Ladderphane copolymers for high-temperature capacitive energy storage.

For capacitive energy storage at elevated temperatures1-4, dielectric polymers are required to integrate low electrical conduction with high thermal conductivity. The coexistence of these seemingly contradictory properties remains a persistent challenge for existing polymers. We describe here a class of ladderphane copolymers exhibiting more than one order of magnitude lower electrical conductivity than the existing polymers at high electric fields and elevated temperatures. Consequently, the ladderphane copolymer possesses a discharged energy density of 5.34 J cm-3 with a charge-discharge efficiency of 90% at 200 °C, outperforming the existing dielectric polymers and composites. The ladderphane copolymers self-assemble into highly ordered arrays by π-π stacking interactions5,6, thus giving rise to an intrinsic through-plane thermal conductivity of 1.96 ± 0.06 W m-1 K-1. The high thermal conductivity of the copolymer film permits efficient Joule heat dissipation and, accordingly, excellent cyclic stability at elevated temperatures and high electric fields. The demonstration of the breakdown self-healing ability of the copolymer further suggests the promise of the ladderphane structures for high-energy-density polymer capacitors operating under extreme conditions.

Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.

GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential.

Comprehensive analysis of T-cell receptor repertoires reveals antigen-driven T-cell clusters in patients with Behçet's syndrome.

T lymphocytes are the major components of adaptive immunity in Behçet's syndrome (BS) pathology. However, the precise mechanism of T-cell-induced inflammatory condition remains to be determined. We applied bulk sequencing of the T-cell receptor (TCR) ß chain in peripheral blood samples from 45 patients with BS and 10 healthy donors as controls. TCR repertoires in BS patients displayed more clonality and less diversity than in healthy donors. Male patients exhibited lower diversity metrics of TCR and had a larger proportion in the top 10 clones than females (p = 0.016). There were no TCR clonality differences in other clinical features, such as age, disease duration, organ involvement, disease severity, and activity. By "Grouping of Lymphocyte Interactions by Paratope Hotspots" (GLIPH2) for antigen prediction, we found distinct 2477 clusters of TCR-ß sequences that potentially recognize similar antigens shared between BS patients. We observed clonal T-cell expansion in BS patients. Sexual differences in TCR clonal expansion and public TCR groups deserve further study to reveal the underline T-cell-mediated immunity in BS.

Stabilizing High-Valence Copper(I) Sites with Cu-Ni Interfaces Enhances Electroreduction of CO2 to C2+ Products.

In this study, the copper-nickel (Cu-Ni) bimetallic electrocatalysts for electrochemical CO2 reduction reaction(CO2RR) are fabricated by taking the finely designed poly(ionic liquids) (PIL) containing abundant Salen and imidazolium chelating sites as the surficial layer, wherein Cu-Ni, PIL-Cu and PIL-Ni interaction can be readily regulated by different synthetic scheme. As a proof of concept, Cu@Salen-PIL@Ni(NO3)2 and Cu@Salen-PIL(Ni) hybrids differ significantly in the types and distribution of Ni species and Cu species at the surface, thereby delivering distinct Cu-Ni cooperation fashion for the CO2RR. Remarkably, Cu@Salen-PIL@Ni(NO3)2 provides a C2+ faradaic efficiency (FEC2+) of 80.9% with partial current density (jC 2+) of 262.9 mA cm-2 at -0.80 V (versus reversible hydrogen electrode, RHE) in 1 m KOH in a flow cell, while Cu@Salen-PIL(Ni) delivers the optimal FEC2+ of 63.8% at jC2+ of 146.7 mA cm-2 at -0.78 V. Mechanistic studies indicates that the presence of Cu-Ni interfaces in Cu@Salen-PIL@Ni(NO3)2 accounts for the preserve of high-valence Cu(I) species under CO2RR conditions. It results in a high activity of both CO2-to-CO conversion and C-C coupling while inhibition of the competitive HER.

Mechanisms of Resistance to Tyrosine Kinase Inhibitors in ROS1 Fusion-Positive Nonsmall Cell Lung Cancer.

BACKGROUND: ROS1 fusion-positive (ROS1+) nonsmall cell lung cancer (NSCLC) patients are highly sensitive to tyrosine kinase inhibitor (TKI) treatments. However, acquired TKI resistance remains the major hurdle preventing patients from experiencing prolonged benefits. METHODS: 107 advanced or metastatic ROS1+ NSCLC patients who progressed on crizotinib and lorlatinib were recruited. Tissue and plasma samples were collected at baseline (N = 50), postcrizotinib (N = 91), and postlorlatinib (N = 21), which were all subject to the 139-gene targeted next-generation DNA sequencing. Molecular dynamics modeling was performed to investigate the effects of ROS1 mutations on binding to different TKIs. RESULTS: In patients with postcrizotinib and postlorlatinib samples, an accumulation of on- and off-target resistance alterations after multiple TKI treatments was observed. ROS1 G2032R and MET amplification were the most common on-target and off-target alterations, respectively. Patients with CD74-ROS1 and SLC34A2-ROS1 had longer progression-free survival (PFS) (P < 0.001) and higher rates of resistance mutations (on-target, P = 0.001; off-target, P = 0.077) than other ROS1 fusion variants following crizotinib treatment. Ten distinct on-target resistance mutations were detected after TKI therapies, of which 4 were previously unreported (ROS1 L2010M, G1957A, D1988N, L1982V). Molecular dynamics simulations showed that all 4 mutations were refractory to crizotinib, while G1957A, D1988N, and L1982V were potentially sensitive to lorlatinib and entrectinib. CONCLUSIONS: This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

Global burden of hip fracture: The Global Burden of Disease Study.

This study is the first to measure global burden of hip fracture in patients aged 55 years and older across 204 countries and territories from 1990 to 2019. Our study further proved that the global burden of hip fracture is still large. Hip fractures among males are perhaps underestimated, and older adults should be given more attention. PURPOSE: Hip fracture is a tremendous universal public health challenge, but no updated comprehensive and comparable assessment of hip fracture incidence and burden exists for most of the world in older adults. METHODS: Using data from the Global Burden of Diseases (GBD) 2019, we estimated the number and rates of the incidence, prevalence, and years lived with disability (YLD) of hip fracture across 204 countries and territories in patients aged 55 years and older from 1990 to 2019. RESULTS: In 2019, the incidence, prevalence, and YLDs rates of hip fracture in patients aged 55 years and older were 681.35 (95% UI 508.36-892.27) per 100000 population, 1191.39 (95% UI 1083.80-1301.52) per 100000 population, and 130.78 (95% UI 92.26-175.30) per 100000 population. During the three decades, the incidence among people aged below 60 years showed a downward trend, whereas it showed a rapid upward trend among older adults. All the numbers and rates of hip fractures among females were higher than those among males and increased with age, with the highest number and rate in the highest age group. Notably, the male to female ratio of the incidence for people aged over 55 years increased from 0.577 in 1990 to 0.612 in 2019. Falls were the leading cause among both sexes and in all age groups. CONCLUSIONS: The incidence and the number of hip fractures among patients aged 55 years and older increased over the past three decades, indicating that the global burden of hip fracture is still large. Hip fractures among males are perhaps underestimated, and older adults should be given more attention.

Phase unwrapping algorithm based on phase diversity wavefront reconstruction and virtual Hartmann-Shack technology.

Phase unwrapping (PU) algorithms play a crucial role in various phase measurement techniques. Traditional algorithms cannot work well in strong noise environments, which makes it very difficult to obtain the accurate absolute phase from the noisy wrapped phase. In this Letter, we introduce a novel, to the best of our knowledge, phase unwrapping algorithm named PD-VHS. This algorithm innovatively employs point spread function (PSF) filtering to eliminate noise from the wrapped phase. Furthermore, it combines a phase diversity (PD) wavefront reconstruction technology with a virtual Hartmann-Shack (VHS) technology for phase reconstruction and phase unwrapping of the filtered PSFs. In simulations, hundreds of random noise wrapped phases, containing the first 45 Zernike polynomials (excluding piston and the two tilt terms) and the wavefront RMS = 0.5λ and 1λ, are used to compare the classical quality-map guided algorithm, the VHS algorithm with decent noise immunity, with our PD-VHS algorithm. When signal-to-noise ratio (SNR) drops to just 2 dB, the mean root mean square errors (RMSEs) of the residual wavefront between the unwrapped result and the absolute phase of the quality-map guided algorithm and the VHS algorithm are up to 3.99λ, 0.44λ, 4.29λ, and 0.85λ, respectively; however, our algorithm RMSEs are low: 0.11λ and 0.17λ. Simulation results demonstrated that the PD-VHS algorithm significantly outperforms the quality-map guided algorithm and the VHS algorithm under large-scale noise conditions.

Analytical Impact-Excitation Theory of Er/O/B Codoped Si Light-Emitting Diodes.

Er doped Si light-emitting diodes may find important applications in silicon photonics and optical quantum computing. These diodes exhibit an emission efficiency 2 orders of magnitude higher at reverse bias than forward bias due to impact excitation. However, physics of impact excitation in these devices remains largely unexplored. In this work, we fabricated an Er/O/B codoped Si light-emitting diode which exhibits a strong electroluminescence by the impact excitation of electrons inelastically colliding the Er ions. An analytical impact-excitation theory was established to predict the electroluminescence intensity and internal quantum efficiency which fit well with the experimental data. From the fittings, we find that the excitable Er ions reach a record concentration of 1.8×10^{19} cm^{-3} and up to 45% of them is in an excitation state by impact excitation. This work has important implications for developing efficient classical and quantum light sources based on rare earth elements in semiconductors.

Early change of plasma Epstein-Barr virus DNA load and the viral lytic genome level could positively predict clinical outcome in recurrent or metastatic nasopharyngeal carcinoma receiving anti-programmed cell death 1 monotherapy.

PURPOSE: Patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) have proven benefit from anti-programmed cell death 1 (anti-PD-1) monotherapy. Here, we retrospectively analyze the association of plasma Epstein-Barr virus (EBV) DNA load and tumor viral lytic genome with clinical outcome from 2 registered phase I trials. METHODS: Patients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined "EBV response" as 3 consecutive timepoints of load below 50% of baseline, and "EBV progression" as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples. RESULTS: We found that the baseline EBV DNA load was positively correlated with tumor size (spearman p < 0.001). Both partial response (PR) and stable disease (SD) patients had significantly lower EBV load than progression disease (PD) patients. EBV assessment was highly consistent with radiographic evaluation. Patients with EBV response had significantly improved overall survival (OS) than patients with EBV progression (log-rank p = 0.004, HR = 0.351 [95% CI: 0.171-0.720], median 22.5 vs. 11.9 months). The median time to initial EBV response and progression were 25 and 36 days prior to initial radiographic response and progression, respectively. Patients with high levels of EBV lytic genomes at baseline, including BKRF2, BKRF3 and BKRF4, had better progression-free survival (PFS) and OS. CONCLUSION: In summary, early clearance of plasma EBV DNA load and high levels of lytic EBV genes were associated with better clinical outcome in patients with RM-NPC receiving anti-PD-1 monotherapy.

The long-term efficacy of eltrombopag in children with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is the most common autoimmune disorder characterized by decreased platelet counts and impaired platelet production. Eltrombopag has been demonstrated to be safe and effective for children with ITP. It is reported eltrombopag can achieve a sustained response off treatment. However, data on its overall efficacy and safety profile are scarce in children. This study aimed to investigate the long-term efficacy of eltrombopag in children with ITP. Treatment overall response (OR), complete response (CR), response (R), durable response (DR), no response (NR), treatment free remission (TFR), and relapse rate, were assessed in 103 children with ITP during eltrombopag therapy. The OR rate, CR rate, R rate, DR rate, NR rate, TFR rate, and relapse rate were 67.0%, 55.3%, 11.7%, 56.3%, 33.0%, 60%, 36.2%, respectively. Importantly, we discovered that newly diagnosed ITP patients showed a higher DR rate, TFR rate and lower relapse rate compared to persistent and chronic ITP patients. Furthermore, the CR rate, DR rate, and TFR rate of 5 patients under six months were 100%. None of them suffered relapse. The most common adverse event (AEs) was hepatotoxicity (7.77%). Our study highlighted the critical role of eltrombopag as the second-line treatment in children with ITP who were intolerant to first-line therapy.

Synthesis of 1-Benzyl-2,4-diarylimidazole through I2/CuI-Catalyzed Cyclization of Benzylamine and Hydrazone.

In this paper, we report an innovative method for synthesizing 1-benzyl-2,4-diarylimidazole utilizing 1-phenylethanone-2-(2-pyridinyl) hydrazine and benzylamine, catalyzed by an I2/CuI system. This approach represents a significant departure from traditional methods for synthesizing polysubstituted imidazoles; it employs the I2/CuI catalyst to replace rare metal catalysts, thereby achieving high yields of substitution products (≤85%). This method for the generation of 1,2,4-triimidazole derivatives is characterized by its exceptional chemical selectivity and extensive substrate compatibility.

Targeting PRSS23 with tipranavir induces gastric cancer stem cell apoptosis and inhibits growth of gastric cancer via the MKK3/p38 MAPK-IL24 pathway.

Gastric cancer stem cells (GCSCs) contribute to the refractory features of gastric cancer (GC) and are responsible for metastasis, relapse, and drug resistance. The key factors drive GCSC function and affect the clinical outcome of GC patients remain poorly understood. PRSS23 is a novel serine protease that is significantly up-regulated in several types of cancers and cancer stem cells, and related to tumor progression and drug resistance. In this study, we investigated the role of PRSS23 in GCSCs as well as the mechanism by which PRSS23 regulated the GCSC functions. We demonstrated that PRSS23 was critical for sustaining GCSC survival. By screening a collection of human immunodeficiency virus (HIV) protease inhibitors (PIs), we identified tipranavir as a PRSS23-targeting drug, which effectively killed both GCSC and GC cell lines (its IC50 values were 4.7 and 6.4 µM in GCSC1 cells and GCSC2 cells, respectively). Administration of tipranavir (25 mg·kg-1·d-1, i.p., for 8 days) in GCSC-derived xenograft mice markedly inhibited the growth of subcutaneous GCSC tumors without apparent toxicity. In contrast, combined treatment with 5-FU plus cisplatin did not affect the tumor growth but causing significant weight loss. Furthermore, we revealed that tipranavir induced GCSC cell apoptosis by suppressing PRSS23 expression, releasing MKK3 from the PRSS23/MKK3 complex to activate p38 MAPK, and thereby activating the IL24-mediated Bax/Bak mitochondrial apoptotic pathway. In addition, tipranavir was found to kill other types of cancer cell lines and drug-resistant cell lines. Collectively, this study demonstrates that by targeting both GCSCs and GC cells, tipranavir is a promising anti-cancer drug, and the clinical development of tipranavir or other drugs specifically targeting the PRSS23/MKK3/p38MAPK-IL24 mitochondrial apoptotic pathway may offer an effective approach to combat gastric and other cancers.

Multidimensional Cell-Free DNA Fragmentomic Assay for Detection of Early-Stage Lung Cancer.

Rationale: Cell-free DNA (cfDNA) analysis holds promise for early detection of lung cancer and benefits patients with higher survival. However, the detection sensitivity of previous cfDNA-based studies was still low to suffice for clinical use, especially for early-stage tumors. Objectives: Establish an accurate and affordable approach for early-stage lung cancer detection by integrating cfDNA fragmentomics and machine learning models. Methods: This study included 350 participants without cancer and 432 participants with cancer. The participants' plasma cfDNA samples were profiled by whole-genome sequencing. Multiple cfDNA features and machine learning models were compared in the training cohort to achieve an optimal model. Model performance was evaluated in three validation cohorts. Measurements and Main Results: A stacked ensemble model integrating five cfDNA features and five machine learning algorithms constructed in the training cohort (cancer: 113; healthy: 113) outperformed all the models built on individual feature-algorithm combinations. This integrated model yielded superior sensitivities of 91.4% at 95.7% specificity for cohort validation I (area under the curve [AUC], 0.984), 84.7% at 98.6% specificity for validation II (AUC, 0.987), and 92.5% at 94.2% specificity for additional validation (AUC, 0.974), respectively. The model's high performance remained consistent when sequencing depth was down to 0.5× (AUC, 0.966-0.971). Furthermore, our model is sensitive to identifying early pathological features (83.2% sensitivity for stage I, 85.0% sensitivity for <1 cm tumor at the 0.66 cutoff). Conclusions: We have established a stacked ensemble model using cfDNA fragmentomics features and achieved superior sensitivity for detecting early-stage lung cancer, which could promote early diagnosis and benefit more patients.

Effect of two different doses of nalbuphine for postoperative analgesia in children with cleft palate: a randomized controlled trial.

BACKGROUND: Cleft palate repair surgery may result in severe pain in the immediate postoperative period. The aim of this study is to compare the effects of different doses of nalbuphine for postoperative analgesia in children with cleft palate. METHODS: From November 2019 to June 2021, 90 children (45 males and 45 females, age 9-20 months old, ASA class I-II) were selected for palatoplasty. They were randomly divided into three groups: the control group (Group C), the N1 group (postoperative analgesia with 0.05 mg/kg/h nalbuphine) and the N2 group (postoperative analgesia with 0.075 mg/kg/h nalbuphine). Each group had 30 cases. Nalbuphine was not continuously infused in Group C but was continuously infused in Groups N1 and N2 at rates of 0.05 mg/kg/h and 0.075 mg/kg/h, respectively, for 24 h for postoperative analgesia. The FLACC analgesia score and Ramsay Sedation score were recorded at 10 min (T1), 30 min (T2), 2 h (T3), 12 h (T4) and 24 h (T5) after the operation. Adverse reactions such as nausea, vomiting and respiratory depression were observed and recorded. RESULTS: Compared with those in Group C, the FLACC scores in the N1 and N2 groups decreased significantly at T1-T5 (p < 0.05); the Ramsay Sedation score in the N1 group was significantly higher at T3 and T4 (p < 0.05), and that in the N2 group was significantly higher at T1-T5 (p < 0.05). Compared with that in the N1 group, the FLACC score in the N2 group was not significantly different, and the Ramsay Sedation score increased significantly at T5 (p < 0.05). CONCLUSION: Using 0.05 mg/kg/h Nalbuphine continuously for 24 h for postoperative analgesia in children with cleft palate has a better effect and fewer adverse reactions. TRIAL REGISTRATION: This study was registered at ChiCTR1900027385 (11/11/2019).

A prospective comparison of a modified miniaturised hand-held epifluorescence microscope and touch imprint cytology for evaluation of axillary sentinel lymph nodes intraoperatively in breast cancer patients.

BACKGROUND: The management of axillary lymph nodes in early-stage breast cancer patients has changed considerably, with the primary focus shifting from the examination of sentinel lymph nodes (SLNs) to toward the detection of all macro-metastases. However, current methods, such as touch imprint cytology (TIC) and frozen sections, are inadequate for clinical needs. To address this issue, we proposed a novel miniaturised epifluorescence widefield microscope (MEW-M) to assess SLN status intraoperatively for improved diagnostic efficiency. METHODS: A prospective, side-by-side comparison of intraoperative SLN evaluation between MEW-M and TIC was performed. RESULTS: A total of 73 patients with 319 SLNs consecutive enrolled in this study. MEW-M showed significantly superior image quality compared to TIC (median score 3.1 vs 2.1, p < 0.0001) and had a shorter time to issue results (10.3 vs 19.4 min, p < 0.0001). Likelihood ratio analysis illustrated that the positive likelihood ratio value of MEW-M compared with TIC was infinitely great vs 52.37 (95% CI, 21.96-124.90) in model 1 (classifying results into negative/positive), infinitely great vs 52.37 (95% CI, 21.96-124.90) in model 2 (classifying results into macro-metastasis/others, and TIC results followed the same classification as model 1), respectively. Similarly, the negative likelihood ratio values of MEW-M compared with TIC were 0.055 (95% CI, 0.018-0.160) and 0.074 (95% CI, 0.029-0.190) in model 1; and 0.019 (95% CI, 0.003-0.130) vs 0.020 (95% CI, 0.003-0.140) in model 2, respectively. CONCLUSIONS: MEW-M is a promising technique that can be utilised to provide a rapid and accurate intraoperative assessment of SLN in a clinical setting to help improve decision-making in axillary surgery.

Testing the generalizability of cfDNA fragmentomic features across different studies for cancer early detection.

cfDNA fragmentomic features have been used in cancer detection models; however, the generalizability of the models needs to be tested. We proposed a type of cfDNA fragmentomic feature named chromosomal arm-level fragment size distribution (ARM-FSD), evaluated and compared its performance and generalizability for lung cancer and pan-cancer detection with existing cfDNA fragmentomic features (as reference) by using cohorts from different institutions. The ARM-FSD lung cancer model outperformed the reference model by ∼10% when being tested by two external cohorts (AUC: 0.97 vs. 0.86; 0.87 vs. 0.76). For pan-cancer detection, the performance of the ARM-FSD based model is consistently higher than the reference (AUC: 0.88 vs. 0.75, 0.98 vs. 0.63) in a pan-cancer and a lung cancer external validation cohort, indicating that ARM-FSD model produces stable performance across multiple cohorts. Our study reveals ARM-FSD based models have a higher generalizability, and highlights the necessity of cross-study validation for predictive model development.

Cross-linked Sodium Hyaluronate Gel with PLLA-b-PEG Microsphere for Facial Contouring in Chinese: A Retrospective Study.

BACKGROUND: In Asia, the demand for cosmetic facial treatments has surged due to technological advancements, increased social acceptability, and affordability. Poly-L-lactic acid (PLLA) fillers, known for their biocompatibility and biodegradability, have emerged as a popular choice for facial contouring, yet studies specifically addressing their use in Asian populations are scarce. METHODS: This retrospective study examined 30 Chinese patients who underwent facial contouring with PLLA fillers, focusing on product composition, injection techniques, and safety measures. A comprehensive clinical evaluation was performed, including the Global Aesthetic Improvement Scale (GAIS) and Global Impression of Change Scale (GICS) for effectiveness and patient satisfaction, respectively. RESULTS: No significant difference in GAIS scores was observed between injectors and blinded evaluators over a 12-month period, indicating consistent effectiveness. Patient satisfaction remained high, with GICS scores reflecting positive outcomes. The safety profile was favorable, with no serious adverse events reported. The study highlighted the importance of anatomical knowledge to avoid complications, particularly in areas prone to blindness. CONCLUSIONS: PLLA fillers offer a safe, effective option for facial contour correction in the Asian population, achieving high patient satisfaction and maintaining results over time. The study underscores the need for tailored approaches in cosmetic procedures for Asians, considering their unique facial structures and aesthetic goals. Further research with larger, multicenter cohorts is recommended to validate these findings and explore long-term effects. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Identification of TCR rearrangements specific for genetic alterations in EGFR-mutated non-small cell lung cancer: results from the ADJUVANT-CTONG1104 trial.

Tumor response T cells, which have specific T cell receptor (TCR) rearrangements in tumor-infiltrating lymphocytes, determine their ability to interact with the mutation-derived neoantigens presented by antigen-presenting cells. Little is known about the genetic alterations related to specific TCR clones in non-small cell lung cancer (NSCLC) patients who have an epidermal growth factor receptor (EGFR) mutation. In this study, tumor tissues were collected from 101 patients with stage II/III resectable NSCLC with an EGFR mutation (57 patients were treated with gefitinib and 44 were treated with chemotherapy) in the ADJUVANT-CTONG1104 trial for high-throughput TCRß V region and exome sequencing. Ten clonal TCRs were associated with EGFR exon 19 deletion (del), EGFR exon 21 mutation (L858R), RB1 alteration, TP53 exon 4/5 missense mutation, TP53 nonsense mutation, or copy number gains in NKX2-1 and CDK4. Among the TCRs, there was frequent use of Vß20-1Jß2-3 specifically for EGFR exon 19 del or Vß9Jß2-1 specifically for EGFR exon 21 mutation (L858R), and these were significantly associated with favorable overall survival (OS) for NSCLC patients harboring EGFR exon 19 del or exon 21 L858R, particularly in the adjuvant gefitinib setting. Moreover, in comparison with the chemotherapy-preferable (CP) group, higher frequencies of Vß20-1Jß2-3 and Vß9Jß2-1 were found in the highly TKI-preferable (HTP) or TKI-preferable (TP) groups. Altogether, we identified ten TCR rearrangements specific for genetic alterations in NSCLC. Importantly, high abundance Vß20-1Jß2-3 or Vß9Jß2-1 may be an immune biomarker for guiding adjuvant gefitinib decisions for NSCLC patients harboring EGFR exon 19 del or EGFR exon 21 L858R.

Sn-Ag Synergistic Effect Enhances High-Rate Electrocatalytic CO2 -to-Formate Conversion on Porous Poly(Ionic Liquid) Support.

The electrocatalytic transformation of carbon dioxide (CO2 ) to formate is a promising route for highly efficient conversion and utilization of CO2 gas, due to the low production cost and the ease of storage of formate. In this work, porous poly(ionic liquid) (PPIL)-based tin-silver (Sn-Ag) bimetallic hybrids (PPILm -Snx Ag10- x ) are prepared for high-performance formate electrolytic generation. Under optimal conditions, an excellent formate Faradaic efficiency of 95.5% with a high partial current density of 214.9 mA cm-2 is obtained at -1.03 V (vs reversible hydrogen electrode). Meanwhile, the high selectivity of formate (>≈83%) is maintained in a wide potential range (>630 mV). Mechanistic studies demonstrate that the presence of Ag-species is vital for the formation, maintenance, and high dispersion of tetravalent Sn(IV)-species, which accounts for the active sites for CO2 -to-formate conversion. Further, the introduction of Ag-species significantly enhances the activity by increasing the electron density near the Fermi energy level.

Utility of Circulating Free DNA Fragmentomics in the Prediction of Pathological Response after Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

BACKGROUND: A "Watch and Wait" (W&W) approach has become an alternative to surgery for locally advanced rectal cancer (LARC) after neoadjuvant chemoradiotherapy (nCRT). Precise prediction of pathological complete response (pCR) will improve patient selection for W&W. We investigated the utility of cell-free DNA (cfDNA) fragmentomics in predicting pCR. METHODS: We recruited 119 LARC patients and evaluated nCRT response by pCR status and pathological or MRI tumor regression grade (mrTRG). Plasma samples before, during, and after nCRT were applied to deep targeted-panel sequencing, with 103 patients having complete samples. cfDNA fragment and 5'-end motif profiles were used to construct elastic-net logistic regression models to predict non-pCR. Predictive performance was measured by area under the receiver operator characteristic curve (AUC), sensitivity, and specificity. RESULTS: In the training cohort, the model based on 5'-end motif profile plus mrTRG achieved the highest cross-validation AUC (0.92, 95% CI, 0.91-0.93). The AUC in a testing cohort was 0.96 (95% CI, 0.90-1.00). The models based on 5'-end motif profile alone or in combination with mrTRG both maintained good predictive ability for patients without detectable circulating tumor DNA (AUC 0.94, 95% CI, 0.93-0.95; AUC 0.95, 95% CI, 0.94-0.96). In an external validation cohort, the model trained with a local 5'-end motif profile obtained an AUC of 0.878 (95% CI, 0.801-0.956) in discriminating colorectal cancer from healthy subjects. CONCLUSIONS: The combination of a 5'-end motif profile with mrTRG has the potential to predict the response to nCRT, and therefore may improve the patient selection for a W&W approach.