Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

Objective:To explore the relationship between the length of cervical spinous process and cervical motion and affected segment of cervical spondylotic myelopathy(CSM).Methods:Retrospective analysis was performed on 375 patients who underwent cervical surgical treatment due to single-segment cervical spondylotic myelopathy from January 2015 to January 2019. There were 200 males and 175 females, aged 50.72±9.39 (range 40 to 60) years. Several parameters, including the sagittal diameter of vertebral body, the sagittal diameter of cervical canal, the length of cervical spinous process, C 3-C 7 lordotic angle, range of motion (ROM) at C 3-C 7 and segmental ROM were measured via preoperative plain radiographs. All parameters were tested via Shapiro-Wilk method. Pearson correlation analyses was used to quantify the relationship between the lengths of C 3-C 7 spinous process and segmental ROMs. Receiver operating characteristic (ROC) curve was mapped to obtain the cut-off points according to the length of cervical spinous process which had significant differences. Patients were divided into two groups based on the cut-off points. χ2 test and t test were used to exclude the interference of age, gender and other anatomical factors and compare the differences in the affected segment of cervical spondylotic myelopathy between groups, so as to analyze the relationship between the length of cervical spinous process and affected segment of cervical spondylotic myelopathy. Results:There were significant differences of C 6 spinous process 27.82±6.01 mm and significantly negative correlation between the length of C 6 spinous process and the ROM at C 6,7 segment ( r=-0.338, P<0.001), while no significant correlations were found in other segments. ROC curves were mapped to obtain the cut-off points, and the cut-off point was 0.76. Group I: the ratio of the length of spinous process of C 6/C 7 (C 6/C 7 ratio, range 0.49 to 1.01) under 0.76, Group II: C 6/C 7 ratio more than 0.76. Compared with patients with longer-type C 6 spinous process (C 6/C 7 ratio ≥0.76), patients with shorter-type C 6 spinous process (C 6/C 7 ratio <0.76) had significantly bigger ROM at C 6,7 segment (10.11° vs 7.10°, P<0.001) and higher incidence of C 6,7 spinal cord compression ( χ2=16.642, P<0.001, OR=2.521), while differences in age, sex, sagittal diameters of vertebral body and spinal canal between two groups were not significant. Conclusion:The length of C 6 spinous process was significantly correlated with ROM at C 6,7 segment and the incidence of C 6,7 degenerative myelopathy. The length of C 6 spinous process can be considered as a predictor of development of C 6,7 degenerative myelopathy.

With the number of cases of coronavirus disease-2019 (COVID-19) increasing rapidly, the World Health Organization (WHO) has recommended that patients with mild or moderate symptoms could be released from quarantine without nucleic acid retesting, and self-isolate in the community. This may pose a potential virus transmission risk. We aimed to develop a nomogram to predict the duration of viral shedding for individual COVID-19 patients. This retrospective multicentric study enrolled 135 patients as a training cohort and 102 patients as a validation cohort. Significant factors associated with the duration of viral shedding were identified by multivariate Cox modeling in the training cohort and combined to develop a nomogram to predict the probability of viral shedding at 9, 13, 17, and 21 d after admission. The nomogram was validated in the validation cohort and evaluated by concordance index (C-index), area under the curve (AUC), and calibration curve. A higher absolute lymphocyte count (
Aged ; Aged, 80 and over ; Antibodies, Viral/blood* ; Area Under Curve ; COVID-19/virology* ; Female ; Humans ; Lymphocyte Count ; Male ; Middle Aged ; Nomograms ; Proportional Hazards Models ; Retrospective Studies ; Viral Load ; Virus Shedding

To strengthen the quality control of palbociclib, three related substances were separated from the bulk drug. These substances were identified as 8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido ［2, 3-d］ pyrimidin-7(8H)-one(A), 8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridine-2-yl)amino)-6-vinylpyrido ［2, 3-d］ pyrimidin-7(8H)-one(B), tert-butyl4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido ［2, 3-d］ pyrimidin-2-yl)amino)pyridin-3-yl)piperazi-ne-1-carboxylate(C). Based on the structures of the impurities, the possible routes to them were discussed, and their structures were elucidated by 1H NMR and MS.

This study examined the ability of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (β-PGG) to induce the expression of heme oxygenase-1 (HO-1) in the PC12 cells and its regulation in the PC12 cells. One week before treatment with the drug, nerve growth factor (NGF) was added to the cultures at a final concentration of 50 ng/mL to induce neuronal differentiation. After drug treatment, HO-1 gene transcription was analyzed by reverse transcription polymerase chain reaction (RT-PCR). Expression of HO-1 and NF-E2-related factor2 (Nrf2) and activation of extracellular signal-regulated kinase (ERK) and Akt were detected by Western blotting. The viability of the PC12 cells treated with different medicines was examined by MTT assay. The oxidative stress in the PC12 cells was evaluated qualitatively and quantitatively by DCFH-DA. The results showed that β-PGG up-regulated HO-1 expression and this increased expression provided neuroprotection against MPP(+)-induced oxidative injury. Moreover, β-PGG induced Nrf2 nuclear translocation, which was found to be upstream of β-PGG-induced HO-1 expression, and the activation of ERK and Akt, a pathway that is involved in β-PGG-induced Nrf2 nuclear translocation, HO-1 expression and neuroprotection. In conclusion, β-PGG up-regulates HO-1 expression by stimulating Nrf2 nuclear translocation in an ERK- and Akt-dependent manner, and HO-1 expression by β-PGG may provide the PC12 cells with an acquired antioxidant defense capacity to survive the oxidative stress.
Animals ; Cell Death ; drug effects ; genetics ; Cell Line, Tumor ; Heme Oxygenase-1 ; genetics ; Hydrolyzable Tannins ; pharmacology ; MAP Kinase Signaling System ; drug effects ; genetics ; PC12 Cells ; Piperidines ; adverse effects ; Proto-Oncogene Proteins c-akt ; genetics ; Pyrazoles ; adverse effects ; Rats

This study examined the ability of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (β-PGG) to induce the expression of heme oxygenase-1 (HO-1) in the PC12 cells and its regulation in the PC12 cells. One week before treatment with the drug, nerve growth factor (NGF) was added to the cultures at a final concentration of 50 ng/mL to induce neuronal differentiation. After drug treatment, HO-1 gene transcription was analyzed by reverse transcription polymerase chain reaction (RT-PCR). Expression of HO-1 and NF-E2-related factor2 (Nrf2) and activation of extracellular signal-regulated kinase (ERK) and Akt were detected by Western blotting. The viability of the PC12 cells treated with different medicines was examined by MTT assay. The oxidative stress in the PC12 cells was evaluated qualitatively and quantitatively by DCFH-DA. The results showed that β-PGG up-regulated HO-1 expression and this increased expression provided neuroprotection against MPP(+)-induced oxidative injury. Moreover, β-PGG induced Nrf2 nuclear translocation, which was found to be upstream of β-PGG-induced HO-1 expression, and the activation of ERK and Akt, a pathway that is involved in β-PGG-induced Nrf2 nuclear translocation, HO-1 expression and neuroprotection. In conclusion, β-PGG up-regulates HO-1 expression by stimulating Nrf2 nuclear translocation in an ERK- and Akt-dependent manner, and HO-1 expression by β-PGG may provide the PC12 cells with an acquired antioxidant defense capacity to survive the oxidative stress.