A potent Henipavirus cross-neutralizing antibody reveals a dynamic fusion-triggering pattern of the G-tetramer.

The Hendra and Nipah viruses (HNVs) are highly pathogenic pathogens without approved interventions for human use. In addition, the interaction pattern between the attachment (G) and fusion (F) glycoproteins required for virus entry remains unclear. Here, we isolate a panel of Macaca-derived G-specific antibodies that cross-neutralize HNVs via multiple mechanisms. The most potent antibody, 1E5, confers adequate protection against the Nipah virus challenge in female hamsters. Crystallography demonstrates that 1E5 has a highly similar binding pattern to the receptor. In cryo-electron microscopy studies, the tendency of 1E5 to bind to the upper or lower heads results in two distinct quaternary structures of G. Furthermore, we identify the extended outer loop ß1S2-ß1S3 of G and two pockets on the apical region of fusion (F) glycoprotein as the essential sites for G-F interactions. This work highlights promising drug candidates against HNVs and contributes deeper insights into the viruses.

Renal anatomical classification systems cannot predict the occurrence of vascular complications after partial nephrectomy.

OBJECTIVES: To determine the relationship between renal tumor complexity and vascular complications after partial nephrectomy using PADUA, RENAL, and ZS scores. METHODS: Between January 2007 and December 2018, a total of 1917 patients with available cross-sectional imaging were enrolled in the study. Logistic regressions were used to identify independent predictors of vascular complications. RESULTS: Of 1917 patients, 31 (1.6%) developed vascular complications, including 10 females and 21 males. The high-complexity category was significantly associated with a decreased risk of vascular complication in PADUA (OR = 0.256; 95%CI = 0.086-0.762; P = 0.014) and ZS score (OR = 0.279; 95%CI = 0.083-0.946; P = 0.040). Laparoscopic partial nephrectomy and robot-assisted laparoscopic partial nephrectomy were independent risk factors for vascular complications. Meanwhile, the incidence was significantly reduced in the recent 4 years in the high score tumor group alone in PADUA (0.2% [1/474] vs. 2.2% [3/139], P = 0.038) and ZS score (0.2% [1/469] vs. 2.7% [3/112], P = 0.024). In the first 8 years, laparoscopic partial nephrectomy and robot-assisted laparoscopic partial nephrectomy were the only two independent risk factors for vascular complications. In the recent 4 years, only the high-complexity category was significantly associated with a decreased risk of vascular complication in the PADUA score (OR = 0.110; 95%CI = 0.013-0.938; P = 0.044). CONCLUSION: The renal anatomic classification system cannot predict the occurrence of vascular complications after partial nephrectomy.

Association of healthy lifestyle score with control of hypertension among treated and untreated hypertensive patients: a large cross-sectional study.

Background: Hypertension stands as the leading single contributor to the worldwide burden of mortality and disability. Limited evidence exists regarding the association between the combined healthy lifestyle score (HLS) and hypertension control in both treated and untreated hypertensive individuals. Therefore, we aimed to investigate the association between HLS and hypertension control among adults with treated and untreated hypertension. Methods: This cross-sectional study, including 311,994 hypertension patients, was conducted in Guangzhou using data from the National Basic Public Health Services Projects in China. The HLS was defined based on five low-risk lifestyle factors: healthy dietary habits, active physical activity, normal body mass index, never smoking, and no alcohol consumption. Controlled blood pressure was defined as systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg. A multivariable logistic regression model was used to assess the association between HLS and hypertension control after adjusting for various confounders. Results: The HLS demonstrated an inverse association with hypertension control among hypertensive patients. In comparison to the low HLS group (scored 0-2), the adjusted odds ratios (95% confidence intervals) for hypertension were 0.76 (0.74, 0.78), 0.59 (0.57, 0.60), and 0.48 (0.46, 0.49) for the HLS groups scoring 3, 4, and 5, respectively (Ptrend < 0.001). Notably, an interaction was observed between HLS and antihypertensive medication in relation to hypertension control (Pinteraction < 0.001). When comparing the highest HLS (scored 5) with the lowest HLS (scored 0-2), adjusted odds ratios (95% confidence intervals) were 0.50 (0.48, 0.52, Ptrend < 0.001) among individuals who self-reported using antihypertensive medication and 0.41 (0.38, 0.44, Ptrend < 0.001) among those not using such medication. Hypertensive patients adhering to a healthy lifestyle without medication exhibited better blood pressure management than those using medication while following a healthy lifestyle. Conclusion: HLS was associated with a reduced risk of uncontrolled blood pressure.

Boosting with an aerosolized Ad5-nCoV elicited robust immune responses in inactivated COVID-19 vaccines recipients.

Introduction: The SARS-CoV-2 Omicron variant has become the dominant SARS-CoV-2 variant and exhibits immune escape to current COVID-19 vaccines, the further boosting strategies are required. Methods: We have conducted a non-randomized, open-label and parallel-controlled phase 4 trial to evaluate the magnitude and longevity of immune responses to booster vaccination with intramuscular adenovirus vectored vaccine (Ad5-nCoV), aerosolized Ad5-nCoV, a recombinant protein subunit vaccine (ZF2001) or homologous inactivated vaccine (CoronaVac) in those who received two doses of inactivated COVID-19 vaccines. Results: The aerosolized Ad5-nCoV induced the most robust and long-lasting neutralizing activity against Omicron variant and IFNg T-cell response among all the boosters, with a distinct mucosal immune response. SARS-CoV-2-specific mucosal IgA response was substantially generated in subjects boosted with the aerosolized Ad5-nCoV at day 14 post-vaccination. At month 6, participants boosted with the aerosolized Ad5-nCoV had remarkably higher median titer and seroconversion of the Omicron BA.4/5-specific neutralizing antibody than those who received other boosters. Discussion: Our findings suggest that aerosolized Ad5-nCoV may provide an efficient alternative in response to the spread of the Omicron BA.4/5 variant. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=152729, identifier ChiCTR2200057278.

Nipah virus attachment glycoprotein ectodomain delivered by type 5 adenovirus vector elicits broad immune response against NiV and HeV.

Nipah virus (NiV) and Hendra virus (HeV) are newly emerging dangerous zoonotic pathogens of the Henipavirus genus of the Paramyxoviridae family. NiV and HeV (HNVs) which are transmitted by bats cause acute respiratory disease and fatal encephalitis in humans. To date, as there is a lack of antiviral drugs or effective antiviral therapies, the development of vaccines against those two viruses is of primary importance, and the immunogen design is crucial to the success of vaccines. In this study, the full-length protein (G), the ectodomain (Ge) and the head domain (Gs) of NiV attachment glycoprotein were delivered by the replication-defective type 5 adenovirus vector (Ad5) respectively, and the recombinant Ad5-NiV vaccine candidates (Ad5-NiVG, Ad5-NiVGe and Ad5-NiVGs) were constructed and their immunogenicity were evaluated in mice. The results showed that all the vaccine candidates stimulated specific humoral and cellular immune responses efficiently and rapidly against both NiV and HeV, and the Ad5-NiVGe elicited the strongest immune responses after a single-dose immunization. Furthermore, the potent conserved T-cell epitope DTLYFPAVGFL shared by NiV and HeV was identified in the study, which may provide valid information on the mechanism of HNVs-specific cellular immunity. In summary, this study demonstrates that the Ad5-NiVGe could be a potent vaccine candidate against HNVs by inducing robust humoral and cellular immune responses.

Multiregional radiomic model for breast cancer diagnosis: value of ultrasound-based peritumoral and parenchymal radiomics.

Background: Breast cancer consists not only of neoplastic cells but also of significant changes in the surrounding and parenchymal stroma, which can be reflected in radiomics. This study aimed to perform breast lesion classification through an ultrasound-based multiregional (intratumoral, peritumoral, and parenchymal) radiomic model. Methods: We retrospectively reviewed ultrasound images of breast lesions from institution #1 (n=485) and institution #2 (n=106). Radiomic features were extracted from different regions (intratumoral, peritumoral, and ipsilateral breast parenchymal) and selected to train the random forest classifier with the training cohort (n=339, a subset of the institution #1 dataset). Then, the intratumoral, peritumoral, and parenchymal, intratumoral & peritumoral (In&Peri), intratumoral & parenchymal (In&P), and intratumoral & peritumoral & parenchymal (In&Peri&P) models were developed and validated on the internal (n=146, another subset of institution 1) and external (n=106, institution #2 dataset) test cohorts. Discrimination was evaluated using the area under the curve (AUC). Calibration curve and Hosmer-Lemeshow test assessed calibration. Integrated discrimination improvement (IDI) was used to assess performance improvement. Results: The performance of the In&Peri (AUC values 0.892 and 0.866), In&P (0.866 and 0.863), and In&Peri&P (0.929 and 0.911) models was significantly better than that of the intratumoral model (0.849 and 0.838) in the internal and external test cohorts (IDI test, all P<0.05). The intratumoral, In&Peri and In&Peri&P models showed good calibration (Hosmer-Lemeshow test, all P>0.05). The multiregional (In&Peri&P) model had the highest discrimination among the 6 radiomic models in the test cohorts, respectively. Conclusions: The multiregional model combining radiomic information of intratumoral, peritumoral, and ipsilateral parenchymal regions yielded better performance than the intratumoral model in distinguishing malignant breast lesions from benign lesions.

Prognostic evaluation based on radiological morphological characteristic for tumors larger than 7 cm in renal cell carcinoma.

PURPOSE: To predict survival prognosis of renal cell carcinoma (RCC) patients with tumors larger than 7 cm by preoperative radiological morphological features. METHODS: We reviewed the medical records of RCC patients with tumors larger than 7 cm from 2007 to 2017 in Zhongshan Hospital, Fudan University. A total of 251 patients' clinical data were collected. 25 and 9 patients were excluded due to loss of follow-up and lack of imaging data, respectively. PFS and OS from date of surgery were evaluated. We defined the irregularity of the tumor as the morphological feature studied and quantified it according to a theorem of the ellipse: the length from the midpoint of the ellipse to any point on the ellipse is shorter than or equal to 1/2 of the long axis. The cutoff value of irregularity was calculated based on the ROC curve. Cox proportional hazards regression models were used to test associations between features and outcome. RESULTS: Of all the 217 patients included in the study, 67 patients had disease progression and 30 patients died. The cutoff value of the irregularity was selected to be 0.5335. Adrenal invasion, presence of distant metastasis and irregularity of tumors were significantly associated with PFS, and presence of distant metastasis and irregularity of tumors were significantly associated with OS. CONCLUSIONS: For patients with tumors larger than 7 cm in RCC, we found a radiological index that is closely related to the prognosis: irregularity. This is an unreported independent prognostic risk factor that can be quantified before surgery.

Predictive Factors for Acute Kidney Injury and Long-Term Renal Function Loss After Partial Nephrectomy: A Prospective Single-Center Study.

OBJECTIVE: To find factors related to postoperative acute kidney injury and long-term significant renal function (RF) loss after partial nephrectomy (PN) in Chinese population. METHODS: The main outcome was significant RF loss during the last follow-up, which was defined as >25% decrease in estimated glomerular filtration rate. RESULTS: A total of 416 patients were included with median age as 57 (interquartile ranges,IQR 49.8-65.0) year with body mass index as 24.2 (IQR 22.0-26.5) kg/m2 and preoperative estimated glomerular filtration rate as 90.5 (IQR 79.8-101) mL/min. Summarily, 259 (62.3%) patients were male, 54 (13%) had diabetes, 180 (43.3%) hypertension and 80 (19.2%) hyperuricemia. Median (IQR) tumor diameter was 3.1 (2.4-4.1) cm. All patients underwent PN, in which 135 (32.5%) by open PN approach, 109 (26.2%) by laparoscopic PN and 172 (41.3%) by robot assisted PN. RF was followed up for 16.88 (10.15-36.37) months, where 58 (13.9%) patients suffered significant RF loss. Multivariable analysis showed age (P = .0039), body mass index (P = .0049), diabetes (P = .0351), operative time > 110 minutes (P = .0034), diameter classification by Diameter-Axial-Polar score (diameter 2.4 cm-4.4 cm, P = .0225: diameter > 4.4 cm, P = .0207), postoperative acute kidney injury (P < .001) to be predictors of RF loss with area under the curve as 0.850. CONCLUSION: We prospectively found predictive factors of short and long-term significant RF loss in all operative methods and constructed a clinical nomogram for long-term Chinese patients RF loss.

Prognostic value of tumour contour irregularity on surgical strategies for T1bN0M0 renal cell carcinoma: A multi-institutional study.

PURPOSE: To determine the prognostic value of tumour contour irregularity degree (CID) in surgical strategy options for T1bN0M0 renal cell carcinoma (RCC). MATERIALS AND METHODS: We performed a retrospective multi-institutional review of 489 patients with T1bN0M0 RCC treated between January 2009 and June 2019. Cox regression and Kaplan-Meier analyses were performed to analyse the impact of CID on disease-free survival (DFS). RESULTS: The median follow-up time was 55 months (interquartile range, 40-81 months) for 55 (11.2 %) patients with metastasis or recurrence. Logistic analysis indicated that CID was associated with World Health Organization/International Society of Urological Pathology (WHO/ISUP) grades III-IV (odds ratio, 1.015; 95 % confidence interval [CI], 1.008-1.023; p < 0.001). After being classified into high CID (≥50 %) and low CID (<50 %) groups, those with a high CID showed a significantly higher ratio of WHO/IUSP grades III-IV (74/277 [26.7 %] vs 25/212 [11.8 %]) and shorter DFS than the low CID group (p < 0.001). Multivariable Cox regression showed that partial nephrectomy (PN; hazard ratio [HR], 1.889; 95 % CI, 1.020-3.499; p = 0.043), high CID (HR, 6.685; 95 % CI, 2.776-16.100; p < 0.001), and WHO/ISUP grade III-IV (HR, 1.950; 95 % CI, 1.100-3.458; p = 0.022) were independent prognostic factors for DFS. The Kaplan-Meier plot showed that PN had a DFS rate comparable to that of radical nephrectomy (RN; p = 0.994). In the low CID group, patients who underwent PN showed comparable DFS to those who underwent RN (p = 0.903). Furthermore, patients with a high CID tended to have worse DFS in the PN versus RN group (p = 0.044). Multivariable Cox regression showed that PN (HR, 2.049; 95 % CI, 1.065-3.942; p = 0.032) and WHO/ISUP grade III-IV (HR, 2.148; 95 % CI, 1.189-3.881; p = 0.011) were independent prognostic factors of DFS in the high CID group. CONCLUSIONS: CID is a reliable preoperative parameter which is positively correlated with WHO/ISUP grade and can help with surgical decision-making in patients with T1bN0M0 RCC.

Does intraoperative cyst rupture of malignant cystic renal masses really have no negative impact on oncologic outcomes?

BACKGROUND: To assess the impact of malignant cystic renal masses (CRM) rupture on oncologic outcomes. METHODS: The study included 406 cases with partial nephrectomy (PN) and 17 cases with cyst decortication confirmed as malignant CRM by pathology. Recurrence-free survival (RFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were analyzed by the Kaplan-Meier method and log-rank test. Cox regression was used to identify risk factors associated with RFS, MFS, CSS, and OS. Logistic regression was performed to explore predictors of rupture. RESULTS: Tumor rupture occurred in 32 of 406 cases (7.9%). With median follow-up of 43 months, 4 (12.5%) and 5 (1.3%) cases experienced recurrence in rupture and non-rupture group, respectively (P = 0.003). Estimated RFS, MFS, and CSS were shorter in cyst ruptured (CR) group than non-ruptured (nonCR) cases (P < 0.001; P = 0.001; P < 0.001). Cox regression analysis indicated that CR was an independent prognostic factor for RFS (HR = 7.354; 95% CI = 1.839-29.413; P = 0.005), MFS (HR = 8.069; 95% CI = 1.804-36.095; P = 0.006), and CSS (HR = 9.643; 95% CI = 2.183-42.599; P = 0.003). Multivariable logistic regression showed that Bosniak IV was a protective factor for CR (OR = 0.065; 95% CI = 0.018-0.239; P < 0.001). However, compared to Bosniak III and I-IIF, Bosniak IV CRMs showed higher rate of clear cell renal cell carcinoma (ccRCC) (76.8% vs 36.5% vs 81.4%) (P < 0.001) and lower rate of Fuhrman I staging (11.2% vs 66.7% vs 7.4%) (P < 0.001). Therefore, in ruptured cases, the recurrence rate was higher in CRM with Bosniak IV (50%, 2/4) than Bosniak I-III (4.4%, 2/45) (P = 0.029). CONCLUSIONS: Intraoperative malignant CRM rupture had negative impacts on oncologic outcomes. Bosniak IV was more aggressive than Bosniak I-III and had a higher risk of recurrence after rupture. However, Bosniak IV had a lower risk of rupture, which could weaken even cover-up of the true effect of tumor rupture on oncologic outcomes.

An immune-related gene signature for the prognosis of human bladder cancer based on WGCNA.

The innovation of immunotherapy was a milestone in the treatment of bladder cancer (BLCA). However, the treatment benefits varied by individual thus promoting the investigation of the biomarker of the patients. Unfortunately, there were not many effective predictive models, which were desired by clinicians, for BLCA that can predict the prognosis and benefit of immunotherapy. We constructed a three genes prognosis prediction model termed RiskScore based on the result of weighted correlation network analysis (WGCNA) from The Cancer Genome Atlas (TCGA) cohort (n = 406). We then validated the prediction accuracy with three validation cohort(GSE13507 (n = 165), GSE48075(n = 73), GSE32894(n = 224)). We compared the differences in gene expression, immune relate function, and immune infiltration between two groups divided by RiskScore. We further discovered the potential drug target and suitable compounds for high-risk groups. Our results suggested that the low-risk group may be more potential for immunotherapy for they have higher B cell infiltration, higher expression of immune checkpoints(PDCD1, CTLA4), and much more active immune-related pathways(B cell and T cell receptor signaling pathway). The RiskScore showed a well predictive accuracy for the prognosis of BLCA. After Spearman analysis, we found the suitable drug target and compounds for the patients in the high-risk group. The model we constructed is able to predict the prognosis of BLCA patients with ease and accuracy. PLK1 and gefitinib may be utilized for further treatment of BLCA patients.

Oligomeric interactions maintain active-site structure in a noncooperative enzyme family.

The evolutionary benefit accounting for widespread conservation of oligomeric structures in proteins lacking evidence of intersubunit cooperativity remains unclear. Here, crystal and cryo-EM structures, and enzymological data, demonstrate that a conserved tetramer interface maintains the active-site structure in one such class of proteins, the short-chain dehydrogenase/reductase (SDR) superfamily. Phylogenetic comparisons support a significantly longer polypeptide being required to maintain an equivalent active-site structure in the context of a single subunit. Oligomerization therefore enhances evolutionary fitness by reducing the metabolic cost of enzyme biosynthesis. The large surface area of the structure-stabilizing oligomeric interface yields a synergistic gain in fitness by increasing tolerance to activity-enhancing yet destabilizing mutations. We demonstrate that two paralogous SDR superfamily enzymes with different specificities can form mixed heterotetramers that combine their individual enzymological properties. This suggests that oligomerization can also diversify the functions generated by a given metabolic investment, enhancing the fitness advantage provided by this architectural strategy.

Predictive value of renal tumor contour irregularity score in pathological T3a upstaging of clinical T1 renal cell carcinoma: A multi-institutional study.

PURPOSE: To explore the predictive value of renal tumor contour irregular degree (CID) in pathological T3a upstaging of clinical T1 renal cell carcinoma (RCC). MATERIALS AND METHODS: We performed a retrospective multi-institutional review of 1,487 patients with clinical T1N0M0 RCC between January 2009 and June 2019. Kaplan-Meier survival curve and Cox regressions were used to analyze the prognostic factors of disease-free survival (DFS). Logistic regressions were performed to determine predictors of pathological T3a upstaging in clinical T1 RCC. RESULTS: Among 1,487 patients with cT1 RCC, 96 (6.5%) were pathological T3a upstaging. Multivariable logistic regression analysis showed that age (odds ratio [OR] = 1.022, 95% confidence interval [CI] = 1.001-1.042, P = 0.036), tumor maximum diameter(OR = 1.242, 95% CI = 1.042--1.480, P = 0.015) and CID (OR = 1.067, 95% CI = 1.051-1.083, P < 0.001) were independent predictors of pathological T3a upstaging. The area under the curve (AUC) of the prediction model that included the CID was 0.846, while the AUC of the prediction model that did not include CID was only 0.741, the difference was statistically significant (P < 0.001). Kaplan-Meier survival curve showed that patients with pathological T3a upstaging had significantly worse DFS than patients without pathological T3a upstaging (P < 0.001). Multivariable Cox analysis showed that pathological T3a upstaging (HR = 1.836, 95% CI = 1.013-3.329, P = 0.002) is an independent prognostic factor for DFS in patients with cT1N0M0 RCC. CONCLUSIONS: The predictive model of CID combined with tumor maximum diameter and age significantly improved the ability to predict pathological T3a upstaging in clinical T1 RCC, compared with the prediction model of tumor maximum diameter combined with age. The predictive model of CID combined with tumor maximum diameter and age may be applicable to patients considering partial vs. radical nephrectomy.

Explore the Diagnostic Efficiency of Chinese Thyroid Imaging Reporting and Data Systems by Comparing With the Other Four Systems (ACR TI-RADS, Kwak-TIRADS, KSThR-TIRADS, and EU-TIRADS): A Single-Center Study.

Purpose: To explore the characteristics of C-TIRADS by comparing it with ACR-TIRADS, Kwak-TIRADS, KSThR-TIRADS and EU-TIRADS. Methods: A total of 1096 nodules were collected from 884 patients undergoing thyroidectomy in our center between May 2018 and December 2020. Divided the nodules into two groups: ">10mm" and "≤10mm". Ultrasound characteristics of each nodule were observed and recorded by 2 doctors, then classified based on ACR-TIRADS, Kwak-TIRADS, KSThR-TIRADS, EU-TIRADS, and C-TIRADS. Results: A total of 682 benign nodules cases (62.23%) and 414 malignant nodules cases (37.77%) were identified. The ICC value of each guideline was:0.937(ACR-TIRADS), 0.858(EU-IRADS), 0.811(Kwak-TIRADS), 0.835(KTA/KSThR-TIRADS) and 0.854(C-TIRADS). The nodule malignancy rates in the groups(Kwak-TIRADS 4B, C-TIRADS 4B、4C) of two sizes were significantly different (all p<0.05). There was no statistical difference in the other grades of two sizes (all p>0.05). Unnecessary biopsy rates were the lowest in C-TIRADS (49.02% p<0.001). Furthermore, Kwak-TIRADS had the highest sensitivity and NPV (89.9%, 91.0%, all p<0.05), while C-TIRADS had the highest specificity and PPV (82.3%, 69.2%, all p<0.05). C-TIRADS and Kwak-TIRADS had the highest accuracy (76.0%, 72.5%, P=0.071). The AUCs of the 5 guidelines were C-TIRADS(0.816, P<0.05), Kwak-TIRADS(0.789, P<0.05) KTA/KSThR-TIRADS and ACR-TIRADS(0.773, 0.763, P=0.305), EU-TIRADS(0.734, P<0.05). The AUCs of the five guidelines were not statistically different between "nodules>10mm" and "nodules ≤ 10mm" (all P>0.05). Conclusions: All five guides showed excellent interobserver agreement. C-TIRADS was slightly efficient than Kwak-IRADS, KTA/KSThR-TIRADS and ACR-TIRADS, and had greater advantages than EU-TIRADS. The diagnostic abilities of the five guidelines for "nodules ≤ 10mm" were not inferior to that of "nodules> 10mm". C-TIRADS is simple and easy to implement and can provide effective thyroid tumor risk stratification for thyroid nodule diagnosis, especially in China.

Construction and Immunological Evaluation of an Adenoviral Vector-Based Vaccine Candidate for Lassa Fever.

Lassa virus (LASV) is a rodent-borne arenavirus circulating in West African regions that causes Lassa fever (LF). LF is normally asymptomatic at the initial infection stage, but can progress to severe disease with multiorgan collapse and hemorrhagic fever. To date, the therapeutic choices are limited, and there is no approved vaccine for avoiding LASV infection. Adenoviral vector-based vaccines represent an effective countermeasure against LASV because of their safety and adequate immunogenicity, as demonstrated in use against other emerging viral infections. Here, we constructed and characterized a novel Ad5 (E1-, E3-) vectored vaccine containing the glycoprotein precursor (GPC) of LASV. Ad5-GPCLASV elicited both humoral and cellular immune responses in BALB/c mice. Moreover, a bioluminescent imaging-based BALB/c mouse model infected with GPC-bearing and luciferase-expressing replication-incompetent LASV pseudovirus was utilized to evaluate the vaccine efficacy. The bioluminescence intensity of immunized mice was significantly lower than that of control mice after being inoculated with LASV pseudovirus. This study suggests that Ad5-GPCLASV represents a potential vaccine candidate against LF.

Nomograms Combining Ultrasonic Features With Clinical and Pathological Features for Estimation of Delphian Lymph Node Metastasis Risk in Papillary Thyroid Carcinoma.

BACKGROUND: This work explores the clinical significance of Delphian lymph nodes (DLN) in thyroid papillary carcinoma (PTC). At the same time, a nomogram is constructed based on clinical, pathological, and ultrasonic (US) features to evaluate the possibility of DLN metastasis (DLNM) in PTC patients. This is the first study to predict DLNM using US characteristics. METHODS: A total of 485 patients, surgically diagnosed with PTC between February 2017 and June 2021, all of whom underwent thyroidectomy, were included in the study. Using the clinical, pathological, and US information of patients, the related factors of DLNM were retrospectively analyzed. The risk factors associated with DLNM were identified through univariate and multivariate analyses. According to clinical + pathology, clinical + US, and clinical + US + pathology, the predictive nomogram for DLNM was established and validated. RESULTS: Of the 485 patients with DLN, 98 (20.2%) exhibited DLNM. The DLNM positive group had higher positive rates of central lymph node metastasis (CLNM), lateral lymph node metastasis (LLNM), and T3b-T4b thyroid tumors than the negative rates. The number of CLNM and LLNM lymph nodes in the DLNM+ group was higher as compared to that in the DLNM- group. Multivariate analysis demonstrated that the common independent risk factors of the three prediction models were male, bilaterality, and located in the isthmus. Age ≥45 years, located in the lower pole, and nodural goiter were protective factors. In addition, the independent risk factors were classified as follows: (I) P-extrathyroidal extension (ETE) and CLNM based on clinical + pathological characteristics; (II) US-ETE and US-CLNM based on clinical + US characteristics; and (III) US-ETE and CLNM based on clinical +US + pathological features. Better diagnostic efficacy was reported with clinical + pathology + US diagnostic model than that of clinical + pathology diagnostic model (AUC 0.872 vs. 0.821, p = 0.039). However, there was no significant difference between clinical + pathology + US diagnostic model and clinical + US diagnostic model (AUC 0.872 vs. 0.821, p = 0.724). CONCLUSIONS: This study found that DLNM may be a sign that PTC is more invasive and has extensive lymph node metastasis. By exploring the clinical, pathology, and US characteristics of PTC progression to DLNM, three prediction nomograms, established according to different combinations of features, can be used in different situations to evaluate the transfer risk of DLN.

Tumor contour irregularity on preoperative imaging: a practical and useful prognostic parameter for papillary renal cell carcinoma.

OBJECTIVES: To illustrate tumor contour irregularity on preoperative imaging with a practical method and further determine its value in predicting disease-free survival (DFS) in patients with pRCC (papillary renal cell carcinoma). METHODS: We performed a retrospective single-institution review of 267 Chinese pRCC patients between March 2009 and May 2019. Contour irregularity on cross-section was classified into smooth but distorted margin, unsmooth and sharply nodular margin, and blurred margin. Then, the ratio of the cross-section numbers of irregularity and the total tumor was defined as the contour irregular degree (CID). Cox regression and Kaplan-Meier analysis were performed to analyze the impact of CID on DFS. Then, the prognostic performance of CID was compared with pRCC risk stratification published by Leibovich et al. RESULTS: The median follow-up was 45 months (IQR: 23-69), in which 27 (10%) patients had metastasis or recurrence. Observed DFS rates were 95%, 90%, and 88% at 1, 3, and 5 years. The CID was an independent prognostic factor of DFS (HR = 1.048, 95% CI = 1.029-1.068, p < 0.001). The Kaplan-Meier plot showed that high-risk patients (CID ≥ 50%) tended to have a significantly shorter DFS (p < 0.001). The CID and Leibovich's pRCC model for DFS prediction had a C-index of 0.934 (95% CI = 0.907-0.961) and 0.833 (95% CI = 0.739-0.927) respectively. CONCLUSIONS: With our standard and practical method, the CID can be a reliable imaging marker for DFS prediction in patients with pRCC. KEY POINTS: • The updated contour irregularity was an independent parameter for predicting disease-free survival in patients with pRCC. • High-risk pRCC patients (contour irregular degree ≥ 50%) tended to have a shorter disease-free survival. • Tumor contour irregularity in pRCC risk stratification outperformed Leibovich's model from our cohort.

Tumor-infiltrating TNFRSF9+ CD8+ T cells define different subsets of clear cell renal cell carcinoma with prognosis and immunotherapeutic response.

Objectives: Tumor necrosis receptor super family (TNFRSF) plays an important role in regulating the function of CD8+ T cells. In this study, we explored the clinical significance and immune profile of TNFRSF9+ CD8+ T cells in clear cell renal cell carcinoma (ccRCC). Methods: The infiltration of immune cells was determined by immunohistochemistry in ZS cohort from our hospital and their prognostic value was further determined by Cox regression. Functional status of CD8+ T cells in ccRCC was determined by flow cytometry in 29 fresh tumor samples. In silico analysis on a TCGA cohort and other datasets was performed to further demonstrate our findings. Results: High TNFRSF9+ CD8+ T cells infiltration was associated with inferior overall survival in ZS cohort (p = .0016) and TCGA-KIRC cohort (p = .018). TNFRSF9+ CD8+ T cells expressed higher exhaustion markers (PD-1, TIM-3, CTLA-4, and TIGIT), and effector markers (IFN-γ, GZMB, CD107a, and Ki-67), than their TNFRSF9 negative counterparts. In silico analysis indicated the expression of TNFRSF9 was significantly correlated with IFNG, GZMK, MKI-67, PDCD1, HAVCR2, TIGIT, and CTLA-4 in CD8+ T cells. However, higher TNFRSF9 signature was correlated with larger tumor size shrinkage (p = .003) and better progression-free survival (p = .012) in patients treated with nivolumab but not everolimus. Conclusion: TNFRSF9+ CD8+ T cells, which possessed both exhaustion and effector phenotype, were identified as an adverse prognosticator in ccRCC. These cells enrichment was associated with better immunotherapy response which indicated these cells potentially be crucial in immunotherapy.

Fc-Based Recombinant Henipavirus Vaccines Elicit Broad Neutralizing Antibody Responses in Mice.

The genus Henipavirus (HNVs) includes two fatal viruses, namely Nipah virus (NiV) and Hendra virus (HeV). Since 1994, NiV and HeV have been endemic to the Asia-Pacific region and responsible for more than 600 cases of infections. Two emerging HNVs, Ghana virus (GhV) and Mojiang virus (MojV), are speculated to be associated with unrecognized human diseases in Africa and China, respectively. Despite many efforts to develop vaccines against henipaviral diseases, there is presently no licensed human vaccine. As HNVs are highly pathogenic and diverse, it is necessary to develop universal vaccines to prevent future outbreaks. The attachment enveloped glycoprotein (G protein) of HNVs mediates HNV attachment to the host cell's surface receptors. G proteins have been used as a protective antigen in many vaccine candidates for HNVs. We performed quantitative studies on the antibody responses elicited by the G proteins of NiV, HeV, GhV, and MojV. We found that the G proteins of NiV and HeV elicited only a limited cross-reactive antibody response. Further, there was no cross-protection between MojV, GhV, and highly pathogenic HNVs. We then constructed a bivalent vaccine where the G proteins of NiV and HeV were fused with the human IgG1 Fc domain. The immunogenicity of the bivalent vaccine was compared with that of monovalent vaccines. Our results revealed that the Fc-based bivalent vaccine elicited a potent antibody response against both NiV and HeV. We also constructed a tetravalent Fc heterodimer fusion protein that contains the G protein domains of four HNVs. Immunization with the tetravalent vaccine elicited broad antibody responses against NiV, HeV, GhV, and MojV in mice, indicating compatibility among the four antigens in the Fc-fusion protein. These data suggest that our novel bivalent and tetravalent Fc-fusion proteins may be efficient candidates to prevent HNV infection.

Responses of bladder smooth muscle to the stretch go through extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 protein kinase (p90RSK)/Nuclear factor-κB (NF-κB) Pathway.

AIMS: The present study was designed to study changes and its potential mechanisms in human bladder smooth muscle subjected to stretch. METHODS: Bioinformatics analyses including differential expression analysis, overrepresentation enrichment analysis, principal component analysis, and weighted gene coexpression network analysis were used to analyze a microarray dataset (GSE47080) of partial bladder outlet obstruction (pBOO) in rat to find the potential changes of gene expressions. Bladder from pBOO model and human bladder smooth muscle cells (HBSMCs) subjected to sustained prolonged stretch were collected for Western blot analysis, real-time polymerase chain reaction, and fluorescence analysis to verify the changes of gene expressions and preliminarily study the potential role of signaling pathway regulation in treatment of pBOO. RESULTS: The bioinformatics analysis showed that chronic obstruction activated mitogen-activated protein kinase pathway and changed cytoskeleton structure in bladder smooth muscle. In in vivo experiments in mice, pBOO was verified by cystometry. Partial BOO activated the extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 protein kinase (p90RSK)/nuclear factor-κB (NF-κB) signaling pathway in DM. The messenger RNA (mRNA) expressions of contractile phenotypic proteins increased after pBOO. In in vitro experiments of HBSMCs, mechanical stretch activated ERK/p90RSK/NF-κB in HBSMCs in a time-dependent manner. The mRNA expressions of α-smooth muscle actin and SM22 also increased and filamentous actin (F-actin) polymerization was enhanced as well. Inhibition of ERK/p90RSK/NF-κB pathway reversed mechanical stretch-induced changes of contractile phenotypic expression and F-action polymerization. CONCLUSIONS: Continuous stretch increases expressions of contractile phenotypic proteins and promotes the polymerization of F-actin. This process partially goes through ERK/p90RSK/NF-κB pathway.