Molecular basis of receptor binding and antibody neutralization of Omicron.

The SARS-CoV-2 Omicron variant exhibits striking immune evasion and is spreading rapidly worldwide. Understanding the structural basis of the high transmissibility and enhanced immune evasion of Omicron is of high importance. Here, using cryo-electron microscopy, we present both the closed and the open states of the Omicron spike (S) protein, which appear more compact than the counterparts of the G614 strain1, potentially related to enhanced inter-protomer and S1-S2 interactions induced by Omicron residue substitution. The closed state showing dominant population may indicate a conformational masking mechanism for the immune evasion of Omicron. Moreover, we captured three states for the Omicron S-ACE2 complex, revealing that the substitutions on the Omicron RBM result in new salt bridges and hydrogen bonds, more favourable electrostatic surface properties, and an overall strengthened S-ACE2 interaction, in line with the observed higher ACE2 affinity of Omicron S than of G614. Furthermore, we determined the structures of Omicron S in complex with the Fab of S3H3, an antibody that is able to cross-neutralize major variants of concern including Omicron, elucidating the structural basis for S3H3-mediated broad-spectrum neutralization. Our findings shed light on the receptor engagement and antibody neutralization or evasion of Omicron and may also inform the design of broadly effective vaccines against SARS-CoV-2.

Matrixed CDR grafting: A neoclassical framework for antibody humanization and developability.

Discovery and optimization of a biotherapeutic monoclonal antibody requires a careful balance of target engagement and physicochemical developability properties. To take full advantage of the sequence diversity provided by different antibody discovery platforms, a rapid and reliable process for humanization of antibodies from nonhuman sources is required. Canonically, maximizing homology of the human variable region (V-region) to the original germline was believed to result in preservation of binding, often without much consideration for inherent molecular properties. We expand on this approach by grafting the complementary determining regions (CDRs) of a mouse anti-LAG3 antibody into an extensive matrix of human variable heavy chain (VH) and variable light chain (VL) framework regions with substantially broader sequence homology to assess the impact on complementary determining region-framework compatibility through progressive evaluation of expression, affinity, biophysical developability, and function. Specific VH and VL framework sequences were associated with major expression and purification phenotypes. Greater VL sequence conservation was correlated with retained or improved affinity. Analysis of grafts that bound the target demonstrated that initial developability criteria were significantly impacted by VH, but not VL. In contrast, cell binding and functional characteristics were significantly impacted by VL, but not VH. Principal component analysis of all factors identified multiple grafts that exhibited more favorable antibody properties, notably with nonoptimal sequence conservation. Overall, this study demonstrates that modern throughput systems enable a more thorough, customizable, and systematic analysis of graft-framework combinations, resulting in humanized antibodies with improved global properties that may progress through development more quickly and with a greater probability of success.

Switchable assembly and function of antibody complexes in vivo using a small molecule.

The antigen specificity and long serum half-life of monoclonal antibodies have made them a critical part of modern therapeutics. These properties have been coopted in a number of synthetic formats, such as antibody-drug conjugates, bispecific antibodies, or Fc-fusion proteins to generate novel biologic drug modalities. Historically, these new therapies have been generated by covalently linking multiple molecular moieties through chemical or genetic methods. This irreversible fusion of different components means that the function of the molecule is static, as determined by the structure. Here, we report the development of a technology for switchable assembly of functional antibody complexes using chemically induced dimerization domains. This approach enables control of the antibody's intended function in vivo by modulating the dose of a small molecule. We demonstrate this switchable assembly across three therapeutically relevant functionalities in vivo, including localization of a radionuclide-conjugated antibody to an antigen-positive tumor, extension of a cytokine's half-life, and activation of bispecific, T cell-engaging antibodies.

A first-principles study of 2D single-layer SiP as anode materials for lithium-ion batteries and sodium-ion batteries.

The promotion of lithium-ion batteries and sodium-ion batteries is limited by the deficiency of suitable anode materials with desired electrochemical properties. In this work, the models of 2D single-layer SiP are constructed to explore its potential as an anode material for LIBs and SIBs using density functional theory (DFT). The diffusion of Li in bulk SiP is anisotropic. There is a low diffusion energy barrier of 0.28 eV along the X-axis. The low surface exfoliation energy suggests that there is a high probability of preparing 2D single-layer SiP experimentally. Its structure stability is verified by ab initio molecular dynamics (AIMD) simulations at 300 K and 400 K. The intercalation and diffusion behaviors of Li/Na on 2D single-layer SiP indicate that Li/Na tends to diffuse along the X-axis direction of 2D single-layer SiP. The diffusion energy barrier of Li/Na on 2D single-layer SiP is lower compared to that of bulk SiP. The conductivity of 2D single-layer SiP is improved after lithiation due to the upshift of Fermi levels. 2D single-layer SiP has a lower average open circuit voltage (1.50 V for LIBs and 1.08 V for SIBs) and a high theoretical capacity (520 mA h g-1). Hence, 2D single-layer SiP can be an ideal anode material for LIBs and SIBs.

Exosomal lncRNA HEIH, an essential communicator for hepatocellular carcinoma cells and macrophage M2 polarization through the miR-98-5p/STAT3 axis.

Part of human long noncoding RNAs (lncRNAs) has been elucidated to play an essential role in the carcinogenesis and progression of hepatocellular carcinoma (HCC), a type of malignant tumor with poor outcomes. Tumor-derived exosomes harboring lncRNAs have also been implicated as crucial mediators to orchestrate biological functions among neighbor tumor cells. The recruitment of tumor-associated macrophages (TAMs) exerting M2-like phenotype usually indicates the poor prognosis. Yet, the precise involvement of tumor-derived lncRNAs in cross-talk with environmental macrophages has not been fully identified. In this study, we reported the aberrantly overexpressed HCC upregulated EZH2-associated lncRNA (HEIH) in tumor tissues and cell lines was positively correlated with poor prognosis, as well as enriched exosomal HEIH levels in blood plasma and cell supernatants. Besides, HCC cell-derived exosomes transported HEIH into macrophages for triggering macrophage M2 polarization, thereby in turn promoting the proliferation, migration, and invasion of HCC cells. Mechanistically, HEIH acted as a miRNA sponge for miR-98-5p to up-regulate STAT3, which was then further verified in the tumor xenograft models. Collectively, our study provides the evidence for recognizing tumor-derived exosomal lncRNA HEIH as a novel regulatory function through targeting miR-98-5p/STAT3 axis in environmental macrophages, which may shed light on the complicated tumor microenvironment among tumor and immune cells for HCC treatment.

Implications of GCLC in prognosis and immunity of lung adenocarcinoma and multi-omics regulation mechanisms.

BACKGROUND: Ferroptosis is an iron-dependent type of regulated cell death, and has been implicated in lung adenocarcinoma (LUAD). Evidence has proved the key role of glutamate-cysteine ligase catalytic subunit (GCLC) in ferroptosis, but its role in LUAD remains unclear. Herein, we explored the implications of GCLC and relevant genes in LUAD prognosis and immunity as well as underlying molecular mechanisms. METHODS: This work gathered mRNA, miRNA, DNA methylation, somatic mutation and copy-number variation data from TCGA-LUAD. WGCNA was utilized for selecting GCLC-relevant genes, and a GCLC-relevant prognostic signature was built by uni- and multivariate-cox regression analyses. Immune compositions were estimated via CIBERSORT, and two immunotherapy cohorts of solid tumors were analyzed. Multi-omics regulatory mechanisms were finally assessed. RESULTS: Our results showed that GCLC was overexpressed in LUAD, and potentially resulted in undesirable survival. A prognostic model was generated, which owned accurate and independent performance in prognostication. GCLC, and relevant genes were notably connected with immune compositions and immune checkpoints. High GCLC expression was linked with better responses to anti-PD-L1 and anti-CTLA-4 treatment. Their possible DNA methylation sites were inferred, e.g., hypomethylation in cg19740353 might contribute to GCLC up-regulation. Frequent genetic mutations also affected their expression. Upstream transcription factors (E2F1/3/4, etc.), post-transcriptional regulation of miRNAs (hsa-mir-30c-1, etc.), lncRNAs (C8orf34-AS1, etc.), and IGF2BP1-mediated m6A modification were identified. It was also found NOP58-mediated SUMOylation post-translational modification. CONCLUSIONS: Together, we show that GCLC and relevant genes exert crucial roles in LUAD prognosis and immunity, and their expression can be controlled by complex multi-omics mechanisms.

SCARA5 as a downstream factor of PCAT29, inhibits proliferation, migration, and invasion of bladder cancer.

Scavenger receptor class A, member 5 (SCARA5) has been identified a novel tumor suppressor in several cancers. However, the functional and underlying mechanism of SCARA5 in bladder cancer (BC) need investigation. Here, we found SCARA5 expression was downregulated in both BC tissues and cell lines. Low SCARA5 in BC tissues was associated with a shorter overall survival. Moreover, SCARA5 overexpression reduced BC cell viability, colony formation, invasion, and migration. Further investigation demonstrated that the expression of SCARA5 was negatively regulated by miR-141. Furthermore, the long non-coding RNA prostate cancer associated transcript 29 (PCAT29) inhibited the proliferation, invasion, and migration of BC cells by sponging miR-141. Luciferase activity assays revealed that PCAT29 targeted miR-141 and miR-141 targeted SCARA5. In conclusion, SCARA5, as a downstream factor of the PCAT29/miR-141 axis, inhibited the proliferation, migration, and invasion of BC cells. These findings provide novel insights into the detailed molecular mechanisms of BC development.

Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial.

BACKGROUND: Doxycycline was demonstrated in a retrospective study to be associated with greater survival in patients with light chain amyloidosis. Therefore, we prospectively compared the efficacy of bortezomib-cyclophosphamide-dexamethasone (CyBorD) and CyBorD combined with doxycycline for cardiac light chain amyloidosis. METHODS: This was a multicenter, open-label, randomized controlled trial. Patients with Mayo 2004 stage II to III light chain amyloidosis were included. Patients were randomized to doxycycline 100 mg twice daily along with 9 cycles of CyBorD (doxycycline group) or to 9 cycles of CyBorD alone (control group). The primary outcome was 2-year progression-free survival (PFS). PFS was defined as the time from randomization to death, hematologic progression, or organ progression (heart, kidney or liver). Hematologic progression was defined on the basis of a substantial increase in free light chain. An increase in either NT-proBNP (N-terminal pro B-type natriuretic peptide) or cardiac troponin was the main criterion for defining cardiac progression. Cardiac PFS, defined as the time from randomization to cardiac progression or death, was compared between groups in an exploratory analysis. The corresponding treatment hazard ratio was estimated with a Cox regression model. RESULTS: One hundred forty patients underwent randomization, with 70 in each group. The median age was 61 years (range, 33-78 years) with a male:female ratio of 1.75:1. Stage II disease was present in 34 (48.6%) and 33 (47.1%) patients in the doxycycline and control groups, respectively. After a median follow-up duration of 24.4 months, 32 of 70 (45.7%) patients in the doxycycline group and 30 of 70 (42.9%) patients in the control group experienced progression. PFS was not significantly different between groups (hazard ratio, 0.97 [95% CI, 0.59-1.60]; P=0.91). Cardiac progression occurred in 29 of 70 (41.4%) patients in the doxycycline group and 26 of 70 (37.1%) patients in the control group. The death rates for both groups by the end of follow-up was the same, 25 of 70 (35.7%). No significant differences were observed for either cardiac PFS (hazard ratio, 0.91 [95% CI, 0.54-1.55]; P=0.74) or overall survival (hazard ratio, 1.04 [95% CI, 0.60-1.81]; P=0.89). CONCLUSIONS: Our trial demonstrated that doxycycline combined with CyBorD failed to prolong PFS or cardiac PFS compared with CyBorD alone in cardiac light chain amyloidosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03401372.

Neutralization of African enterovirus A71 genogroups by antibodies to canonical genogroups.

Enterovirus 71 (EV-A71) is a major public health problem, causing a range of illnesses from hand-foot-and-mouth disease to severe neurological manifestations. EV-A71 strains have been phylogenetically classified into eight genogroups (A to H), based on their capsid-coding genomic region. Genogroups B and C have caused large outbreaks worldwide and represent the two canonical circulating EV-A71 subtypes. Little is known about the antigenic diversity of new genogroups as compared to the canonical ones. Here, we compared the antigenic features of EV-A71 strains that belong to the canonical B and C genogroups and to genogroups E and F, which circulate in Africa. Analysis of the peptide sequences of EV-A71 strains belonging to different genogroups revealed a high level of conservation of the capsid residues involved in known linear and conformational neutralization antigenic sites. Using a published crystal structure of the EV-A71 capsid as a model, we found that most of the residues that are seemingly specific to some genogroups were mapped outside known antigenic sites or external loops. These observations suggest a cross-neutralization activity of anti-genogroup B or C antibodies against strains of genogroups E and F. Neutralization assays were performed with diverse rabbit and mouse anti-EV-A71 sera, anti-EV-A71 human standards and a monoclonal neutralizing antibody. All the batches of antibodies that were tested successfully neutralized all available isolates, indicating an overall broad cross-neutralization between the canonical genogroups B and C and genogroups E and F. A panel constituted of more than 80 individual human serum samples from Cambodia with neutralizing antibodies against EV-A71 subgenogroup C4 showed quite similar cross-neutralization activities between isolates of genogroups C4, E and F. Our results thus indicate that the genetic drift underlying the separation of EV-A71 strains into genogroups A, B, C, E and F does not correlate with the emergence of antigenically distinct variants.

Therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development through HSPA5/NFκB/CD55 pathway in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. Hyperthermia is widely used in combination with chemotherapy and radiotherapy to enhance therapeutic efficacy in NPC treatment, but the underlying anti-tumor mechanisms of hyperthermia remain unclear. Complement C3 has been reported to participate in the activation of immune system in the tumor microenvironment, leading to tumor growth inhibition. In this study, we aimed to explore the effect and mechanisms of hyperthermia and investigate the functional role of complement C3 in NPC hyperthermia therapy (HT). The serum levels of complement C3 before and after hyperthermia therapy in patients with NPC were analyzed. NPC cell lines SUNE1 and HONE1 were used for in vitro experiment to evaluate the function of complement C3 and HT on cell proliferation and apoptosis. SUNE1 xenograft mouse model was established and tumor-bearing mice were treated in water bath at a constant temperature of 43°C. Tumor samples were collected at different time points to verify the expression of complement C3 by immunohistochemical staining and western blot. The differential expressed genes after hyperthermia were analyzed by using RNA sequencing. We found that complement could enhance hyperthermia effect on suppressing proliferation and promoting apoptosis of tumor cells in NPC. Hyperthermia decreased the mRNA expression of complement C3 in tumor cells, but promoted the aggregation and activation circulating C3 in NPC tumor tissue. By using in vitro hyperthermia-treated NPC cell lines and SUNE1 xenograft tumor-bearing mice, we found that the expression of heat shock protein 5 (HSPA5) was significantly upregulated. Knockdown of HSPA5 abrogated the anti-tumor effect of hyperthermia. Moreover, we demonstrated that hyperthermia downregulated CD55 expression via HSPA5/NFκB (P65) signaling and activated complement cascade. Our findings suggest that therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development via HSPA5/NFκB/CD55 pathway in NPC.

3 L split-dose polyethylene glycol is superior to 2 L polyethylene glycol in colonoscopic bowel preparation in relatively high-BMI (≥ 24 kg/m2) individuals: a multicenter randomized controlled trial.

BACKGROUND: Whether body mass index (BMI) is a risk factor for poor bowel preparation is controversial, and the optimal bowel preparation regimen for people with a high BMI is unclear. METHODS: We prospectively included 710 individuals with high BMIs (≥ 24 kg/m2) who were scheduled to undergo colonoscopy from January to November 2021 at 7 hospitals. Participants were randomly allocated into 3 L split-dose polyethylene glycol (PEG) group (n=353) and 2 L PEG group (n=357). The primary outcome was the rate of adequate bowel preparation, and the secondary outcomes included Boston Bowel Preparation Scale (BBPS) score, polyp detection rate, cecal intubation rate, and adverse reactions during bowel preparation. Furthermore, we did exploratory subgroup analyses for adequate bowel preparation. RESULTS: After enrollment, 15 individuals didn't undergo colonoscopy, finally 345 participants took 3 L split-dose PEG regimen, and 350 participants took 2 L PEG regimen for colonoscopic bowel preparation. 3 L split-dose PEG regimen was superior to 2 L PEG regimen in the rate of adequate bowel preparation (81.2% vs. 74.9%, P = 0.045), BBPS score (6.71±1.15 vs. 6.37±1.31, P < 0.001), and the rate of polyp detection (62.0% vs. 52.9%, P = 0.015). The cecal intubation rate was similar in both groups (99.7%). Regarding adverse reactions, individuals were more likely to feel nausea in the 3 L PEG group (30.9% vs. 19.3%; P = 0.001); however, the degree was mild. In the subgroup analysis for adequate bowel preparation, 3 L split-dose PEG regimen performed better than 2 L PEG regimen in the overweight (BMI 25-29.9 kg/m2 ) (P = 0.006) and individuals with constipation (P = 0.044), while no significant differences were observed in relatively normal (BMI 24-24.9 kg/m2) (P = 0.593) and obese individuals (BMI ≥ 30 kg/m2) (P = 0.715). CONCLUSIONS: 3 L split-dose PEG regimen is superior to 2 L PEG regimen for colonoscopic Bowel Preparation in relatively high-BMI individuals, especially overweight individuals (BMI 25-29.9 kg/m2 ). TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trials Registry (ChiCTR2000039068). The date of first registration, 15/10/2020, http://www.chictr.org.cn.

Increased Metallothionein-1 Associated with Gout Activity and Tophi.

BACKGROUND AND AIMS: Gout is a chronic self-limiting inflammatory arthritis. An increase in metallothionein-1 (MT-1) has been reported in rheumatoid arthritis and osteoarthritis, and it attenuates inflammation and the pathology of diseases. This study aims to detect MT-1 levels in patients with gout and to explore its correlation with disease activity, clinical indexes, and inflammatory cytokines. METHODS: The expression of MT-1 messenger RNAs (mRNAs) and protein levels in patients with gout were measured using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Correlations between MT-1 and clinical indexes or inflammatory mediators were analyzed using Spearman's correlation test. RESULTS: Compared with healthy controls (HCs, n = 43), patients with active gout (n = 27) showed higher levels of MT-1 mRNA in peripheral blood mononuclear cells and protein in serum, particularly those with tophi. No significant difference in serum MT-1 levels was observed among patients with inactive gout, HCs, and patients with hyperuricemia without gout. Furthermore, no significant difference was observed between patients with gout with kidney damage and HCs. In addition, serum interleukin (IL)-1ß, IL-6, and IL-8 levels were significantly increased in patients with active gout, particularly in those with tophi. The serum MT-1 level was positively correlated with C-reactive protein, as well as with IL-1ß, IL-6, and IL-18. CONCLUSION: The higher levels of MT-1 were found in patients with gout, which were correlated with disease activity and gout related pro-inflammatory cytokines. Indicating MT-1 may serve as a new marker for predicting disease activity.Abbreviations: IL-1ß: Interleukin 1ß; MT-1: Metallothionein-1; CRP: C-Reactive Protein; ROS: Reactive Oxygen Species; IL-10: Interleukin 10; TGF-ß: Transforming Growth Factor Beta.

Feminizing gender-affirming hormone therapy for the transgender and gender diverse population: An overview of treatment modality, monitoring, and risks.

AIMS: Feminizing gender-affirming hormone therapy (GAHT) can be utilized to help transfeminine transgender and gender diverse (TGD) individuals achieve the transformation of outward sex characteristics, thereby leading to improvements in psychological and social well-being. In this narrative review, we aim to summarize current guidelines for feminizing GAHT management as well as the available literature describing the associated health risks pertaining to cardiovascular disease, thromboembolic disease, bone health, and cancer risks. METHODS: Relevant literature from January 2019 through July 2022 pertaining to feminizing GAHT was identified using PubMed, Cochrane Library, EMBASE, and MEDLINE. A narrative summary was performed with the inclusion of more recently published guidance from the World Professional Association for Transgender Health, Standards of Care Version 8. RESULTS: Guidance regarding the prescribing of feminizing GAHT with estrogen, antiandrogen, and progesterone medications is summarized along with considerations of the cardiovascular, thromboembolic, bone health, and cancer risks associated with these therapies. CONCLUSIONS: Feminizing GAHT is a highly effective method for transfeminine TGD patients to achieve medically necessary changes in secondary sex characteristics. Knowledge of the health risks of feminizing GAHT is largely drawn from research in the cisgender population, with a growing body of literature in TGD-specific patient populations. Feminizing GAHT appears to carry a low risk profile for most patients; however, further research describing the risks of hormone management around the time of gender-affirming surgery and in the aging TGD population is needed to optimize GAHT in the context of the evolving health risks over a TGD patient's lifespan.

Lattice oxygen activation in disordered rocksalts for boosting oxygen evolution.

The recent development of some special oxygen evolution reaction (OER) electrocatalysts shows that the lattice oxygen could participate in the catalysis process via the lattice oxygen oxidation mechanism (LOM), which the provides good possibility of exploring advanced electrocatalysts that could overcome the scaling relationship in conventional catalysis processes through a traditional adsorbate evolution mechanism. In this work, we theoretically predict that, benefiting from the unhybridized O-Li orbitals and the resulting metastable Li-O-Li ligands, the lattice oxygen could be easily activated and oxidized at relatively high oxidation voltages. Thus, lithium-excess disordered rocksalts (DRX) should possess the potential for acting as active OER electrocatalysts, which catalyze through the LOM pathway. The isotope labelling experimental results show that the lattice oxygen in the DRX was activated and participated in the OER process through the LOM pathway. The typical DRX of Li1.2Fe0.4Ti0.5O2 displays obviously pH-dependent OER activity under the LOM process and shows a low overpotential of 263 mV to reach 10 mA cm-2 with long-term stability for 100 hours. The turnover frequency of Li1.2Fe0.4Ti0.5O2 is nearly 9 times that of LiFePO4 at the overpotential of 300 mV. This work opens a new chemical space for exploring efficient electrocatalysts to enhance the OER performance through the LOM pathway.

Chronobiology discrepancies between patients with acute type a aortic dissection complicated with and without sleep apnea syndrome: a single-center seven-year retrospective study.

BACKGROUND: The present study aimed to investigate the differences in chronobiology and prevention between patients with acute type-A aortic dissection (ATAAD) complicated with sleep apnea syndrome (SAS) and without sleep apnea syndrome (non-SAS). METHODS: We retrospectively analyzed the clinical information of ATAAD patients using hospital medical records and regional meteorological and chronological information between January 2013 and December 2019. RESULTS: An early mortality rate of 16.9% (196 out of 1160 cases) was observed, comprising 95 cases of aortic rupture before surgery and 101 surgery-related deaths. Eighty-one of the 964 survivors were screened for SAS using complete morphological characteristics. Of these patients, 291 (33.0%) suffered from SAS, while 590 (67.0%) had no SAS. Based on a Circular Von Mises distribution analysis, the non-SAS patients experienced a significant morning peak in the occurrence of ATAAD at 10:04 (r1 = 0.148, p < 0.01). In contrast, the SAS patients experienced a significantly different (non-SAS vs. SAS, U2 = 0.947, p < 0.001) nighttime peak at 23:48 (r2 = 0.489, p < 0.01). Moreover, both non-SAS (Z = 39.770, P < 0.001) and SAS (Z = 55.663, P < 0.001) patients showed a comparable peak during January (non-SAS vs. SAS, U2 = 0.173, p > 0.05). Furthermore, SAS patients experienced a peak on Fridays (χ2 = 36.419, p < 0.001), whereas there was no significant difference in the weekly distribution in non-SAS patients (χ2 = 11.315, p = 0.079). CONCLUSIONS: The analyses showed that both SAS and non-SAS patients showed distinct rhythmicity in ATAAD onset. These findings highlight the chronobiological triggers within different ATAAD subpopulations and may contribute to the prevention of this potentially fatal occurrence.

Endovascular repair of aortic pathologies involving the aortic arch using castor stent-graft combined with in-vitro fenestration technology.

BACKGROUND: Aortic arch pathologies are concerning clinical conditions with poor prognoses. The use of thoracic endovascular aortic repair (TEVAR) has been investigated to treat aortic arch pathologies. Nonetheless, cerebral blood flow regulation during endovascular aortic arch repair therapy remains challenging. Castor, a unique single-branched stent graft, has been proven effective for retaining the left subclavian artery (LSA). This study aimed to determine whether endovascular therapy for pathologies involving the aortic arch using Castor in combination with the in-vitro fenestration technique is promising, effective, and safe. METHODS: Eligible patients were enrolled between June 2018 and December 2021. All patients underwent TEVAR with an evaluated proximal landing zone for "Castor" located in Ishimaru zones 0-1. Moreover, the supra-aortic branches (SABs) were reconstructed using the Castor in combination with the in-vitro fenestration technique. RESULTS: Herein, 57 patients with aortic arch lesions were treated with Castor in combination with the in-vitro fenestration technique. Innominate artery and the left carotid artery (LCA) were reconstructed in 5 patients, LCA and left subclavian artery (LSA) were reconstructed in 22 patients, and the total SABs were effectively reconstructed in 30 patients (including a hybrid arch repair case). Among them (excluding a hybrid arch repair case) were in-vitro fenestration methodologies for LCA in 32 of 34 cases (2 switched to in-situ fenestration) and LSA in 51 of 56 cases (3 switched to in-situ fenestration and 2 converted to spring coil caulking); furthermore, LCA and LSA in-vitro fenestration were simultaneously successfully performed in 27 of 34 cases. There were no surgical-related neurological complications, and early mortality was estimated at 5.26%. At a mean follow-up of 3.75 months, computed tomography (CTA) images confirmed that each branch stent remained patent. There were no signs of endoleaks, migrative manifestations, or the need for secondary endovascular intervention or conversion to open surgical procedures. CONCLUSION: Castor, in combination with in-vitro fenestration, reflects a feasible, efficient procedure for re-developing SABs.

Cost-effectiveness analysis of robot-assisted laparoscopic surgery for complex pediatric surgical conditions.

BACKGROUND: Robotics has been used safely and successfully in a variety of adult surgeries and is gradually gaining ground in pediatrics. While the benefits of robotic-assisted surgery in disease treatment are well recognized, its high cost has led to questions. To investigate whether robotic-assisted laparoscopic surgery (RALS) is cost-effective compared to conventional laparoscopic surgery (LS) in pediatric surgery, we attempted to construct a model to perform an analysis of these two surgical approaches using Python statistical analysis software. METHODS: We selected four common complex pediatric surgical conditions (choledochal cyst, Hirschsprung's disease, vesicoureteral reflux, and congenital hydronephrosis) from three systems (pediatric hepatobiliary, gastroenterology, and urology). Models were constructed using Python statistical software to compare hospital costs and surgical outcomes for RALS and LS. In addition, we performed a preferred strategy analysis for both surgical modalities while assessing model uncertainty using one-way sensitivity analysis. RESULTS: For the four diseases, the operative time decreased sequentially. The total inpatient costs of RALS were 10,816.72, 9145.44, 8414.29, 7973.58 dollars, respectively, yielding 1.789, 1.712, 1.749, 1.792 quality adjustment life years (QALYs) over two years post-operatively. The incremental cost of RALS relative to LS for each disease was 3523.44, 3200.20, 3049.79, 3043.66 dollars, respectively, with an incremental utility of 0.060, 0.054, 0.051, 0.050 QALYs. The incremental cost-effectiveness ratios (ICERs) for RALS for each of the four diseases were 58,724.01, 59,262.95, 59,799.79, 60,873.20 dollars/QALY, all less than 100,000 dollars/QALY. The cost of robot consumables was the main incremental cost of RALS and had the most significant impact on the model. CONCLUSION: For the four pediatric surgical conditions described above, RALS has higher inpatient costs than LS, but it has better postoperative outcomes, and all four RALS treatments are cost-effective. Children with complex diseases and long operative times appear to benefit more from RALS.

A prognostic nomogram incorporating tumor size and lymph node size for patients with nasopharyngeal carcinoma.

PURPOSE: The goal of this study was to establish a nomogram that included pre-treatment tumor size and lymph node (LN) size to assess personalized overall survival (OS) of patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results dataset was used to extract statistics for 1083 individuals with NPC (training cohort). In the validation cohort, 266 patients were included from the Affiliated Cancer Hospital & Institute of Guangzhou Medical University. Age, tumor-node-metastasis (TNM) stage, pre-treatment tumor size, and LN size were chosen in both the training and validation sets to build a nomogram to forecast the 3-year and 5-year OS probability using the multivariate Cox regression model. Using the C-index, calibration plot, and receiver operating characteristic (ROC) curve, the predictive model's predictive value and discriminative capacity were determined. RESULTS: Pre-treatment tumor size, LN size, age, and TNM stage were all independent prognostic factors in the multivariate analysis. After combining these characteristics, a nomogram with a C-index of 0.7367 in the training cohort and 0.795 in the validation cohort was created, suggesting strong predictive capacity. Analysis of the ROC curve revealed that the constructed nomogram was clinically applicable. CONCLUSIONS: In patients with NPC, the developed nomogram, which includes pre-treatment tumor size, LN size, age, and TNM stage, is a reliable predictive predictor of OS.

Culture Conditions for Human Induced Pluripotent Stem Cell-Derived Schwann Cells: A Two-Centre Study.

Adult human Schwann cells represent a relevant tool for studying peripheral neuropathies and developing regenerative therapies to treat nerve damage. Primary adult human Schwann cells are, however, difficult to obtain and challenging to propagate in culture. One potential solution is to generate Schwann cells from human induced pluripotent stem cells (hiPSCs). Previously published protocols, however, in our hands did not deliver sufficient viable cell numbers of hiPSC-derived Schwann cells (hiPSC-SCs). We present here, two modified protocols from two collaborating laboratories that overcome these challenges. With this, we also identified the relevant parameters to be specifically considered in any proposed differentiation protocol. Furthermore, we are, to our knowledge, the first to directly compare hiPSC-SCs to primary adult human Schwann cells using immunocytochemistry and RT-qPCR. We conclude the type of coating to be important during the differentiation process from Schwann cell precursor cells or immature Schwann cells to definitive Schwann cells, as well as the amounts of glucose in the specific differentiation medium to be crucial for increasing its efficiency and the final yield of viable hiPSC-SCs. Our hiPSC-SCs further displayed high similarity to primary adult human Schwann cells.

Efficacy and safety of mesenchymal stem cells in the treatment of perianal fistulas in Crohn's disease: a meta-analysis of randomized controlled trials.

OBJECTIVES: Local mesenchymal stem cell (MSC) therapy for perianal fistulas in Crohn's disease (CD) has yielded promising results, but it still remains controversial. In this study, we aimed to conduct a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of MSC therapy for perianal CD (pCD). METHODS: RCTs reporting MSC therapy for perianal fistulas in CD were searched and included. The effectiveness and safety data were analyzed using RevMan 5.3. RESULTS: A total of 7 RCTs were included in this meta-analysis. The analysis showed that patients receiving MSC therapy presented a higher healing rate (HR) of pCD than those in the control group (odds ratio (OR)=1.42; 95% confidence interval (CI) 1.18, 1.71; P=0.0002). Compared with placebo (saline solution), MSC therapy improved the HR of pCD (OR=1.85; 95% CI 1.32, 2.60; P=0.0004). MSC therapy showed significant long-term efficacy (OR=1.36; P=0.009; 95% CI 1.08, 1.71). When MRI was used to evaluate fistula healing, a pooled analysis showed that the MSC group achieved a higher HR than the control group (OR=1.95; 95% CI 1.33, 2.87; P=0.0007). Allogeneic MSC therapy was superior to the control treatment in improving HR (OR = 1.97; 95% CI 1.40, 2.75; P<0.001). Furthermore, no significant differences were observed between MSC therapy and placebo in terms of adverse events (AEs) (OR = 1.16; 95% CI 0.76, 1.76; P = 0.48). None of the AEs were judged to be related to MSC treatment. CONCLUSIONS: This meta-analysis of RCTs provided evidence that local MSC injection is safe and efficacious for perianal fistulas in CD. In addition, this treatment has favorable long-term efficacy and safety profiles.