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

An quantificational method for 51 pesticide residues determination in Pu'er tea by LC-MS/MS

Pesticide residues in tea is a major issue due to their widely used in tea cultivation. Thus, to protect consumers, an appropriate method for determination of their residues in tea should be done. In this study, a method for the simultaneous determination of 51 pesticides in tea was developed and validated. The tea sample was extracted by acetonitrile and purified SPE clearnet TPT column followed by liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) with multi-reaction monitoring (MRM) mode. The method was validated according to the linearity, limit of detention, precision, the percentage of recovery at three different spike levels. The linear concentration range used was 10-100ng/ mL, the square of Correlation coefficient r2 was more than >0.995. Recoveries were adequate being in the acceptable range of 72-89% and RSD of <19 % for all the analytes at three level of 0.01,0.05 and 0.11mg/kg, the LOD of all chemicals from 0.001 mg/kg to 0.01 mg/kg .The method was applied for the determination for 400 tea samples collected from Pu'er which contain green tea and black tea. Among the analyzed samples , 36 % samples had Imidacloprid and 25% sample contain Acetamiprid, which were at a level below the European Union maximum residue levels (EU-MRLs). The information would be beneficial for Pu'er tea exporters

Rasd1 aggravates white matter injury after subarachnoid hemorrhage in rats by promoting ferroptosis in oligodendrocytes

Objective To explore the underlying mechanism in which Ras related dexamethasone induced 1(Rasd1) is involved in white matter injury through neuron-oligodendrocyte communication after subarachnoid hemorrhage (SAH) in SD rats. Methods Ninety male SD rats (180~250 g) were randomly divided into sham operation group, SAH group, SAH+LV-NC group, SAH+LV-Rasd1 group and SAH+sh-Rasd1 group, with 12 rats in each group.Intravascular puncture was used to construct the rat model of SAH.Rasd1 overexpression/knockdown lentivirus was injected into the lateral ventricle.Neurobehavioral rating scale was used to observe the changes in neural function, transmission electron microscopy was employed to detect the myelin detachment in callosum region and the occurrence of ferroptosis in oligodendrocytes, and Prussian blue staining was applied to measure iron deposition.Malondialdehyde (MDA) and glutathione (GSH) contents were detected with corresponding reagent kits, Rasd1 mRNA level was detected by PCR, and protein levels of nuclear receptor coactivator 4(NCOA4), 2′, 3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase), glutathione peroxidase 4(GPX4) and ferritin were measured with Western blotting. Results SAH resulted in significantly highly expressed Rasd1, which was mainly distributed in the cortical neurons (P < 0.01), myelin loss, and ferroptosis in oligodendrocytes.Rasd1 overexpression significantly reduced the neurobehavioral scores, but increased myelin loss, ferroptosis and iron deposition in oligodendrocytes, elevated MDA content (P < 0.01) but decreased GSH content (P < 0.01), and up-regulation of NCOA4 expression (P < 0.01) and down-regulation of ferritin and GPX4(P < 0.01).However, Rasd1 knockdown reversed all above changes with statistical significances (all P < 0.01). Conclusion Rasd1 promotes ferroptosis in oligodendrocytes through ferritinophagy, and then is involved in white matter injury after SAH

Internal Stability Evaluation of Soils

Suffusion constitutes a major threat to the foundation of a dam, and the likelihood of suffusion is always determined by the internal stability of soils. It has been verified that internal stability is closely related to the grain size distribution (GSD) of soils. In this study, a numerical model is developed to simulate the suffusion process. The model takes the combined effects of GSD and porosity (n) into account, as well as Wilcock and Crowe&rsquo;s theory, which is also adopted to quantify the inception and transport of soils. This proposed model is validated with the experimental data and shows satisfactory performance in simulating the process of suffusion. By analyzing the simulation results of the model, the mechanism is disclosed on how soils with specific GSD behaving internally unstable. Moreover, the internal stability of soils can be evaluated through the model. Results show that it is able to distinguish the internal stability of 30 runs out of 36, indicating a 83.33% of accuracy, which is higher than the traditional GSD-based approaches

Numerical Study on Characteristics of Convection and Temperature Evolution in Microchannel of Thermal Flowmeter

During practical usage, thermal flowmeters have a limited range of applications. The present work investigates the factors influencing thermal flowmeter measurements and observes the effects of buoyancy convection and forced convection on the flow rate measurement sensitivity. The results show that the gravity level, inclination angle, channel height, mass flow rate, and heating power affect the flow rate measurements by influencing the flow pattern and the temperature distribution. Gravity determines the generation of convective cells, while the inclination angle affects the location of the convective cells. Channel height affects the flow pattern and temperature distribution. Higher sensitivity can be achieved with smaller mass flow rates or higher heating power. According to the combined influence of the aforementioned parameters, the present work investigates the flow transition based on the Reynolds number and the Grashof number. When the Reynolds number is below the critical value corresponding to the Grashof number, convective cells emerge and affect the accuracy of flowmeter measurements. The research on influencing factors and flow transition presented in this paper has potential implications for the design and manufacture of thermal flowmeters under different working conditions

A new style of rare metal granite with Nb-rich mica: The Early Cretaceous Huangshan rare-metal granite suite, northeast Jiangxi Province, southeast China

International audienc

Thioredoxin-Interacting Protein Mediates Apoptosis in Early Brain Injury after Subarachnoid Haemorrhage

Early brain injury (EBI) is considered to be the major factor associated with high morbidity and mortality after subarachnoid haemorrhage (SAH). Apoptosis is the major pathological mechanism of EBI, and its pathogenesis has not been fully clarified. Here, we report that thioredoxin-interacting protein (TXNIP), which is induced by protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK), participates in EBI by promoting apoptosis. By using adult male Sprague-Dawley rats to establish SAH models, as well as Terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining, immunofluorescence, and western blot, we found that TXNIP expression significantly increased after SAH in comparison to the sham group and peaked at 48 h (up to 3.2-fold). Meanwhile, TXNIP was widely expressed in neurons and colocalized with TUNEL-positive cells in the hippocampus and cortex of SAH rats. After administration of TXNIP inhibitor-resveratrol (60 mg/kg), TXNIP small interfering RNA (siRNA) and the PERK inhibitor GSK2656157, TXNIP expression was significantly reduced, accompanied by an attenuation of apoptosis and prognostic indicators, including SAH grade, neurological deficits, brain water content, and blood-brain barrier (BBB) permeability. Collectively, these results suggest that TXNIP may participate in EBI after SAH by mediating apoptosis. The blockage of TXNIP induced by PERK could be a potential therapeutic strategy for SAH treatment