. These findings would help clinical decision-making by patients and physicians.Clinical trial registration: UMIN000031133.

4.
FASEB J ; 36 Suppl 12022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35567473

RESUMO

INTRODUCTION: Heart transplantation (HTx) is the primary therapy for end-stage heart failure. For HTx, donor hearts are typically preserved on ice in a cooler (devoid of oxygen), termed cold static storage (CSS). CSS beyond 4 hrs increases the risk of primary graft dysfunction (PGD), the leading cause of early death post-HTx. Hypothermic ex vivo perfusion (HEVP) of donor hearts allows oxygen delivery during preservation, and we hypothesise, may safely extend donor heart preservation time without increasing PGD risk. We sought to compare post-HTx recipient survival, cardiac contractility, mitochondrial function, and injury following donor heart preservation by CSS (2 hrs) or HEVP (2 and 8 hrs). METHODS: Brain death was induced in donor sheep for 24 hrs, hearts were then preserved by a) CSS for 2 hrs (n=8), b) HEVP for 2 hrs (n=6), or c) HEVP for 8 hrs (n=7). Orthotopic HTx was performed in matched recipients, with progressive hemodynamic management and monitoring for 6 hrs post-HTx. Recipient cardiac function was assessed by echocardiography, and troponin I levels were measured in plasma. Mitochondrial function, in vitro contractile responses to noradrenaline (trabeculae), and histopathological changes were determined in cardiac tissue collected at end-study. RESULTS: All HEVP recipients survived to 6 hrs post-HTx, compared to 6/8 CSS recipients. HEVP (2 and 8 hrs) recipients required less vasoactive support for adequate hemodynamic function, and exhibited reduced blood lactate levels compared to CSS. Post-HTx cardiac function and troponin I levels were comparable between groups over time, however improved contractile responses to noradrenaline were observed in isolated trabeculae from 2 and 8 hr HEVP hearts. Cardiac mitochondrial function was similar between all groups, except for the 2 hrs HEVP left ventricle, where greater improvements in mitochondrial membrane potential generation were observed. Regardless of preservation technique, histological scores revealed widespread cardiac injury (e.g. myocytolysis and neutrophil infiltration). CONCLUSION: Donor heart preservation by HEVP shows promising post-HTx outcomes in comparison to CSS in a sheep HTx model. HEVP can be safely extended up to 8 hrs, without compromising post-HTx recipient survival, cardiac contractile or mitochondrial function. HEVP may assist in overcoming limitations in preservation time associated with HTx, without increasing PGD risk. The Australian Non-Ischemic Heart Preservation (NIHP) trial is currently assessing extended HEVP in clinical HTx (ACTRN12620000595910p).

5.
Cell ; 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35568035

RESUMO

Soon after the emergence and global spread of the SARS-CoV-2 Omicron lineage BA.1, another Omicron lineage, BA.2, began outcompeting BA.1. The results of statistical analysis showed that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralization experiments revealed that immunity induced by COVID vaccines widely administered to human populations is not effective against BA.2, similar to BA.1, and that the antigenicity of BA.2 is notably different from that of BA.1. Cell culture experiments showed that the BA.2 spike confers higher replication efficacy in human nasal epithelial cells and is more efficient in mediating syncytia formation than the BA.1 spike. Furthermore, infection experiments using hamsters indicated that the BA.2 spike-bearing virus is more pathogenic than the BA.1 spike-bearing virus. Altogether, the results of our multiscale investigations suggest that the risk of BA.2 to global health is potentially higher than that of BA.1.

6.
Dig Surg ; 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35439756

RESUMO

INTRODUCTION: The benefits of surgery in older patients with gastric cancer are controversial. This single-institution retrospective study in Japan aimed to evaluate the impact of gastrectomy in older patients with gastric cancer. METHODS: A series of 234 patients aged ≥ 80 years with histologically confirmed gastric cancer had indications for surgical treatment at the Gastroenterological Center, Yokohama City University Medical Center between April 2002 and December 2018. Patients who: lost to follow-up (n=27), had tumors not eligible for surgery (n=14), and could not achieve R0 resection (n=7) were excluded from this retrospective study. The remaining 186 patients were included. Patient characteristics, intraoperative outcomes, postoperative complications, and long-term survival were evaluated. RESULTS: The incidence of postoperative complications with Clavien-Dindo grade ≥II was observed in 61 patients (32.8%). The five-year relapse-free survival and overall survival (OS) rates were 84.2% and 63.4%, respectively. Multivariate analysis showed that geriatric nutritional risk index (<98) (odds ratio, 1.97; p=0.047), neutrophil/lymphocyte ratio (>2.36) (odds ratio, 1.94; 95% confidence interval, 1.02-3.67; p=0.043), and total gastrectomy (TG) (odds ratio, 1.97; p=0.042) significantly predicted postoperative complications. Moreover, TG (hazard ratio, 1.91; p=0.036) was an independent prognostic factor of OS. CONCLUSIONS: Poor immunonutritional status and TG led to worse short-term outcomes. Moreover, TG was an independent prognostic factor of OS in older patients with gastric cancer. It is necessary to provide effective perioperative care, including nutritional support, to clarify whether short-term outcomes would be improved.

7.
Intensive Care Med Exp ; 10(1): 12, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35377109

RESUMO

BACKGROUND: Fluid resuscitation is the standard treatment to restore circulating blood volume and pressure after massive haemorrhage and shock. Packed red blood cells (PRBC) are transfused to restore haemoglobin levels. Restoration of microcirculatory flow and tissue oxygen delivery is critical for organ and patient survival, but these parameters are infrequently measured. Patient Blood Management is a multidisciplinary approach to manage and conserve a patient's own blood, directing treatment options based on broad clinical assessment beyond haemoglobin alone, for which tissue perfusion and oxygenation could be useful. Our aim was to assess utility of non-invasive tissue-specific measures to compare PRBC transfusion with novel crystalloid treatments for haemorrhagic shock. METHODS: A model of severe haemorrhagic shock was developed in an intensive care setting, with controlled haemorrhage in sheep according to pressure (mean arterial pressure 30-40 mmHg) and oxygen debt (lactate > 4 mM) targets. We compared PRBC transfusion to fluid resuscitation with either PlasmaLyte or a novel crystalloid. Efficacy was assessed according to recovery of haemodynamic parameters and non-invasive measures of sublingual microcirculatory flow, regional tissue oxygen saturation, repayment of oxygen debt (arterial lactate), and a panel of inflammatory and organ function markers. Invasive measurements of tissue perfusion, oxygen tension and lactate levels were performed in brain, kidney, liver, and skeletal muscle. Outcomes were assessed during 4 h treatment and post-mortem, and analysed by one- and two-way ANOVA. RESULTS: Each treatment restored haemodynamic and tissue oxygen delivery parameters equivalently (p > 0.05), despite haemodilution after crystalloid infusion to haemoglobin concentrations below 70 g/L (p < 0.001). Recovery of vital organ-specific perfusion and oxygen tension commenced shortly before non-invasive measures improved. Lactate declined in all tissues and correlated with arterial lactate levels (p < 0.0001). The novel crystalloid supported rapid peripheral vasodilation (p = 0.014) and tended to achieve tissue oxygen delivery targets earlier. PRBC supported earlier renal oxygen delivery (p = 0.012) but delayed peripheral perfusion (p = 0.034). CONCLUSIONS: Crystalloids supported vital organ oxygen delivery after massive haemorrhage, despite haemodilution to < 70 g/L, confirming that restrictive transfusion thresholds are appropriate to support oxygen delivery. Non-invasive tissue perfusion and oximetry technologies merit further clinical appraisal to guide treatment for massive haemorrhage in the context of Patient Blood Management.

9.
PLoS Comput Biol ; 18(4): e1010053, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35468127

RESUMO

In HIV-1-infected individuals, transmitted/founder (TF) virus contributes to establish new infection and expands during the acute phase of infection, while chronic control (CC) virus emerges during the chronic phase of infection. TF viruses are more resistant to interferon-alpha (IFN-α)-mediated antiviral effects than CC virus, however, its virological relevance in infected individuals remains unclear. Here we perform an experimental-mathematical investigation and reveal that IFN-α strongly inhibits cell-to-cell infection by CC virus but only weakly affects that by TF virus. Surprisingly, IFN-α enhances cell-free infection of HIV-1, particularly that of CC virus, in a virus-cell density-dependent manner. We further demonstrate that LY6E, an IFN-stimulated gene, can contribute to the density-dependent enhancement of cell-free HIV-1 infection. Altogether, our findings suggest that the major difference between TF and CC viruses can be explained by their resistance to IFN-α-mediated inhibition of cell-to-cell infection and their sensitivity to IFN-α-mediated enhancement of cell-free infection.


Assuntos
Infecções por HIV , HIV-1 , Antivirais , Infecções por HIV/tratamento farmacológico , Humanos , Interferon-alfa/farmacologia
10.
Crit Care Explor ; 4(4): e0666, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35372843

RESUMO

This narrative review aims to discuss the potential applicability of speckle-tracking echocardiography (STE) in patients under mechanical ventilation (MV) and mechanical circulatory support (MCS). Both its benefits and limitations were considered through critical analyses of the current available evidence. DATA SOURCES AND STUDY SELECTION: A literature search was conducted in PubMed and Excerpta Medica Database indexed databases (2012-2021). In addition, the reference lists of all selected studies were manually scanned for further identification of potentially relevant studies. DATA EXTRACTION: The terms "Speckle-Tracking Echocardiography," "Mechanical Ventilation," "Mechanical Circulatory Support," "Extracorporeal Membrane Oxygenation," "Ventricular Assist Devices," and "Left Ventricular Unloading Devices" were searched for the identification of relevant articles for narrative synthesis. DATA SYNTHESIS: STE is a well-established post-processing method of analyzing myocardial function, with potentially greater clinical utility than conventional 2D echocardiography. STE has been incorporated into the guideline recommendations for both the diagnostic and prognostic evaluations of myocardial and valvular pathologies. However, the potential of STE application within critical care settings has not yet been fully realized. Its utility in the assessment of patients undergoing MV and MCS is substantial. Specifically, it may serve as an ideal modality in the assessment of subtle changes in cardiac function. In the limited number of studies reviewed, STE was consistently a more sensitive marker of myocardial functional change, compared with traditional markers of 2D and Doppler parameters during changes in MV and MCS. CONCLUSIONS: Although current evidence is extremely limited, STE strain is suggested to be a more sensitive and reproducible parameter of myocardial function than conventional echocardiographic parameters and may have value in the assessment of patients undergoing MV and MCS in critical care settings. Further studies in larger populations are required to elucidate STE's prognostic capability and its value as a point-of-care tool in guiding clinical practice for subjects under MV and MCS.

11.
BMC Cardiovasc Disord ; 22(1): 123, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35321649

RESUMO

BACKGROUND: The influence of renin-angiotensin-aldosterone system (RAAS) inhibitors on the critically ill COVID-19 patients with pre-existing hypertension remains uncertain. This study examined the impact of previous use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) on the critically ill COVID-19 patients. METHODS: Data from an international, prospective, observational cohort study involving 354 hospitals spanning 54 countries were included. A cohort of 737 COVID-19 patients with pre-existing hypertension admitted to intensive care units (ICUs) in 2020 were targeted. Multi-state survival analysis was performed to evaluate in-hospital mortality and hospital length of stay up to 90 days following ICU admission. RESULTS: A total of 737 patients were included-538 (73%) with pre-existing hypertension had received ACEi/ARBs before ICU admission, while 199 (27%) had not. Cox proportional hazards model showed that previous ACEi/ARB use was associated with a decreased hazard of in-hospital death (HR, 0.74, 95% CI 0.58-0.94). Sensitivity analysis adjusted for propensity scores showed similar results for hazards of death. The average length of hospital stay was longer in ACEi/ARB group with 21.2 days (95% CI 19.7-22.8 days) in ICU and 6.7 days (5.9-7.6 days) in general ward compared to non-ACEi/ARB group with 16.2 days (14.1-18.6 days) and 6.4 days (5.1-7.9 days), respectively. When analysed separately, results for ACEi or ARB patient groups were similar for both death and discharge. CONCLUSIONS: In critically ill COVID-19 patients with comorbid hypertension, use of ACEi/ARBs prior to ICU admission was associated with a reduced risk of in-hospital mortality following adjustment for baseline characteristics although patients with ACEi/ARB showed longer length of hospital stay. Clinical trial registration The registration number: ACTRN12620000421932; The date of registration: 30, March 2020; The URL of the registration: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12620000421932 .


Assuntos
COVID-19 , Hipertensão , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Estudos de Coortes , Estado Terminal , Mortalidade Hospitalar , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Estudos Prospectivos , Sistema Renina-Angiotensina , Estudos Retrospectivos
12.
Surg Today ; 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35338428

RESUMO

PURPOSE: Early management is crucial for acute intestinal blood flow disorders; however, no published study has identified criteria for the time limit for blood flow resumption. This study specifically examines the time factors for avoiding intestinal resection. METHODS: The subjects of this retrospective cohort study were 125 consecutive patients who underwent emergency surgery for a confirmed diagnosis of intestinal strangulation (n = 86), incarceration (n = 27), or volvulus (n = 12), between January 2015 and March 2021. Intestinal resection was performed when intestinal irreversible changes had occurred even after ischemia was relieved surgically. We analyzed the relationship between the time from computed tomography (CT) imaging to the start of surgery (C-S time) and intestinal resection using the Kaplan-Meier method and calculated the estimated intestinal rescue rate. Patient background factors affecting intestinal resection were also examined. RESULTS: The time limit for achieving 80% intestinal rescue rate was 200 min in C-S time, and when this exceeded 300 min, the intestinal rescue rate dropped to less than 50%. Multivariate analysis identified the APACHE II score as a significant influencing factor. CONCLUSION: A rapid transition from early diagnosis to early surgery is critical for patients with acute abdomen originating from intestinal blood flow disorders. The times from presentation at the hospital to surgery should be reduced further, especially for severe cases.

13.
Artigo em Inglês | MEDLINE | ID: mdl-35230525

RESUMO

PURPOSE: Few studies have reported the impact of chemoradiotherapy (CRT) on the objective response of patients with locally advanced unresectable esophageal squamous cell carcinoma (ESCC). We evaluated the factors predicting therapeutic effectiveness and the short- and long-term outcomes in patients with T4b ESCC treated with CRT. METHODS: We included 155 patients with T4b ESCC who underwent CRT at the Department of Surgery, Gastroenterological Center, Yokohama City University, between January 2000 and December 2018. Responders were defined as patients who demonstrated a complete response (CR) or partial response (PR). Multivariate analysis for objective response was performed using a logistic regression model, and prognostic factors were evaluated by univariate and multivariate analyses. RESULTS: Among the 155 patients included, 20 and 84 patients demonstrated a CR and PR, respectively, resulting in a response rate of 67.1%. The median overall survival (OS) was 15.2 months, and the 3-year survival rate was 32.1%. High Glasgow prognostic score (GPS) and advanced N-category independently predicted the objective response to CRT. GPS and objective response were independent prognostic factors for OS. There was no significant difference in the long-term survival of responders who received subsequent chemotherapy or salvage surgery. CONCLUSIONS: High GPS and advanced N-category predicted a poor objective response to CRT in patients with T4b ESCC. Therefore, chemotherapeutic regimens with a higher efficacy are required. The indications for salvage surgery for responders should be carefully considered, with care taken to avoid complications. To confirm this, prospective randomized controlled studies are necessary.

14.
World J Gastroenterol ; 28(8): 868-877, 2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35317096

RESUMO

BACKGROUND: During pancreaticoduodenectomy in patients with celiac axis (CA) stenosis due to compression by the median arcuate ligament (MAL), the MAL has to be divided to maintain hepatic blood flow in many cases. However, MAL division often fails, and success can only be determined intraoperatively. To overcome this problem, we performed endovascular CA stenting preoperatively, and thereafter safely performed pancreaticoduodenectomy. We present this case as a new preoperative treatment strategy that was successful. CASE SUMMARY: A 77-year-old man with a diagnosis of pancreatic head cancer presented to our department for surgery. Preoperative assessment revealed CA stenosis caused by MAL. We performed endovascular stenting in the CA preoperatively because we knew that going into the operation without a strategy could lead to ischemic complications. Double-antiplatelet therapy (DAPT) - which is needed when a stent is inserted - was then administered in parallel with neoadjuvant chemotherapy (NAC). This allowed us to administer DAPT for a sufficient period before the main pancreaticoduodenectomy procedure while obtaining therapeutic effects from NAC. Subtotal stomach-preserving pancreaticoduodenectomy was then performed. The operation did not require any unusual techniques and was performed safely. Postoperatively, the patient progressed well, without any ischemic complications. Histopathologically, curative resection was confirmed, and the patient had no recurrence or complications due to ischemia up to six months postoperatively. CONCLUSION: Preoperative endovascular stenting, with NAC and DAPT, is effective and safe prior to pancreaticoduodenectomy in potentially resectable pancreatic cancer.


Assuntos
Arteriopatias Oclusivas , Neoplasias Pancreáticas , Idoso , Arteriopatias Oclusivas/etiologia , Artéria Celíaca/diagnóstico por imagem , Artéria Celíaca/cirurgia , Constrição Patológica/etiologia , Humanos , Masculino , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/efeitos adversos
15.
Nature ; 603(7902): 700-705, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35104835

RESUMO

The emergence of the Omicron variant of SARS-CoV-2 is an urgent global health concern1. In this study, our statistical modelling suggests that Omicron has spread more rapidly than the Delta variant in several countries including South Africa. Cell culture experiments showed Omicron to be less fusogenic than Delta and than an ancestral strain of SARS-CoV-2. Although the spike (S) protein of Delta is efficiently cleaved into two subunits, which facilitates cell-cell fusion2,3, the Omicron S protein was less efficiently cleaved compared to the S proteins of Delta and ancestral SARS-CoV-2. Furthermore, in a hamster model, Omicron showed decreased lung infectivity and was less pathogenic compared to Delta and ancestral SARS-CoV-2. Our multiscale investigations reveal the virological characteristics of Omicron, including rapid growth in the human population, lower fusogenicity and attenuated pathogenicity.


Assuntos
COVID-19/patologia , COVID-19/virologia , Fusão de Membrana , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Internalização do Vírus , Animais , COVID-19/epidemiologia , Linhagem Celular , Cricetinae , Humanos , Técnicas In Vitro , Pulmão/patologia , Pulmão/virologia , Masculino , Mesocricetus , Mutação , SARS-CoV-2/classificação , SARS-CoV-2/crescimento & desenvolvimento , África do Sul/epidemiologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Virulência , Replicação Viral
16.
J Infect Dis ; 2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35176774

RESUMO

We have recently revealed that the SARS-CoV-2 Mu variant shows a pronounced resistance to antibodies elicited by natural SARS-CoV-2 infection and vaccination. However, it remains unclear which mutations determine the resistance of SARS-CoV-2 Mu to antiviral sera. Also, it is unclear how SARS-CoV-2 Mu infection induces antiviral immunity. Here we reveal that the two mutations in the SARS-CoV-2 Mu spike protein, YY144-145TSN and E484K, are responsible for the resistance to COVID-19 convalescent sera during early 2020 and vaccine sera. Notably, the convalescent sera of SARS-CoV-2 Mu-infected individuals are broadly antiviral against Mu as well as other SARS-CoV-2 variants of concern/interest.

17.
Cell Mol Neurobiol ; 42(4): 997-1004, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33136276

RESUMO

Metastatic brain tumors have poor prognoses and pose unmet clinical problems for the patients. The blood-brain barrier (BBB) implication is supposed to play a major role in brain metastasis. However, the role of pericytes remains to be elucidated in the brain metastasis. This pilot study described the expression profile of interactions between pericytes, endothelial cells, and cancer cells. We applied an in vitro BBB model with rat primary cultured BBB-related cells (endothelial cells and pericytes), and performed the gene expression analyses of pericytes under the lung cancer cells coculture conditions. Pericytes demonstrated inhibition of the cancer cell proliferation significantly (p < 0.05). RNA was extracted from the pericytes, complementary DNA library was prepared, and RNA-seq was performed. The sequence read data were analyzed on the Management and Analysis System for Enormous Reads and Tag Count Comparison-Graphical User Interface platforms. No statistically or biologically significant differentially expressed genes (DEGs) were detected in the explanatory analyses. Lot-specific DEG detection demonstrated significant decreases in the expression of two genes (Wwtr1 and Acin1), and enrichment analyses using Metascape software revealed the inhibition of apoptotic processes in fibroblasts. Our results suggest that the expression profiles of brain pericytes are partially implicated in the prevention of lung cancer metastasis to the brain. Pericytes exerted an anti-metastatic effect in the BBB model, and their neurohumoral factors remain to be elucidated.


Assuntos
Neoplasias Encefálicas , Neoplasias Pulmonares , Animais , Barreira Hematoencefálica , Encéfalo/metabolismo , Neoplasias Encefálicas/patologia , Técnicas de Cocultura , Células Endoteliais/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Nucleares/metabolismo , Pericitos/patologia , Projetos Piloto , Ratos , Análise de Sequência de RNA
18.
Nature ; 602(7896): 300-306, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34823256

RESUMO

During the current coronavirus disease 2019 (COVID-19) pandemic, a variety of mutations have accumulated in the viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, at the time of writing, four variants of concern are considered to be potentially hazardous to human society1. The recently emerged B.1.617.2/Delta variant of concern is closely associated with the COVID-19 surge that occurred in India in the spring of 2021 (ref. 2). However, the virological properties of B.1.617.2/Delta remain unclear. Here we show that the B.1.617.2/Delta variant is highly fusogenic and notably more pathogenic than prototypic SARS-CoV-2 in infected hamsters. The P681R mutation in the spike protein, which is highly conserved in this lineage, facilitates cleavage of the spike protein and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity compared with its parental virus. Our data suggest that the P681R mutation is a hallmark of the virological phenotype of the B.1.617.2/Delta variant and is associated with enhanced pathogenicity.


Assuntos
COVID-19/virologia , Fusão de Membrana , Mutação , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/genética , Substituição de Aminoácidos , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , Cricetinae , Células Gigantes/metabolismo , Células Gigantes/virologia , Masculino , Mesocricetus , Filogenia , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Virulência/genética , Replicação Viral
19.
Intern Med ; 61(3): 361-364, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34334565

RESUMO

Congenital afibrinogenemia is a rare autosomal recessive blood disorder that accompanies thrombotic complications and is associated with bleeding tendency. The management of these opposing complications remains a challenge. Endovascular treatment (EVT) for peripheral arterial thrombosis has not been described in previous studies. A 57-year-old man with congenital afibrinogenemia developed back pain and left lower leg pain. The cause of the pain was confirmed to be renal infarction and lower extremity arterial thrombosis by Doppler ultrasound and contrast-enhanced computed tomography. He was treated with EVT for the lower extremity arterial thrombosis, leading to an excellent short-term improvement without bleeding.


Assuntos
Afibrinogenemia , Transtornos da Coagulação Sanguínea , Trombose , Afibrinogenemia/complicações , Extremidades , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/etiologia
20.
Cell Rep ; 38(2): 110218, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34968415

RESUMO

SARS-CoV-2 Lambda, a variant of interest, has spread in some South American countries; however, its virological features and evolutionary traits remain unclear. In this study, we use pseudoviruses and reveal that the spike protein of the Lambda variant is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino acid deletion in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection. Although this mutation generates a nascent N-linked glycosylation site, the additional N-linked glycan is dispensable for the virological property conferred by this mutation. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the RSYLTPGD246-253N mutation is closely associated with the substantial spread of the Lambda variant in South America.


Assuntos
COVID-19/imunologia , Imunidade/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linhagem Celular , Feminino , Glicosilação , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
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