Rethinking therapeutic strategies of dual-target drugs: An update on pharmacological small-molecule compounds in cancer.

Oncogenes and tumor suppressors are well-known to orchestrate several signaling cascades, regulate extracellular and intracellular stimuli, and ultimately control the fate of cancer cells. Accumulating evidence has recently revealed that perturbation of these key modulators by mutations or abnormal protein expressions are closely associated with drug resistance in cancer therapy; however, the inherent drug resistance or compensatory mechanism remains to be clarified for targeted drug discovery. Thus, dual-target drug development has been widely reported to be a promising therapeutic strategy for improving drug efficiency or overcoming resistance mechanisms. In this review, we provide an overview of the therapeutic strategies of dual-target drugs, especially focusing on pharmacological small-molecule compounds in cancer, including small molecules targeting mutation resistance, compensatory mechanisms, synthetic lethality, synergistic effects, and other new emerging strategies. Together, these therapeutic strategies of dual-target drugs would shed light on discovering more novel candidate small-molecule drugs for the future cancer treatment.

Discovery of a novel small-molecule activator of SIRT3 that inhibits cell proliferation and migration by apoptosis and autophagy-dependent cell death pathways in colorectal cancer.

Colorectal cancer (CRC) is well known as a prevalent malignancy affecting the digestive tract, yet its precise etiological determinants remain to be elusive. Accordingly, identifying specific molecular targets for colorectal cancer and predicting potential malignant tumor behavior are potential strategies for therapeutic interventions. Of note, apoptosis (type I programmed cell death) has been widely reported to play a pivotal role in tumorigenesis by exerting a suppressive effect on cancer development. Moreover, autophagy-dependent cell death (type II programmed cell death) has been implicated in different types of human cancers. Thus, investigating the molecular mechanisms underlying apoptosis and autophagy-dependent cell death is paramount in treatment modalities of colorectal cancer. In this study, we uncovered that a new small-molecule activator of SIRT3, named MY-13, triggered both autophagy-dependent cell death and apoptosis by modulating the SIRT3/Hsp90/AKT signaling pathway. Consequently, this compound inhibited tumor cell proliferation and migration in RKO and HCT-116 cell lines. Moreover, we further demonstrated that the small-molecule activator significantly suppressed tumor growth in vivo. In conclusion, these findings demonstrate that the novel small-molecule activator of SIRT3 may hold a therapeutic potential as a drug candidate in colorectal cancer.

Correlation between tumor budding and the long-term follow-up outcomes after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

BACKGROUND: The effect of tumor budding (TB) on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) after endoscopic submucosal dissection (ESD) remains unclear. We evaluated the long-term outcomes of patients with superficial ESCC after ESD and the risk factors of TB for the long-term prognosis. METHODS: We conducted a retrospective study in a Chinese hospital. All patients with ESCC treated by ESD and reported TB were included consecutively. Comparative analyses were conducted in three parts: specimen analysis, follow-up analyses of unmatched patients, and propensity score-matched (PSM) patients. Cox proportional hazard regression models were constructed to identify risk factors for overall survival and recurrence-free survival (RFS). RESULTS: A total of 437 patients were enrolled [154 TB and 283 no tumor budding (NTB)], and 258 patients (52 TB and 206 NTB) were included in the follow-up analysis. Results showed that the invasion depth, differentiation type, and positive vascular invasion (all p < 0.001) of the TB group were significantly different from the NTB group. The all-cause mortality and the median RFS time between the two groups were comparable. RFS rate at 5 years were 84.6% and 80.6%, respectively (p = 0.43). Cox analyses identified that having other cancers but not TB, as a risk factor independently associated with overall survival and RFS after ESD. CONCLUSION: TB tends to be associated with invasion depth, differentiation type, and positive vascular invasion. However, it might not affect the long-term outcomes of patients with superficial ESCC after ESD when other high-risk factors are negative.

A Review of Recent Advances in Chromatographic Quantification Methods for Cyanogenic Glycosides.

Cyanogenic glycosides are naturally occurring compounds found in numerous plant species, which can release toxic hydrogen cyanide upon hydrolysis. The quantification of cyanogenic glycosides is essential for assessing their potential toxicity and health risks associated with their consumption. Liquid chromatographic techniques coupled with various detectors have been widely used for the quantification of cyanogenic glycosides. In this review, we discuss recent advances in chromatographic quantification methods for cyanogenic glycosides, including the development of new stationary phases, innovative sample preparation methods, and the use of mass spectrometry. We also highlight the combination of chromatographic separation with mass spectrometric detection for the identification and quantification of specific cyanogenic glycosides and their metabolites in complex sample matrices. Lastly, we discuss the current challenges and future perspectives in the development of reliable reference standards, optimization of sample preparation methods, and establishment of robust quality control procedures. This review aims to provide an overview of recent advances in chromatographic quantification methods for cyanogenic glycosides and their applications in various matrices, including food products, biological fluids, and environmental samples.

Impact of Submucosal Saline Injection During Cold Snare Polypectomy for Colorectal Polyps Sized 3-9 mm: A Multicenter Randomized Controlled Trial.

INTRODUCTION: The role of submucosal injection during cold snare polypectomy (CSP) remains uncertain. In this study, we investigated the impact of submucosal saline injection during CSP for colorectal polyps sized 3-9 mm. METHODS: This was a multicenter randomized controlled trial conducted in 6 Chinese centers between July and September 2020 (ChiCTR2000034423). Patients with nonpedunculated colorectal polyps sized 3-9 mm were randomized in a 1:1 ratio to either CSP with submucosal injection (SI-CSP) or conventional CSP (C-CSP). The primary outcome was the incomplete resection rate (IRR). Secondary outcomes included procedure time, intraprocedural bleeding, delayed bleeding, and perforation. RESULTS: One hundred fifty patients with 234 polyps in the SI-CSP group and 150 patients with 216 polyps in the C-CSP group were included in the analysis. The IRR was not decreased in the SI-CSP group compared with that in the C-CSP group (1.7% vs 1.4%, P = 1.000). The median procedure time in the SI-CSP group was significantly longer than that in the C-CSP group (108 seconds vs 48 seconds, P < 0.001). The incidences of intraprocedural bleeding and delayed bleeding were not significantly different between the 2 groups ( P = 0.531 and P = 0.250, respectively). There was no perforation in either group. DISCUSSION: Submucosal saline injection during CSP for colorectal polyps sized 3-9 mm did not decrease the IRR or reduce adverse events but prolonged the procedure time.

Artificial intelligence for detecting and delineating the extent of superficial esophageal squamous cell carcinoma and precancerous lesions under narrow-band imaging (with video).

BACKGROUND AND AIMS: Although narrow-band imaging (NBI) is a useful modality for detecting and delineating esophageal squamous cell carcinoma (ESCC), there is a risk of incorrectly determining the margins of some lesions even with NBI. This study aimed to develop an artificial intelligence (AI) system for detecting superficial ESCC and precancerous lesions and delineating the extent of lesions under NBI. METHODS: Nonmagnified NBI images from 4 hospitals were collected and annotated. Internal and external image test datasets were used to evaluate the detection and delineation performance of the system. The delineation performance of the system was compared with that of endoscopists. Furthermore, the system was directly integrated into the endoscopy equipment, and its real-time diagnostic capability was prospectively estimated. RESULTS: The system was trained and tested using 10,047 still images and 140 videos from 1112 patients and 1183 lesions. In the image testing, the accuracy of the system in detecting lesions in internal and external tests was 92.4% and 89.9%, respectively. The accuracy of the system in delineating extents in internal and external tests was 88.9% and 87.0%, respectively. The delineation performance of the system was superior to that of junior endoscopists and similar to that of senior endoscopists. In the prospective clinical evaluation, the system exhibited satisfactory performance, with an accuracy of 91.4% in detecting lesions and an accuracy of 85.9% in delineating extents. CONCLUSIONS: The proposed AI system could accurately detect superficial ESCC and precancerous lesions and delineate the extent of lesions under NBI.

Discussion on the common controversies of Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori ( H. pylori ) can persistently colonize on the gastric mucosa after infection and cause gastritis, atrophy, metaplasia, and even gastric cancer (GC). METHODS: Therefore, the detection and eradication of H. pylori are the prerequisite. RESULTS: Clinically, there are some controversial issues, such as why H. pylori infection is persistent, why it translocases along with the lesser curvature of the stomach, why there is oxyntic antralization, what the immunological characteristic of gastric chronic inflammation caused by H. pylori is, whether H. pylori infection is associated with extra-gastric diseases, whether chronic atrophic gastritis (CAG) is reversible, and what the potential problems are after H. pylori eradication. What are the possible answers? CONCLUSION: In the review, we will discuss these issues from the attachment to eradication in detail.

Directionality in the interrelations between approximate number, verbal number, and mathematics in preschool-aged children.

A fundamental question in numerical development concerns the directional relation between an early-emerging non-verbal approximate number system (ANS) and culturally acquired verbal number and mathematics knowledge. Using path models on longitudinal data collected in preschool children (Mage  = 3.86 years; N = 216; 99 males; 80.8% White; 10.8% Multiracial, 3.8% Latino; 1.9% Black; collected 2013-2017) over 1 year, this study showed that earlier verbal number knowledge was associated with later ANS precision (average ß = .32), even after controlling for baseline differences in numerical, general cognitive, and language abilities. In contrast, earlier ANS precision was not associated with later verbal number knowledge (ß = -.07) or mathematics abilities (average ß = .10). These results suggest that learning about verbal numbers is associated with a sharpening of pre-existing non-verbal numerical abilities.

The developmental relationship between nonsymbolic and symbolic fraction abilities.

A fundamental research question in quantitative cognition concerns the developmental relationship between nonsymbolic and symbolic quantitative abilities. This study examined this developmental relationship in abilities to process nonsymbolic and symbolic fractions. There were 99 6th graders (Mage = 11.86 years), 101 10th graders (Mage = 15.71 years), and 102 undergraduate and graduate students (Mage = 21.97 years) participating in this study, and their nonsymbolic and symbolic fraction abilities were measured with nonsymbolic and symbolic fraction comparison tasks, respectively. Nonsymbolic and symbolic fraction abilities were significantly correlated in all age groups even after controlling for the ability to process nonsymbolic absolute quantity and general cognitive abilities, including working memory and inhibitory control. Moreover, the strength of nonsymbolic-symbolic correlations was higher in 6th graders than in 10th graders and adults. These findings suggest a weakened association between nonsymbolic and symbolic fraction abilities during development, and this developmental pattern may be related with participants' increasing proficiency in symbolic fractions.

Does auditory numerosity and non-numerical magnitude affect visual non-symbolic numerical representation?

In the present study, we investigated the effects of auditory numerosity and magnitude (loudness) on visual numerosity processing. Participants compared numerosities of two sequential dot arrays. The second dot array was paired with a tone array that was independent of visual comparison. The numerosity (One-tone vs. Multiple-tone) and the non-numerical magnitude of tones (loudness) were manipulated in Experiments 1 and 2, respectively. In Experiment 1, participants' inverse efficiency score (IES), that is, the quotient between response time and accuracy, was significantly smaller in the One-tone and Multiple-tone conditions than that in the No-tone condition, and linear trend analyses showed that the IES decreased with the number of tones. In Experiment 2, the IES in the Loud-tone condition was significantly smaller than that in the No-tone condition, and the IES decreased as the loudness of the tones increased. In Experiment 3, both auditory numerosity and magnitude were manipulated. For soft tones, the IES was smaller in the Multiple-tone condition than in the One-tone condition, whereas no significant difference was found between two conditions in loud tones. In sum, these findings suggest that the visual numerical representation can be spontaneously affected by the numerosity and non-numerical magnitude of stimuli from another modality.

Promoting condom negotiation self-efficacy among young women in China: the effects of traditional sexual values and descriptive norms.

This study attempts to design effective messages to promote condom negotiation self-efficacy and safer sex intent among young women in China. An online experiment with 2 (descriptive norm: present versus absent) × 2 (traditional sexual value: high versus low) between-subjects factorial design was conducted on a purposive sample of 241 female Chinese college students. The results demonstrated that culturally tailored messages incorporating descriptive norms information on the popularity of condom negotiation can increase participants' self-efficacy (F(1,237) = 9.01, partial η2 = 0.04, P = 0.003) but not safer sex intent (F(1,237) = 2.80, partial η2 = 0.01, P = 0.096). Participants with a lower level of traditional sexual values had similar levels of condom negotiation self-efficacy as those with a higher level of values: F(1,237) = 2.85, partial η2 = 0.01, P = 0.09. There were no significant interaction effects of traditional sexual value and descriptive norm on condom negotiation self-efficacy and safer sex intent. The findings contribute to the cultural sensitivity perspective in health education in an Eastern context and have implications for public health practitioners and policymakers.

East-west disparities in safer sex inside China: a sociocultural perspective.

BACKGROUND: This study responds to the increasing rate of HIV/AIDS and unplanned pregnancies among Chinese college students from a sociocultural perspective, and investigates the influences of sociocultural factors in shaping sex-related beliefs and acts among Chinese college students. METHODS: An online survey was conducted on a purposive sample of 1286 female college students in four cities in east and west China. RESULTS: Significant east-west disparities have emerged in the rate of sexual intercourse experience, rate of safer sex, conservative sexual values, authority sex education, unofficial sex knowledge access and HIV knowledge. A higher rate of sexual activity, but lower rate of safer sex, were found among the students in the west relative to those in the east. CONCLUSIONS: This study demonstrates that in a large country, such as China, regional disparities in economy, social development and sexual norms are salient to affect individuals' sexual behaviours.

Roles of lncRNAs in pancreatic ductal adenocarcinoma: Diagnosis, treatment, and the development of drug resistance.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, primarily due to its late diagnosis, high propensity to metastasis, and the development of resistance to chemo-/radiotherapy. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are intimately involved in the treatment resistance of pancreatic cancer cells via interacting with critical signaling pathways and may serve as potential diagnostic/prognostic markers or therapeutic targets in PDAC. DATA SOURCES: We carried out a systematic review on lncRNAs-based research in the context of pancreatic cancer and presented an overview of the updated information regarding the molecular mechanisms underlying lncRNAs-modulated pancreatic cancer progression and drug resistance, together with their potential value in diagnosis, prognosis, and treatment of PDAC. Literature mining was performed in PubMed with the following keywords: long non-coding RNA, pancreatic ductal adenocarcinoma, pancreatic cancer up to January 2022. Publications relevant to the roles of lncRNAs in diagnosis, prognosis, drug resistance, and therapy of PDAC were collected and systematically reviewed. RESULTS: LncRNAs, such as HOTAIR, HOTTIP, and PVT1, play essential roles in regulating pancreatic cancer cell proliferation, invasion, migration, and drug resistance, thus may serve as potential diagnostic/prognostic markers or therapeutic targets in PDAC. They participate in tumorigenesis mainly by targeting miRNAs, interacting with signaling molecules, and involving in the epithelial-mesenchymal transition process. CONCLUSIONS: The functional lncRNAs play essential roles in pancreatic cancer cell proliferation, invasion, migration, and drug resistance and have potential values in diagnosis, prognostic prediction, and treatment of PDAC.

Flubendazole Enhances the Inhibitory Effect of Paclitaxel via HIF1α/PI3K/AKT Signaling Pathways in Breast Cancer.

Paclitaxel, a natural anticancer drug, is widely recognized and extensively utilized in the treatment of breast cancer (BC). However, it may lead to certain side effects or drug resistance. Fortunately, combination therapy with another anti-tumor agent has been explored as an option to improve the efficacy of paclitaxel in the treatment of BC. Herein, we first evaluated the synergistic effects of paclitaxel and flubendazole through combination index (CI) calculations. Secondly, flubendazole was demonstrated to synergize paclitaxel-mediated BC cell killing in vitro and in vivo. Moreover, we discovered that flubendazole could reverse the drug resistance of paclitaxel-resistant BC cells. Mechanistically, flubendazole was demonstrated to enhance the inhibitory effect of paclitaxel via HIF1α/PI3K/AKT signaling pathways. Collectively, our findings demonstrate the effectiveness of flubendazole in combination with paclitaxel for treating BC, providing an insight into exploiting more novel combination therapies for BC in the future.

Are they equivalent? An examination of task variants of approximate number comparison.

Nonverbal numerical ability supports individuals' numerical information processing in everyday life and is also correlated with their learning of mathematics. This ability is typically measured with an approximate number comparison paradigm, in which participants are presented with two sets of objects and instructed to choose the numerically larger set. This paradigm has multiple task variants, where the two sets are presented in different ways (e.g., two sets are presented either simultaneously or sequentially, or two sets are presented either intermixed or separately). Despite the fact that different task variants have often been used interchangeably, it remains unclear whether these variants measure the same aspects of nonverbal numerical ability. Using a latent variable modeling approach with 270 participants (Mage = 20.75 years, SDage = 2.03, 94 males), this study examined the degree to which three commonly used task variants tapped into the same construct. The results showed that a bi-factor model corresponding to the hypothesis that task variants had both commonalities and uniqueness was a better fit for the data than a single-factor model, corresponding to the hypothesis that task variants were construct equivalent. These findings suggested that task variants of approximate number comparison did not measure the same construct and cannot be used interchangeably. This study also quantified the extent to which general cognitive abilities were involved in both common and unique parts of these task variants.

Linkage Microenvironment of Azoles-Related Covalent Organic Frameworks Precisely Regulates Photocatalytic Generation of Hydrogen Peroxide.

Artificial H2 O2 photosynthesis by covalent organic frameworks (COFs) photocatalysts is promising for wastewater treatment. The effect of linkage chemistry of COFs as functional basis to photoelectrochemical properties and photocatalysis remains a significant challenge. In this study, three kinds of azoles-linked COFs including thiazole-linked TZ-COF, oxazole-linked OZ-COF and imidazole-linked IZ-COF were successfully synthesized. More accessible channels of charge transfer were constructed in TZ-COF via the donor-π-acceptor structure between thiazole linkage and pyrene linker, leading to efficient suppression of photoexcited charge recombination. Density functional theory calculations support the experimental studies, demonstrating that the thiazole linkage is more favorable for the formation of *O2 intermediate in H2 O2 production than that of the oxazole and imidazole linkages. The real active sites in COFs located at the benzene ring fragment between pyrene unit and azole linkage.

Artificial intelligence for detecting superficial esophageal squamous cell carcinoma under multiple endoscopic imaging modalities: A multicenter study.

BACKGROUND AND AIM: Diagnosis of esophageal squamous cell carcinoma (ESCC) is complicated and requires substantial expertise and experience. This study aimed to develop an artificial intelligence (AI) system for detecting superficial ESCC under multiple endoscopic imaging modalities. METHODS: Endoscopic images were retrospectively collected from West China Hospital, Sichuan University as a training dataset and an independent internal validation dataset. Images from other four hospitals were used as an external validation dataset. The AI system was compared with 11 experienced endoscopists. Furthermore, videos were collected to assess the performance of the AI system. RESULTS: A total of 53 933 images from 2621 patients and 142 videos from 19 patients were used to develop and validate the AI system. In the internal and external validation datasets, the performance of the AI system under all or different endoscopic imaging modalities was satisfactory, with sensitivity of 92.5-99.7%, specificity of 78.5-89.0%, and area under the receiver operating characteristic curves of 0.906-0.989. The AI system achieved comparable performance with experienced endoscopists. Regarding superficial ESCC confined to the epithelium, the AI system was more sensitive than experienced endoscopists on white-light imaging (90.8% vs 82.5%, P = 0.022). Moreover, the AI system exhibited good performance in videos, with sensitivity of 89.5-100% and specificity of 73.7-89.5%. CONCLUSIONS: We developed an AI system that showed comparable performance with experienced endoscopists in detecting superficial ESCC under multiple endoscopic imaging modalities and might provide valuable support for inexperienced endoscopists, despite requiring further evaluation.

Artificial intelligence for diagnosing microvessels of precancerous lesions and superficial esophageal squamous cell carcinomas: a multicenter study.

BACKGROUND: Intrapapillary capillary loop (IPCL) is an important factor for predicting invasion depth of esophageal squamous cell carcinoma (ESCC). The invasion depth is closely related to the selection of treatment strategy. However, diagnosis of IPCLs is complicated and subject to interobserver variability. This study aimed to develop an artificial intelligence (AI) system to predict IPCLs subtypes of precancerous lesions and superficial ESCC. METHODS: Images of magnifying endoscopy with narrow band imaging from three hospitals were collected retrospectively. IPCLs subtypes were annotated on images by expert endoscopists according to Japanese Endoscopic Society classification. The performance of the AI system was evaluated using internal and external validation datasets (IVD and EVD) and compared with that of the 11 endoscopists. RESULTS: A total of 7094 images from 685 patients were used to train and validate the AI system. The combined accuracy of the AI system for diagnosing IPCLs subtypes in IVD and EVD was 91.3% and 89.8%, respectively. The AI system achieved better performance than endoscopists in predicting IPCLs subtypes and invasion depth. The ability of junior endoscopists to diagnose IPCLs subtypes (combined accuracy: 84.7% vs 78.2%, P < 0.0001) and invasion depth (combined accuracy: 74.4% vs 67.9%, P < 0.0001) were significantly improved with AI system assistance. Although there was no significant differences, the performance of senior endoscopists was slightly elevated. CONCLUSIONS: The proposed AI system could improve the diagnostic ability of endoscopists to predict IPCLs classification of precancerous lesions and superficial ESCC.

Safety and efficacy of common endoscopic treatments in patients with decompensated liver cirrhosis.

INTRODUCTION: The safety and efficacy have always been a concern, when patients with decompensated liver cirrhosis (DLC) receive endoscopic treatments. METHODS: To evaluate the safety and efficacy of common endoscopic treatments including endoscopic resection (ER) and endoscopic retrograde cholangiopancreatography (ERCP) applying to patients with DLC, we performed a retrospective study finally including 81 patients receiving ER (43 endoscopic mucosal resection (EMR) and 38 endoscopic submucosal dissection (ESD)) and 131 patients treated by ERCP. RESULTS: There were no significant differences in the rate of degeneration and invariability of Child-Pugh (CP) class and the overall rate of adverse events between two groups (93.8%/8.6% ER vs. 96.2%/15.3% ERCP). Both the degeneration rate of CP class (35.4%) and the rate of adverse events (27.1%) in subgroup CP class C of ERCP group were significantly higher (P=0). The rate of poor outcomes was higher in ERCP group (12.2%) than that in ER group (2.5%) (P=0.02). And subgroup CP class C of ERCP group had a higher poor outcome rate (27.1%) (P=0). CONCLUSION: ER and ERCP could remove focal lesions or relieve symptoms induced by targeted diseases without significant changes of CP class. Significant benefits and risks coexisted in CP class C patients with DLC when receiving ERCP.

Research Progress of H2S Donors Conjugate Drugs Based on ADTOH.

H2S is an endogenous gas signaling molecule and its multiple biological effects have been demonstrated. The abnormal level of H2S is closely related to the occurrence and development of many diseases, and H2S donors has important pharmacological implications. In recent years, H2S donors represented by ADTOH (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione) are often used to synthesize new 'conjugate' compounds that can release H2S and parent drugs. These hybrids retain the pharmacological activity of the parent drugs and H2S and have a synergistic effect. ADTOH and parent drug hybrids have become one of the important strategies for the development of H2S donor conjugate drugs. This review summarizes molecular hybrids between ADTOH and clinical drugs to provide new ideas for the study of H2S donor drug design.