Sustained complete response to first-line immunochemotherapy for highly aggressive TP53/MDM2-mutated upper tract urothelial carcinoma with ERBB2 mutations, luminal immune-infiltrated contexture, and non-mesenchymal state: a case report and literature review

BackgroundUpper tract urothelial carcinoma (UTUC) is a rare malignancy. The management of metastatic or unresectable UTUC is mainly based on evidence extrapolated from histologically homologous bladder cancer, including platinum-based chemotherapy and immune checkpoint inhibitor alone, whereas UTUC exhibits more invasiveness, worse prognosis, and comparatively inferior response to treatments. First-line immunochemotherapy regimens have been attempted in clinical trials for unselected naïve-treated cases, but their efficacies relative to standard chemo- or immuno-monotherapy still remain controversial. Here, we present a case of highly aggressive UTUC for whom comprehensive genetic and phenotypic signatures predicted sustained complete response to first-line immunochemotherapy.Case presentationA 50-year-old man received retroperitoneoscopic nephroureterectomy and regional lymphadenectomy for high-risk locally advanced UTUC. Postoperatively, he developed rapid progression of residual unresectable metastatic lymph nodes. Pathologic analysis and next-generation sequencing classified the tumor as highly aggressive TP53/MDM2-mutated subtype with features more than expression of programmed death ligand-1, including ERBB2 mutations, luminal immune-infiltrated contexture, and non-mesenchymal state. Immunochemotherapy combining gemcitabine, carboplatin, and off-label programmed death-1 inhibitor sintilimab was initiated, and sintilimab monotherapy was maintained up to 1 year. Retroperitoneal lymphatic metastases gradually regressed to complete response. Blood-based analyses were performed longitudinally for serum tumor markers, inflammatory parameters, peripheral immune cells, and circulating tumor DNA (ctDNA) profiling. The ctDNA kinetics of tumor mutation burden and mean variant allele frequency accurately predicted postoperative progression and sustained response to the following immunochemotherapy, which were mirrored by dynamic changes in abundances of ctDNA mutations from UTUC-typical variant genes. The patient remained free of recurrence or metastasis as of this publishing, over 2 years after the initial surgical treatment.ConclusionImmunochemotherapy may be a promising first-line option for advanced or metastatic UTUC selected with specific genomic or phenotypic signatures, and blood-based analyses incorporating ctDNA profiling provide precise longitudinal monitoring

Developing a class of dual atom materials for multifunctional catalytic reactions

Dual atom catalysts, bridging single atom and metal/alloy nanoparticle catalysts, offer more opportunities to enhance the kinetics and multifunctional performance of oxygen reduction/evolution and hydrogen evolution reactions. However, the rational design of efficient multifunctional dual atom catalysts remains a blind area and is challenging. In this study, we achieved controllable regulation from Co nanoparticles to CoN4 single atoms to Co2N5 dual atoms using an atomization and sintering strategy via an N-stripping and thermal-migrating process. More importantly, this strategy could be extended to the fabrication of 22 distinct dual atom catalysts. In particular, the Co2N5 dual atom with tailored spin states could achieve ideally balanced adsorption/desorption of intermediates, thus realizing superior multifunctional activity. In addition, it endows Zn-air batteries with long-term stability for 800 h, allows water splitting to continuously operate for 1000 h, and can enable solar-powered water splitting systems with uninterrupted large-scale hydrogen production throughout day and night. This universal and scalable strategy provides opportunities for the controlled design of efficient multifunctional dual atom catalysts in energy conversion technologies

The signs of computer tomography combined with artificial intelligence can indicate the correlation between status of consciousness and primary brainstem hemorrhage of patients

BackgroundFor patients of primary brainstem hemorrhage (PBH), it is crucial to find a method that can quickly and accurately predict the correlation between status of consciousness and PBH.ObjectiveTo analyze the value of computer tomography (CT) signs in combination with artificial intelligence (AI) technique in predicting the correlation between status of consciousness and PBH.MethodsA total of 120 patients with PBH were enrolled from August 2011 to March 2021 according to the criteria. Patients were divided into three groups [consciousness, minimally conscious state (MCS) and coma] based on the status of consciousness. Then, first, Mann–Whitney U test and Spearman rank correlation test were used on the factors: gender, age, stages of intracerebral hemorrhage, CT signs with AI or radiology physicians, hemorrhage involving the midbrain or ventricular system. We collected hemorrhage volumes and mean CT values with AI. Second, those significant factors were screened out by the Mann–Whitney U test and those highly or moderately correlated by Spearman’s rank correlation test, and a further ordinal multinomial logistic regression analysis was performed to find independent predictors of the status of consciousness. At last, receiver operating characteristic (ROC) curves were drawn to calculate the hemorrhage volume for predictively assessing the status of consciousness.ResultsPreliminary meaningful variables include hemorrhage involving the midbrain or ventricular system, hemorrhage volume, grade of hematoma shape and density, and CT value from Mann–Whitney U test and Spearman rank correlation test. It is further shown by ordinal multinomial logistic regression analysis that hemorrhage volume and hemorrhage involving the ventricular system are two major predictors of the status of consciousness. It showed from ROC that the hemorrhage volumes of <3.040 mL, 3.040 ~ 6.225 mL and >6.225 mL correspond to consciousness, MCS or coma, respectively. If the hemorrhage volume is the same, hemorrhage involving the ventricular system should be correlated with more severe disorders of consciousness (DOC).ConclusionCT signs combined with AI can predict the correlation between status of consciousness and PBH. Hemorrhage volume and hemorrhage involving the ventricular system are two independent factors, with hemorrhage volume in particular reaching quantitative predictions

The Effects of the Temperature and Termination(-O) on the Friction and Adhesion Properties of MXenes Using Molecular Dynamics Simulation

Two-dimensional transition metal carbides and nitrides (MXenes) are widely applied in the fields of electrochemistry, energy storage, electromagnetism, etc., due to their extremely excellent properties, including mechanical performance, thermal stability, photothermal conversion and abundant surface properties. Usually, the surfaces of the MXenes are terminated by –OH, –F, –O or other functional groups and these functional groups of MXenes are related surface properties and reported to affect the mechanical properties of MXenes. Thus, understanding the effects of surface terminal groups on the properties of MXenes is crucial for device fabrication as well as composite synthesis using MXenes. In this paper, using molecular dynamics (MD) simulation, we study the adhesion and friction properties of Ti2C and Ti2CO2, including the indentation strength, adhesion energy and dynamics of friction. Our indentation fracture simulation reveals that there are many unbroken bonds and large residual stresses due to the oxidation of oxygen atoms on the surface of Ti2CO2. By contrast, the cracks of Ti2C keep clean at all temperatures. In addition, we calculate the elastic constants of Ti2C and Ti2CO2 by the fitting force–displacement curves with elastic plate theory and demonstrate that the elastic module of Ti2CO2 is higher. Although the temperature had a significant effect on the indentation fracture process, it hardly influences maximum adhesion. The adhesion energies of Ti2C and Ti2CO2 were calculated to be 0.3 J/m2 and 0.5 J/m2 according to Maugis–Dugdale theory. In the friction simulation, the stick-slip atomic scale phenomenon is clearly observed. The friction force and roughness (Ra) of Ti2C and Ti2CO2 at different temperatures are analyzed. Our study provides a comprehensive insight into the mechanical behavior of nanoindentation and the surface properties of oxygen functionalized MXenes, and the results are beneficial for the further design of nanodevices and composites