Human NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavoenzyme expressed at high levels in multiple solid tumors, making it an attractive target for anticancer drugs. Bioactivatable drugs targeting NQO1, such as β-lapachone (β-lap), are currently in clinical trials for the treatment of cancer. β-Lap selectively kills NQO1-positive (NQO1⁺) cancer cells by inducing reactive oxygen species (ROS) via catalytic activation of NQO1. In this study, we demonstrated that cryptotanshinone (CTS), a naturally occurring compound, induces NQO1-dependent necrosis without affecting NQO1 activity. CTS selectively kills NQO1⁺ cancer cells by inducing NQO1-dependent necrosis. Interestingly, CTS directly binds to NQO1 but does not activate its catalytic activity. In addition, CTS enables activation of JNK1/2 and PARP, accumulation of iron and Ca²⁺, and depletion of ATP and NAD⁺. Furthermore, CTS selectively suppressed tumor growth in the NQO1⁺ xenograft models, which was reversed by NQO1 inhibitor and NQO1 shRNA. In conclusion, CTS induces NQO1-dependent necrosis via the JNK1/2/iron/PARP/NAD⁺/Ca²⁺ signaling pathway. This study demonstrates the non-enzymatic function of NQO1 in inducing cell death and provides new avenues for the design and development of NQO1-targeted anticancer drugs.

Background::Somatic copy number variations (SCNVs) in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma. However, whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia (ESCdys) is unknown. This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate (m/M) ESCdys. Methods::This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China (Ci County, Hebei Province; Yanting, Sichuan Province; Linzhou, Henan Province; Yangzhong, Jiangsu Province; and Feicheng, Shandong Province) from 2005 to 2019. Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients, and a quantitative polymerase chain reaction assay, P16-Light, was used to detect CDKN2A copy number. The cumulative regression and progression rates of ESCdys were evaluated using competing risk models. Results::A total of 205 patients with baseline m/M ESCdys were enrolled. The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts (18.8% [13/69] vs. 35.0% [28/80] vs. 51.8% [29/56], P <0.001). In the univariable competing risk analysis, the cumulative regression rate was statistically significantly lower ( P = 0.008), while the cumulative progression rate was higher ( P = 0.017) in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion. CDKN2A deletion was also an independent predictor of prognosis in ESCdys ( P = 0.004) in the multivariable analysis. Conclusion::The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.

Objective:To investigate the effect of Shenfu injection on serum pepsinogen (PG) Ⅰ, PG Ⅱ and gastrin 17 (G17) in sepsis patients with acute gastrointestinal injury (AGI).Methods:From June 2021 to December 2022, a single-center randomized controlled clinical study was conducted to select patients with sepsis complicated with acute gastrointestinal injury (AGI) admitted to the ICU of the Affiliated Hospital of Xuzhou Medical University. Patients were randomly (random number) divided into Shenfu group and control group. All patients were given routine treatment of sepsis according to the guidelines, including treatment of primary disease, fluid resuscitation and supportive management. The Shenfu group was treated with Shenfu injection at the same time as routine treatment. The gastrointestinal injury indicators (PGⅠ, PGⅡ, G17 and AGI grades) before treatment and on the 3rd and 7th days of treatment, and duration of mechanical ventilation and length of ICU stay of the two groups were recorded and compared.Results:A total of 89 sepsis patients with AGI were enrolled, including 44 patients in the Shenfu group and 45 patients in the control group. Before treatment, there was no statistically significant difference in serum PGⅠ, PGⅡ, and G17 between the two groups of patients (all P>0.05). On the 3rd day of treatment, the serum PGⅠ levels in the Shenfu group were significantly lower than the control group [(156.46±62.90) μg/L vs. (183.03±45.44) μg/L, P<0.05]. There was no statistically significant difference in serum PGⅡ and G17 levels between the two groups (both P>0.05). On the 7th day of treatment, the serum levels of PG I, PG II, and G17 in the Shenfu group were significantly lower than those in the control group [(107.97±23.18) μg/L vs. (154.78±33.11) μg/L, (10.73±5.62) μg/L vs. (13.83±6.30) μg/L, (7.31±3.20) pmol/L vs. (9.29±3.92) pmol/L, all P<0.05]. The AGI grading, duration of mechanical ventilation, and length of ICU stay in Shenfu group were significantly reduced than those in the control group (all P<0.05). Conclusion:Shenfu injection can improve the serum gastric function, lower AGI grading, reduce mechanical ventilation time, and the length of ICU stay in sepsis patients with AGI.

In order to guide clinical blood transfusion practices for pediatric patients, the National Health Commission has released the health standard "Guideline for pediatric transfusion" (WS/T 795-2022). Considering the physiological particularities of the neonatal period, blood transfusion practices for neonates are more complex than those for other children, the guidelines include a separate chapter dedicated to neonatal blood transfusion. This paper interprets the background and evidence for the compilation of the neonatal blood transfusion provisions, hoping to aid in the understanding and implementation of the neonatal blood transfusion section of the guidelines.
Humans ; Infant, Newborn ; Blood Transfusion/standards* ; Practice Guidelines as Topic

Nuclear receptor corepressor (NCoR1) interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids. An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development. In this study, we found that the deletion of NCoR1 in intestinal epithelial cells (IECs) mainly activated the nuclear receptor PPARα and attenuated metabolic syndrome by stimulating thermogenesis. The increase in brown adipose tissue thermogenesis was mediated by gut-derived tricarboxylic acid cycle intermediate succinate, whose production was significantly enhanced by PPARα activation in the fed state. Additionally, NCoR1 deletion derepressed intestinal LXR, increased cholesterol excretion, and impaired duodenal lipid absorption by decreasing bile acid hydrophobicity, thereby reversing the possible negative effects of intestinal PPARα activation. Therefore, the simultaneous regulatory effect of intestinal NCoR1 on both lipid intake and energy expenditure strongly suggests that it is a promising target for developing metabolic syndrome treatment.

Objective: To investigate the clinicopathological features, immunophenotype, and genetic alterations of rectal adenocarcinoma with enteroblastic differentiation. Methods: Four cases of rectal adenocarcinoma with enteroblastic differentiation were collected at the Affiliated Hospital of Qingdao University, Qingdao, China (three cases) and Yantai Yeda Hospital of Shandong Province, China (one case) from January to December 2022. Their clinical features were summarized. Hematoxylin and eosin stain and immunohistochemical stain were performed, while next-generation sequencing was performed to reveal the genetic alterations of these cases. Results: All four patients were male with a median age of 65.5 years. The clinical manifestations were changes of stool characteristics, bloody stools and weight loss. All cases showed mixed morphology composed of conventional adenocarcinoma and adenocarcinoma with enteroblastic differentiation. Most of the tumors consisted of glands with tubular and cribriform features. In one case, almost all tumor cells were arranged in papillary structures. The tumor cells with enteroblastic differentiation were columnar, with relatively distinct cell boundaries and characteristic abundant clear cytoplasm, forming fetal gut-like glands. Immunohistochemically, the tumor cells were positive for SALL4 (4/4), Glypican-3 (3/4) and AFP (1/4, focally positive), while p53 stain showed mutated type in 2 cases. The next-generation sequencing revealed that 2 cases had TP53 gene mutation and 1 case had KRAS gene mutation. Conclusions: Rectal adenocarcinoma with enteroblastic differentiation is rare. It shows embryonal differentiation in morphology and immunohistochemistry, and should be distinguished from conventional colorectal adenocarcinoma.
Humans ; Male ; Aged ; Female ; Biomarkers, Tumor/metabolism* ; Adenocarcinoma/pathology* ; Colorectal Neoplasms ; Rectal Neoplasms/genetics* ; Cell Differentiation

Humans ; Lung Neoplasms/pathology* ; Adenocarcinoma/pathology* ; Papilloma/genetics* ; Receptor, Fibroblast Growth Factor, Type 1/metabolism* ; Gene Amplification ; Carrier Proteins ; Cytoskeletal Proteins

Objective: To investigate the evolution and clinical significance of HER2 low expression status in HER2 negative patients in primary and recurrent/metastatic breast cancers. Methods: The data and archived sections of 259 breast cancer patients with recurrence/metastasis and HER2-negative primary foci were collected from January 2015 to January 2022 at the Fourth Hospital of Hebei Medical University, and the HER2 status of primary and recurrence/metastasis foci was determined by immunohistochemistry (IHC), among which IHC 2+patients were subject to fluorescence in situ hybridization (FISH). The HER2 status was classified as HER2-0 group; patients with IHC 1+, IHC 2+and no FISH amplification were classified as HER2 low expression group; and patients with IHC 3+, IHC 2+and FISH amplified were classified as HER2-positive group. The changes of HER2 status in patients with HER2 low expression in primary versus recurrent/metastatic breast cancer foci were compared, and their clinicopathologic characteristics and prognosis were analyzed. Results: The overall concordance rate between primary and recurrent/metastatic HER2 status in breast cancer was 60.6% (157/259, κ=0.178). A total of 102 patients (102/259, 39.4%) had inconsistent primary and recurrent/metastatic HER2 status; 37 patients (37/259, 14.3%) had HER2-0 at the primary foci and HER2-low expression at the recurrent/metastatic; and 56 patients (56/259, 21.6%) had HER2-low expression in the primary foci and HER2-0 in the recurrent/metastatic. The recurrent/metastatic foci became low-expressing compared with the recurrent/metastatic foci which remained HER2-0 patients, with longer overall survival time, higher ER and PR positivity, lower Ki-67 positivity index, and lower tumor histological grade; all with statistically significant differences (all P<0.05). In the primary HER2-low group, patients with recurrent/metastatic foci became HER2-0 while those with recurrent/metastatic foci remained low expression; there were no statistically significant differences in clinicopathological features and overall survival time (all P>0.05). Conclusions: Unstable HER2 status in patients with HER2-0 and low expression in primary versus recurrent/metastatic breast cancer foci, and HER2-0 in the primary foci but low HER2 expression status in recurrence/metastasis is associated with favourable prognosis, and testing HER2 status in recurrence/metastasis can provide more treatment options for such patients.
Humans ; Breast Neoplasms/genetics* ; Clinical Relevance ; In Situ Hybridization, Fluorescence ; Female

Humans ; B7-H1 Antigen ; Neoplasms/genetics*