Endohedral nitrogen fullerenes have been proposed as building blocks for quantum information processing due to their long spin coherence time. However, addressability of the individual electron spin ...levels in such a multiplet system of 4S3/2 has never been achieved because of the molecular isotropy and transition degeneracy among the Zeeman levels. Herein, by molecular engineering, we lifted the degeneracy by zero‐field splitting effects and made the multiple transitions addressable by a liquid‐crystal‐assisted method. The endohedral nitrogen fullerene derivatives with rigid addends of spiro structure and large aspect ratios of regioselective bis‐addition improve the ordering of the spin ensemble. These samples empower endohedral‐fullerene‐based qudits, in which the transitions between the 4 electron spin levels were respectively addressed and coherently manipulated. The quantum geometric phase manipulation, which has long been proposed for the advantages in error tolerance and gating speed, was implemented in a pure electron spin system using molecules for the first time.
Toward molecular quantum computing, the system needs to have good coherence, scalability, and addressability. Using endohedral nitrogen fullerenes with long coherence time, this work tackled the remaining two challenges by molecular modification and ensemble alignment. The refined molecular system scales up to four addressable quantum levels and enables the first implementation of geometric phase manipulation using pure electron paramagnetic resonance.
High circulating neutrophil-lymphocyte ratio (NLR) appears to be prognostic in metastatic colorectal cancer (mCRC). We investigated the relationship of NLR with circulating cytokines and molecular ...alterations.
We performed retrospective analyses on multiple cohorts of CRC patients (metastatic untreated (n=166), refractory metastatic (n=161), hepatectomy (n=198), stage 2/3 (n=274), and molecularly screened (n=342)). High NLR (ratio of absolute neutrophil-to-lymphocyte counts in peripheral blood) was defined as NLR>5. Plasma cytokines were evaluated using multiplex-bead assays. Kaplan-Meier estimates, non-parametric correlation analysis, and hierarchical cluster analyses were used.
High NLR was associated with poor prognosis in mCRC (hazard ratio (HR) 1.73; 95% confidence interval (CI):1.03-2.89; P=0.039) independent of known prognostic factors and molecular alterations (KRAS/NRAS/BRAF/PIK3CA/CIMP). High NLR correlated with increased expression of interleukin 6 (IL-6), IL-8, IL-2Rα, hepatocyte growth factor, macrophage-colony stimulating factor, and vascular epidermal growth factor in exploratory (n=39) and validation (n=166) cohorts. Fourteen additional cytokines correlated with high NLR in the validation cohort. All 20 cytokines fell into three major clusters: inflammatory cytokines, angiogenic cytokines, and epidermal growth factor ligands. In mCRC, composite stratification based on NLR-cytokine score provided enhanced prognostic information (HR 2.09; 95% CI: 1.59-2.76; P<0.001) over and above NLR.
High NLR is an independent poor prognostic marker in CRC and correlates with a distinct cytokine profile related to key biological processes involved in carcinogenesis. A composite NLR-cytokine stratification has enhanced prognostic value in mCRC.
In the present study, fluid flow and heat transfer in microchannel heat sinks with different inlet/outlet locations (I, C and Z-type), header shapes (triangular, trapezoidal and rectangular) and ...microchannel cross-section shapes (the conventional rectangular microchannel, the microchannel with offset fan-shaped reentrant cavities and the microchannel with triangular reentrant cavities) are numerically studied with computational domain including the entire microchannel heat sink. Detailed three-dimensional numerical simulations are useful in identifying the optimal geometric parameters that provide better heat transfer and flow distribution in a microchannel heat sink. Results highlight that flow velocity uniformity is comparatively better for I-type and poor for Z-type. The flow distribution is found to be symmetrical for I-type. It is seen from the header shapes analysis that the rectangular header shapes provides better flow velocity uniformity than the trapezoidal and triangular headers. The fluid flow mechanism can be attributed to the interaction of the branching of fluid and the friction offered by the walls of the header. Effects of microchannel cross-section shapes emphasize that the microchannel with offset fan-shaped reentrant cavities and the microchannel with triangular reentrant cavities of the heat sinks enhance the heat transfer compared to the conventional rectangular microchannel. The heat transfer mechanism can be attributed to the jetting and throttling effect, the additional flow disturbance near the wall of the reentrant cavities and the form drag of the reentrant cavities. The heat sink C has better heat transfer characteristic for qv=150ml/min and is able to prolong the life of the microelectronic devices.
Recurrence of primary glomerulonephritis in the post-transplant period has been described in the literature but the risk remains poorly quantified and its impact on allograft outcomes and ...implications for subsequent transplants remain under-examined. Here we describe the rates and timing of post-transplant glomerulonephritis recurrence for IgA nephropathy, focal segmental glomerulosclerosis, mesangiocapillary GN and membranous GN based on 28 years of ANZDATA registry transplant data.
We investigated the rates of GN recurrence and subsequent graft outcomes in 7236 patient from 28 years of ANZDATA transplant registry data. Data were analysed in R, using Kaplan Meier Survival analysis and adjusted analyses performed using Cox Proportional Hazards methods. A competing risk model was also analysed.
GN recurrence occurred in 10.5% of transplants and was most common in mesangiocapillary GN. Median time to recurrence was shorter for FSGS compared to IGAN. GN recurrence was less common in patients over 50 years of age and after unrelated kidney donation. We identified a significantly higher risk of recurrence in secondary grafts following recurrence in a primary allograft for FSGS (RR 5.70, 95 CI: 2.41-13.5, p < 0.001) but not IGAN, MCGN or MN. At 10 years, recurrence occurs in 8.7, 10.8, 13.1, and 13.4% of allografts for FSGS, IGAN, MCGN and MN respectively. In all GN, recurrence significantly reduced death censored graft survival at 5 and 10 years.
GN recurrence occurs in a minority of patients at a significantly different rate for each GN. After a recurrence, there is no evidence for an increased risk of further recurrence in a subsequent graft except in FSGS.
Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and ...impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.
Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the ...efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC.
Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib 50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle). The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety.
A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028. The median PFS was 18.0 months in the toripalimab–axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab–axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab–axitinib group and 58.6% of patients in the sunitinib group.
In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile
ClinicalTrials.gov NCT04394975
•Toripalimab plus axitinib provided significantly better PFS than sunitinib as a first-line treatment for advanced RCC.•A significantly higher ORR was found in patients who received toripalimab plus axitinib than those who received sunitinib.•The combination of toripalimab plus axitinib was generally well tolerated.•No new safety signals were identified in the combination outside the known safety profile of toripalimab or axitinib.
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