Structure-based classification predicts drug response in EGFR-mutant NSCLC.

Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)1-3. Targeted therapies are approved for patients with 'classical' mutations and a small number of other mutations4-6. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7-10. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.

Kinetically Controlled Synthesis of Quasi-Square CsPbI3 Nanoplatelets with Excellent Stability.

Nanoplatelets (NPLs) share excellent luminescent properties with their symmetric quantum dots counterparts and entail special characters benefiting from the shape, like the thickness-dependent bandgap and anisotropic luminescence. However, perovskite NPLs, especially those based on iodide, suffer from poor spectral and phase stability. Here, stable CsPbI3 NPLs obtained by accelerating the crystallization process in ambient-condition synthesis are reported. By this kinetic control, the rectangular NPLs into quasi-square NPLs are tuned, where enlarged width endows the NPLs with a lower surface-area-to-volume ratio (S/V ratio), leading to lower surficial energy and thus improved endurance against NPL fusion (cause for spectral shift or phase transformation). The accelerated crystallization, denoting the fast nucleation and short period of growth in this report, is enabled by preparing a precursor with complete transformation of PbI2 into intermediates (PbI3 -), through an additional iodide supplier (e.g., zinc iodide). The excellent color stability of the materials remains in the light-emitting diodes under various bias stresses.

Successful prediction of left bundle branch block-induced cardiomyopathy and treatment effect by artificial intelligence-enabled electrocardiogram.

BACKGROUND: Left bundle branch block (LBBB) induced cardiomyopathy is an increasingly recognized disease entity.  However, no clinical testing has been shown to be able to predict such an occurrence. CASE REPORT: A 70-year-old male with a prior history of LBBB with preserved ejection fraction (EF) and no other known cardiovascular conditions presented with presyncope, high-grade AV block, and heart failure with reduced EF (36%). His coronary angiogram was negative for any obstructive disease. No other known etiologies for cardiomyopathy were identified. Artificial intelligence-enabled ECGs performed 6 years prior to clinical presentation consistently predicted a high probability (up to 91%) of low EF. The patient successfully underwent left bundle branch area (LBBA) pacing with correction of the underlying LBBB. Subsequent AI ECGs showed a large drop in the probability of low EF immediately after LBBA pacing to 47% and then to 3% 2 months post procedure. His heart failure symptoms markedly improved and EF normalized to 54% at the same time. CONCLUSIONS: Artificial intelligence-enabled ECGS may help identify patients who are at risk of developing LBBB-induced cardiomyopathy and predict the response to LBBA pacing.

Successful cardiac resynchronization therapy by left bundle branch area pacing through a chronically occluded left subclavian system with limited vascular access preventing coronary sinus lead implant.

BACKGROUND: Conventional cardiac resynchronization therapy (CRT) involves implantation of a coronary sinus pacing lead through a delivery sheath, which typically requires a large venous access through a safe sheath of 9 French or greater in size. In patients who have very limited access due to scar tissue from previous implants or critical venous stenosis/closure, such large caliber access may not be available. METHODS AND RESULTS: We report a case of CRT procedure in an 84-year-old male with a previous history of ischemic dilated cardiomyopathy (ejection fraction 40%) who was dependent on right ventricular pacing with worsening heart failure symptoms. The patient was incidentally discovered to have chronic total closure (CTO) of the left subclavian vein during the procedure. Although the CTO was crossed by a wire and dilated, the venous access was limited to a 7 French sheath which rendered conventional CRT through coronary sinus lead implant impossible. However, using the left bundle branch area pacing (LBBAP) technique which requires a smaller venous access, we were able to successfully achieve CRT. Postprocedure, the patient's paced QRS duration narrowed from 198 to 130 ms. His heart failure symptoms improved, and ejection fraction increased to 45% one-month after the procedure. CONCLUSIONS: In patients with vascular access limited to a small caliber sheath not suitable for conventional CRT, LBBAP may help achieve procedural success and improve clinical outcome.

Left bundle branch area pacing too far away from the tricuspid annulus may cause pacing induced cardiomyopathy.

BACKGROUND: Physiologic pacing through left bundle branch area pacing (LBBAP) has recently been shown to be a very promising alternative for cardiac resynchronization therapy (CRT) and to avoid pacing induced cardiomyopathy. However, it is not clear whether the position of LABBP lead may affect the clinical outcomes. CASE REPORT: We here report a case of likely LBBAP induced worsening heart failure and cardiomyopathy reversed by re-positioning of the pacing lead towards a more annular position. A 70-year-old male with a previous history of non-ischemic dilated cardiomyopathy (ejection fraction 40%) who developed intermittent complete heart block and required permanent ventricular pacing. LBBAP was performed with the lead positioned to a position relatively far away from the tricuspid annulus (3.7 cm), due to difficulty in fixating the lead deep into the septum at a more annular position. One month post procedure, the patient's heart failure symptoms worsened, and his EF decreased to 31% despite good heart failure management. He underwent CRT upgrade with successful revision of the originally implanted LBBAP lead to a more annular position, using a deflectable delivery sheath. This resulted in further narrowing of the paced QRS duration from 135 to 106 ms. Two months post procedure, his heart failure symptoms improved by one functional class, and EF improved to 41% by echocardiogram. CONCLUSIONS: LBBAP may be harmful when the lead is placed too far away from the annulus and may cause paced induced cardiomyopathy.

Aging-associated susceptibility to stress-induced ventricular arrhythmogenesis is attenuated by tetrodotoxin.

Aging is associated with increased prevalence of life-threatening ventricular arrhythmias, but mechanisms underlying higher susceptibility to arrhythmogenesis and means to prevent such arrhythmias under stress are not fully defined. We aimed to define differences in aging-associated susceptibility to ventricular fibrillation (VF) induction between young and aged hearts. VF induction was attempted in isolated perfused hearts of young (6-month) and aged (24-month-old) male Fischer-344 rats by rapid pacing before and following isoproterenol (1 µM) or global ischemia and reperfusion (I/R) injury with or without pretreatment with low-dose tetrodotoxin, a late sodium current blocker. At baseline, VF could not be induced; however, the susceptibility to inducible VF after isoproterenol and spontaneous VF following I/R was 6-fold and 3-fold higher, respectively, in old hearts (P < 0.05). Old animals had longer epicardial monophasic action potential at 90% repolarization (APD90; P < 0.05) and displayed a loss of isoproterenol-induced shortening of APD90 present in the young. In isolated ventricular cardiomyocytes from older but not younger animals, 4-aminopyridine prolonged APD and induced early afterdepolarizations (EADs) and triggered activity with isoproterenol. Low-dose tetrodotoxin (0.5 µM) significantly shortened APD without altering action potential upstroke and prevented 4-aminopyridine-mediated APD prolongation, EADs, and triggered activity. Tetrodotoxin pretreatment prevented VF induction by pacing in isoproterenol-challenged hearts. Vulnerability to VF following I/R or catecholamine challenge is significantly increased in old hearts that display reduced repolarization reserve and increased propensity to EADs, triggered activity, and ventricular arrhythmogenesis that can be suppressed by low-dose tetrodotoxin, suggesting a role of slow sodium current in promoting arrhythmogenesis with aging.

Metal halide perovskites for light-emitting diodes.

Metal halide perovskites have shown promising optoelectronic properties suitable for light-emitting applications. The development of perovskite light-emitting diodes (PeLEDs) has progressed rapidly over the past several years, reaching high external quantum efficiencies of over 20%. In this Review, we focus on the key requirements for high-performance PeLEDs, highlight recent advances on materials and devices, and emphasize the importance of reliable characterization of PeLEDs. We discuss possible approaches to improve the performance of blue and red PeLEDs, increase the long-term operational stability and reduce toxicity hazards. We also provide an overview of the application space made possible by recent developments in high-efficiency PeLEDs.

Research on Non-Pooling YOLOv5 Based Algorithm for the Recognition of Randomly Distributed Multiple Types of Parts.

Part cleaning is very important for the assembly of precision machinery. After cleaning, the parts are randomly distributed in the collection area, which makes it difficult for a robot to collect them. Common robots can only collect parts located in relatively fixed positions, and it is difficult to adapt these robots to collect at randomly distributed positions. Therefore, a rapid part classification method based on a non-pooling YOLOv5 network for the recognition of randomly distributed multiple types of parts is proposed in this paper; this method classifies parts from their two-dimensional images obtained using industrial cameras. We compared the traditional and non-pooling YOLOv5 networks under different activation functions. Experimental results showed that the non-pooling YOLOv5 network improved part recognition precision by 8% and part recall rate by 3% within 100 epochs of training, which helped improve the part classification efficiency. The experiment showed that the non-pooling YOLOv5 network exhibited improved classification of industrial parts compared to the traditional YOLOv5 network.

Peripheral blood mononuclear cell microRNA profiles in syphilitic patients with serofast status.

Syphilis is a chronic sexually transmitted disease caused by infection with Treponema pallidum, which can invade various system organs, leading to clinical manifestations such as neurosyphilis, ocular syphilis, and cardiovascular syphilis and seriously endangering human health. Serofast status is a common outcome after syphilis treatment that presents an important clinical problem. At present, the etiology of serofast status remains unknown. A systematic investigation of the microRNA (miRNA) expression profiles in peripheral blood mononuclear cells (PBMCs) of patients with serofast status or secondary syphilis and of healthy control subjects was conducted using small RNA-seq. The expression of miRNAs was further confirmed by real-time fluorescence quantitative PCR (qPCR) assays. The data reveal a specific miRNA expression profile that was displayed in cells from patients with serofast status. Known and novel predicted (np)-miRNAs were also identified and verified, such as miR-338-5p, np-miR-163, np-miR-128, np-miR-244, and np-miR-5, which together may be used as indicators for treatment evaluation. The functions of genes targeted by the miRNAs differentially expressed in serofast status patients were further analyzed; these genes were found to be involved in various biological functions, such as T-cell receptor signaling pathways, metabolism, and growth. Our study presents the first systematic landscape of miRNAs in PBMCs from patients with serofast status and proposes specific miRNAs linked with serofast status. Our results provide further evidence that serofast status is closely related to host immune function. Additionally, the miRNA expression profile in PBMCs of patients with serofast status generated by this work offers insight into the complex immune network in humans. We hope our results can provide new insights into the pathogenesis of serofast status.

Efficient and Tunable Electroluminescence from In Situ Synthesized Perovskite Quantum Dots.

Semiconductor quantum dots (QDs) are among the most promising next-generation optoelectronic materials. QDs are generally obtained through either epitaxial or colloidal growth and carry the promise for solution-processed high-performance optoelectronic devices such as light-emitting diodes (LEDs), solar cells, etc. Herein, a straightforward approach to synthesize perovskite QDs and demonstrate their applications in efficient LEDs is reported. The perovskite QDs with controllable crystal sizes and properties are in situ synthesized through one-step spin-coating from perovskite precursor solutions followed by thermal annealing. These perovskite QDs feature size-dependent quantum confinement effect (with readily tunable emissions) and radiative monomolecular recombination. Despite the substantial structural inhomogeneity, the in situ generated perovskite QDs films emit narrow-bandwidth emission and high color stability due to efficient energy transfer between nanostructures that sweeps away the unfavorable disorder effects. Based on these materials, efficient LEDs with external quantum efficiencies up to 11.0% are realized. This makes the technologically appealing in situ approach promising for further development of state-of-the-art LED systems and other optoelectronic devices.

Design rules for minimizing voltage losses in high-efficiency organic solar cells.

The open-circuit voltage of organic solar cells is usually lower than the values achieved in inorganic or perovskite photovoltaic devices with comparable bandgaps. Energy losses during charge separation at the donor-acceptor interface and non-radiative recombination are among the main causes of such voltage losses. Here we combine spectroscopic and quantum-chemistry approaches to identify key rules for minimizing voltage losses: (1) a low energy offset between donor and acceptor molecular states and (2) high photoluminescence yield of the low-gap material in the blend. Following these rules, we present a range of existing and new donor-acceptor systems that combine efficient photocurrent generation with electroluminescence yield up to 0.03%, leading to non-radiative voltage losses as small as 0.21 V. This study provides a rationale to explain and further improve the performance of recently demonstrated high-open-circuit-voltage organic solar cells.

Intrahepatic T-Cell Receptor ß Immune Repertoire Is Essential for Liver Regeneration.

T lymphocytes synergize with the cellular immune system to promote hepatocyte regeneration. The T-cell receptor (TCR) immune repertoire is closely associated with the host immune response and regenerative proliferation. High-throughput sequencing of TCR provides deep insight into monitoring the immune microenvironment. Here, we aimed to determine the role of the TCRß immune repertoire in liver regeneration (LR). We investigated hepatic regeneration in TCRß chain-deficient (tcrb-/- ) mice by two-thirds partial hepatectomy (PHx) method. Our results demonstrated that tcrb-/- mice revealed a reduced capacity for LR, which was characterized by impaired hepatocyte proliferation and enhanced hepatocyte apoptosis. Dysregulation of inflammatory signaling activation and inflammatory factors was observed in regenerated tcrb-/- livers. Simultaneously, significantly altered immunocyte levels and aberrant cytokine levels were observed during hepatic regeneration. In addition, we first determined the profile of the TCRß immune repertoire during LR, indicating that PHx resulted in remarkably lower TCRß diversity in intrahepatic T lymphocytes. Conclusion: Taken together, our data suggest that TCRß deficiency gives a rise to aberrant intrahepatic immune microenvironment that impairs LR, and the TCRß reconstitution is required for hepatic immunocyte recruitment and activation during LR.

Serological response to therapy following retreatment of serofast early syphilis patients with benzathine penicillin.

Background: Some syphilitic patients remain in a serologically positive state after the recommended therapy. Although we often retreat patients in clinical practice, the optimal treatment protocol remains uncertain due to the paucity of data regarding serological response to retreatment and long-term outcomes. Methods: We examined rapid plasma reagin serological test results of 70 serofast early syphilis cases who were retreated with 2.4 million units of benzathine penicillin weekly for 3 weeks. Serological retreatment success was defined as a minimum 4-fold decrease in baseline rapid plasma reagin test antibody titre within 6 months. Results: Thirty-four (48.6%) of the patients who failed to achieve serological cure at 6 months after initial therapy achieved serological cure at 12 months. Patients who had higher non-treponemal titres at baseline and at 6 months were more likely to exhibit serological cure after retreatment than those with lower titres. Conclusions: Our results suggest that the incremental benefit of retreating serofast patients with early syphilis is moderate, considering the almost 1:1 ratio of serological response to serofast state at follow-up.

Outcomes of 200 consecutive, fluoroless atrial fibrillation ablations using a new technique.

INTRODUCTION: A technique was developed to eliminate radiation exposure for routine atrial fibrillation (AF) ablation, to simplify the procedure and to achieve cost effectiveness. We here report the outcomes of this approach. METHODS: Two hundred consecutive AF ablations (55% paroxysmal) were performed by a single operator. Pulmonary vein isolation (PVI) was achieved by antral ablation without left atrial anatomic mapping, guided by contact force sensing and intracardiac echocardiogram (ICE). All ablations were performed using three ipsilateral 8 French catheters (ICE, Lasso, and ablation). Eighty-two percent of the patients underwent ablation of atrial flutter or non-pulmonary vein triggers. All patients underwent provocative testing after PVI. RESULTS: No fluoroscopy was used for the entire study. Two ablations were performed without x-ray available due to unexpected equipment failure. The mean procedure time was 90.3 ± 17.7 (minutes) in patients who only required PVI and 106.2 ± 23.2 (minutes) for the entire cohort, with a success rate of 76% (mean follow-up of 11 months). In contrast, the procedure time and success rate were 127.9 ± 38.2 (minutes) (P < 0.01) and 74%, respectively, for the last 50 standard ablations guided by fluoroscopy (without contact force sensing). Complications included one case of partial right phrenic nerve palsy and one case of right femoral artery pesudoaneurysm. Compared to our previous ablation approaches, the new method resulted in catheter savings of $2,168-$4,568/case. CONCLUSION: The new technique eliminated radiation exposure and shortened the procedure time without significant negative impact on safety or success rate. Substantial cost savings were also achieved by using a minimal number of mostly reprocessed catheters.

Functional Pyrimidine-Based Thermally Activated Delay Fluorescence Emitters: Photophysics, Mechanochromism, and Fabrication of Organic Light-Emitting Diodes.

A new series of molecules, T1-T4, possessing thermally activated delayed fluorescence (TADF) have been strategically designed and synthesized. Molecules T1-T4 contain the dimethyl acridine as the electron donor, which is linked to either symmetrical or unsymmetrical diphenyl pyrimidine as an acceptor. In comparison to the ubiquitous triazine acceptor, the selection of pyrimidine as an acceptor has advantages of facile functionalization and less stabilized unoccupied π orbitals, so that the energy gap toward the blue region can be accessed. Together with acridine donors, the resulting donor-acceptor functional materials reveal remarkable TADF properties. In the solid state, molecules T1-T4 all exhibit intriguing mechanochromism. The crystal structures, together with spectroscopy and dynamics acquired upon application of stressing, lead us to propose two types of structural arrangement that give distinct emission properties, one with and the other without TADF. Upon fabricating organic light-emitting diodes, the T1-T4 films prepared from sublimation all exhibit dominant TADF behavior; this accounts for their high performance: an electroluminescent emission at λ=490 nm, with an external quantum efficiency of 14.2 %, can be attained when T2 is used as an emitter.

EML4-ALK induces epithelial-mesenchymal transition consistent with cancer stem cell properties in H1299 non-small cell lung cancer cells.

The echinoderm microtubule-associated protein-like 4(EML4)--anaplastic lymphoma kinase (ALK) fusion gene has been identified as a driver mutation in non-small-cell lung cancer (NSCLC). However, the role of EML4-ALK in malignant transformation is not entirely clear. Here, for the first time, we showed that H1299 NSCLC cells stably expressing EML4-ALK acquire EMT phenotype, associated with enhanced invasive migration and increased expression of EMT-inducing transcription factors. H1299-EML4-ALK cells also displayed cancer stem cell-like properties with a concomitant up-regulation of CD133 and enhanced ability of mammospheres formation. Moreover, we found that inhibition of ERK1/2 reversed EMT induced by EML4-ALK in H1299 cells. Taken together, these results suggested that EML4-ALK induced ERK activation is mechanistically associated with EMT phenotype. Thus, inhibition of ERK signaling pathway could be a potential strategy in treatment of NSCLC patients with EML4-ALK translocation.

[REGgamma promotes malignant behaviors of lung cancer cells].

OBJECTIVE: To determine the expression of proteasome aotivator gamma (REGgamma) in human lung cancer tissues and cell lines and its association with malignant biological behaviors. METHODS: Immunohistochemistry (IHC) was used to detect the expression of REGgamma in lung cancer and normal lung tissues. The expressions of REGgamma in lung cancer cells and normal epithelial cells were determined by Western blot. The H1975 lung cancer stable cell lines with different levels of REGgamma expression were constructed and their proliferations were evaluated by MTT assay. PI staining was used to assess the influence of REGgamma on cell growth cycle. The effect of REGgamma on the migration of lung cancer cells were observed with the cell scratch experiment. RESULTS: Lung cancer tissues had significantly higher levels of REGgamma expression than normal tissues. Similarly, lung cancer cell lines showed higher levels of REGgamma expression than the normal epithelial cell line. The overexpression of REGgamma enhanced cancer cell proliferations (P < 0.05), promoted more cells into the S+G2/M phase (P < 0.05) and promoted the migration of cancer cells (P < 0.05). All of these effects were reversed after suppression of REGgamma. CONCLUSION: REGgamma facilitates malignant biological behaviors of lung cancers.

Stratifying heart failure patients with graph neural network and transformer using Electronic Health Records to optimize drug response prediction.

OBJECTIVES: Heart failure (HF) impacts millions of patients worldwide, yet the variability in treatment responses remains a major challenge for healthcare professionals. The current treatment strategies, largely derived from population based evidence, often fail to consider the unique characteristics of individual patients, resulting in suboptimal outcomes. This study aims to develop computational models that are patient-specific in predicting treatment outcomes, by utilizing a large Electronic Health Records (EHR) database. The goal is to improve drug response predictions by identifying specific HF patient subgroups that are likely to benefit from existing HF medications. MATERIALS AND METHODS: A novel, graph-based model capable of predicting treatment responses, combining Graph Neural Network and Transformer was developed. This method differs from conventional approaches by transforming a patient's EHR data into a graph structure. By defining patient subgroups based on this representation via K-Means Clustering, we were able to enhance the performance of drug response predictions. RESULTS: Leveraging EHR data from 11 627 Mayo Clinic HF patients, our model significantly outperformed traditional models in predicting drug response using NT-proBNP as a HF biomarker across five medication categories (best RMSE of 0.0043). Four distinct patient subgroups were identified with differential characteristics and outcomes, demonstrating superior predictive capabilities over existing HF subtypes (best mean RMSE of 0.0032). DISCUSSION: These results highlight the power of graph-based modeling of EHR in improving HF treatment strategies. The stratification of patients sheds light on particular patient segments that could benefit more significantly from tailored response predictions. CONCLUSIONS: Longitudinal EHR data have the potential to enhance personalized prognostic predictions through the application of graph-based AI techniques.