Search

As a vital target for the development of novel anti-cancer drugs, human concentrative nucleoside transporter 3 (hCNT3) has been widely concerned. Nevertheless, the lack of a comprehensive understanding of molecular interactions and motion mechanism has greatly hindered the development of novel inhibitors against hCNT3. In this paper, molecular recognition of hCNT3 with uridine was investigated with molecular docking, conventional molecular dynamics (CMD) simulations and adaptive steered molecular dynamics (ASMD) simulations; and then, the uridine derivatives with possibly highly inhibitory activity were designed. The result of CMD showed that more water-mediated H-bonds and lower binding free energy both explained higher recognition ability and transported efficiency of hCNT3. While during the ASMD simulation, nucleoside transport process involved the significant side-chain flip of residues F321 and Q142, a typical substrate-induced conformational change. By considering electronegativity, atomic radius, functional group and key H-bonds factors, 25 novel uridine derivatives were constructed. Subsequently, the receptor-ligand binding free energy was predicted by solvated interaction energy (SIE) method to determine the inhibitor c8 with the best potential performance. This work not only revealed molecular recognition and release mechanism of uridine with hCNT3, but also designed a series of uridine derivatives to obtain lead compounds with potential high activity.

Background Human adenovirus (HAdV) infection can cause a variety of diseases. It is a major pathogen of pediatric acute respiratory tract infections (ARIs) and can be life-threatening in younger children. We described the epidemiology and subtypes shifting of HAdV among children with ARI in Guangzhou, China. Methods We conducted a retrospective study of 161,079 children diagnosed with acute respiratory illness at the Guangzhou Women and Children’s Medical Center between 2010 and 2021. HAdV specimens were detected by real-time PCR and the hexon gene was used for phylogenetic analysis. Results Before the COVID-19 outbreak in Guangzhou, the annual frequency of adenovirus infection detected during this period ranged from 3.92% to 13.58%, with an epidemic peak every four to five years. HAdV demonstrated a clear seasonal distribution, with the lowest positivity in March and peaking during summer (July or August) every year. A significant increase in HAdV cases was recorded for 2018 and 2019, which coincided with a shift in the dominant HAdV subtype from HAdV-3 to HAdV-7. The latter was associated with a more severe disease compared to HAdV-3. The average mortality proportion for children infected with HAdV from 2016 to 2019 was 0.38% but increased to 20% in severe cases. After COVID-19 emerged, HAdV cases dropped to 2.68%, suggesting that non-pharmaceutical interventions probably reduced the transmission of HAdV in the community. Conclusion Our study provides the foundation for the understanding of the epidemiology of HAdV and its associated risks in children in Southern China.

Under normal conditions, the human body employs the synergistic action of osteoblasts and osteoclasts to maintain a dynamic balance between bone formation and resorption. Bone homeostasis plays a very important role in the process of bone formation. Various bone diseases can occur if bone homeostasis is disrupted. In this study, the serum estrogen levels were significantly increased in the granulin (GRN)-deficient mice and PGRN regulates the binding of estrogen and estrogen receptor α (ERα) and then affects estrogen's ability to regulate bone formation and resorption. In addition, this study also explored the role that PGRN plays in regulating bone homeostasis by affecting the binding of estrogen and estrogen receptors through the protein kinase R-like endoplasmic reticulum kinase/phosphorylation of the eukaryotic initiation factor 2 signaling pathway. In summary, we confirmed the important role of PGRN in regulating the estrogen (E2)/ERα signal in maintaining bone homeostasis. Our findings may provide a new strategy for the treatment of osteoporosis and maintaining bone homeostasis. KEY MESSAGES: PGRN is a molecular regulator of the binding of E2 and ERα signal in maintaining bone homeostasis. PGRN plays in regulating bone homeostasis through the PERK/p-eIF2α signaling pathway. The best therapeutic effect of PGRN in osteoporosis is associated with different concentration of E2.

Persistent sinonasal symptoms are common in children with chronic rhinosinusitis. The Sinus and Nasal Quality of Life (QoL) Survey (SN-5) was the first validated questionnaire measuring sinonasal-related QoL in populations aged 2-12 years. No norm has been established for Chinese-speaking countries. We translated the SN-5 into traditional Chinese and evaluated validity and reliability.From December 2016 to December 2017, healthy volunteers and children with persistent sinonasal symptoms were enrolled. Guardians of the participants completed the SN-5, a visual analog scale (VAS) of nasal symptoms, and the Obstructive Sleep Apnea-18 (OSA-18); the responses were used to assess internal consistency, discriminant validity, and treatment responsiveness. A nontreatment group was administered the SN-5 1 week later to assess test-retest reliability.We recruited 31 healthy volunteers and 85 children with rhinosinusitis, 50 and 35 in the treatment and nontreatment groups, respectively. The SN-5 demonstrated good internal consistency (Cronbach's α = 0.86) and test-retest reliability (0.74, p 0.01). It exhibited good discriminant validity between the healthy and rhinosinusitis groups (p 0.001). The SN-5 scores were correlated with the VAS scores (0.63, p 0.001). The effect size of the SN-5 scores was 0.51. The total SN-5 and OSA-18 scores changed significantly after 4-week treatment (p 0.05) and demonstrated good responsiveness. The SN-5 and OSA-18 scores were significantly and positively correlated (rOur traditional Chinese version of the SN-5 is reliable and valid for measuring sinonasal-related QoL in children in Chinese-speaking countries.NCT04836403.

Isotope-labeled four polycyclic aromatic hydrocarbons (PAH4-d12) were applied to study the migration and distribution of PAH4 in oil to French fries during frying. The results showed that the mobilities of PAH4-d12 showed a downtrend within 0-6 h and then an uptrend, and PAH4-d12 were mainly distributed in the crust of the French fries, especially five-ring PAHs-d12. The correlation analysis showed that PAH4-d12 migration was mainly caused by oil absorption of French fries. The low fluidity of the oil slowed down the PAH4-d12 migration, which was accelerated as the total polar component increased (higher than 15-20%). Additionally, higher frying temperature enhanced the crust ratio and porous structure of French fries, which explained the abundant five-ring PAHs-d12 distributed in the crust. This study provided references for optimizing the frying parameters: the exposure of PAH4 in French fries to humans can be reduced by controlling the oil quality and weakening the crust of the French fries.

Copper (Cu) is an essential trace element whose serum levels have been reported to act as an effective indicator of the efficacy of radiotherapy. However, little is known about the role of Cu in radiotherapy. In this study we aimed to determine this role and investigate the precise mechanism by which Cu or Cu-related proteins regulate the radiosensitivity of hepatocellular carcinoma (HCC).The expression and function of Cu and copper metabolism MURR1 domain 10 (COMMD10) were assessed via a Cu detection assay, immunostaining, real-time PCR, western blot, a radiation clonogenic assay and a 5-ethynyl-2'-deoxyuridine assay. Ferroptosis was determined by detecting glutathione, lipid peroxidation, malondialdehyde and ferrous ion (Fe) levels. The in vivo effects of Cu and COMMD10 were examined with Cu/Cu chelator treatment or lentivirus modification of COMMD10 expression in radiated mouse models.We identified a novel role of Cu in promoting the radioresistance of HCC cells. Ionizing radiation (IR) induced a reduction of COMMD10, which increased intracellular Cu and led to radioresistance of HCC. COMMD10 enhanced ferroptosis and radiosensitivity in vitro and in vivo. Mechanistically, low expression of COMMD10 induced by IR inhibited the ubiquitin degradation of HIF1α (by inducing Cu accumulation) and simultaneously impaired its combination with HIF1α, promoting HIF1α nuclear translocation and the transcription of ceruloplasmin (CP) and SLC7A11, which jointly inhibited ferroptosis in HCC cells. In addition, elevated CP promoted HIF1α expression by reducing Fe, forming a positive feedback loop.COMMD10 inhibits the HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe homeostasis in HCC. This work provides new targets and treatment strategies for overcoming radioresistance in HCC.Radiotherapy benefits patients with unresectable or advanced hepatocellular carcinoma (HCC), but its effectiveness is hampered by radioresistance. Herein, we uncovered a novel role for copper in promoting the radioresistance of HCCs. This work has revealed new targets and potential treatment strategies that could be used to sensitize HCC to radiotherapy.

Purpose: Oncology studies employing digital dissection methodologies have provided some insight on the biological features of tumor microenvironment of Triple-negative breast cancer (TNBC), but molecular diagnostics rarely have therapeutic impact. We aimed to identify a novel prognostic biomarker to investigate immune characteristics of TNBC using transcriptomic features. Patients and Methods: We extracted whole transcriptome from breast cancer tissue of 30 TNBC patients and then used bioinformatics approaches to characterize the different immune cell contents in tumor tissue and para-cancerous tissue. We extract 2 indicators to describe the major differences in immune infiltration in the microenvironment between tumor tissue and para-cancerous tissue. We then combined the 2 indicators that represent the levels of increased and decreased infiltration in each sample to obtain the Immune Infiltration Score (IIS). Then we compared the tumor-infiltrating immune cell contents and immune infiltrating status in TNBC samples with CIBERSORT and ESTIMATE score to validate the IIS. Finally, 132 TNBC patients from the Cancer Genome Atlas program (TCGA) dataset was used to validate the predictive power of IIS. Results: 4 types of upregulated and 4 types of downregulated immune cells were identified in the tumor tissue samples of the TNBC patients. Then we developed a novel biomarker, IIS. Results showed that IIS score can clearly separate cancer and para-cancerous tissue. Using the same cutoff value of 0 in the TNBC-TCGA cohort, we show that those patients with a higher IIS had significantly higher PD-L1 expression and shorter progression-free survival time than those with a lower IIS value, indicating IIS score can be generalized to other TNBC datasets. Conclusion: we explored the immune infiltration landscape in 30 TNBC patients and provided IIS as a novel and reliable biomarker to evaluate the progression-free survival and prognosis of the TNBC patients.

Selenium nanoparticles (SeNPs) in an aqueous solution have poor stability and tend to aggregate when stored for a long time. In the present study, SeNPs were stabilized by using Lycium barbarum polysaccharide (LBP) and Lycium barbarum protein (LBPr) conjugates (LBPP) as a stabilizer and dispersing agent. Particularly, the LBPP

The sensitivity of cells to chemotherapeutic agents has a major effect on disease outcome in breast cancer patients. Unfortunately, there are numerous factors involved in the regulation of chemosensitivity, and the mechanisms need to be further investigated. Autophagy/Beclin 1 regulator 1 (Ambra1) is a key protein in the crosstalk between autophagy and apoptosis. It controls the switch between these two processes, which determines whether cells survive or die. Induction of apoptosis is the primary mechanism by which most chemotherapeutic drugs eliminate cancer cells. Recently, Ambra1 has been shown to modulate paclitaxel-induced apoptosis in breast cancer cells via the Bim/mitochondrial pathway, thereby modifying the sensitivity of cells to paclitaxel. However, how Ambra1 regulates Bim expression remains unclear. Here, we further confirmed that Bim plays an indispensable role in Ambra1's regulation of apoptosis and chemosensitivity in breast cancer cells. Furthermore, Ambra1 was found to regulate Bim expression at the transcriptional level through the Akt-FoxO1 pathway. Therefore, we propose a novel pathway, Ambra1-Akt-FoxO1-Bim, which regulates apoptosis and chemosensitivity in breast cancer cells. Thus, Ambra1 may represent a potential target for breast cancer treatment.

The brain activities and the underlying wiring diagrams are vulnerable in multiple sclerosis (MS). Also, it remains unknown whether the complex coupling between these functional and structural brain properties would be affected. To address this issue, we adopted graph frequency analysis to quantify the high-order structural-functional interactions based on a combination of brain diffusion and functional MRI data. The structural-functional decoupling index was proposed to measure how much brain regional functional activity with different graph frequency was organized atop the underlying wiring diagram in MS. The identified patterns in MS included (1) disruption of inherent structural-functional coupling in the somatomotor network (β = 0.05, p = 0.03), and (2) excessive decrease of decoupling in the subcortical (β = -0.10, p = 0.02), visual (β = -0.04, p = 0.01), and dorsal attention networks (β = -0.12, p = 0.03). Besides, this structural-functional coupling signature in the somatomotor network was associated with cognitive worsening of MS patients (β = -24.31, p = 0.006). Overall, our study unveiled a unique signature of brain structural-functional reorganization in MS.

Background Interferon regulatory factor 2 (IRF-2) acts as an anti-oncogene in gastric cancer (GC); however, the underlying mechanism remains unknown. Methods This study determined the expression of IRF-2 in GC tissues and adjacent non-tumor tissues using immunohistochemistry (IHC) and explored the predictive value of IRF-2 for the prognoses of GC patients. Cell function and xenograft tumor growth experiments in nude mice were performed to test tumor proliferation ability, both in vitro and in vivo. Chromatin immunoprecipitation sequencing (ChIP-Seq) assay was used to verify the direct target of IRF-2. Results We found that IRF-2 expression was downregulated in GC tissues and was negatively correlated with the prognoses of GC patients. IRF-2 negatively affected GC cell proliferation both in vitro and in vivo. ChIP-Seq assay showed that IRF-2 could directly activate AMER-1 transcription and regulate the Wnt/β-catenin signaling pathway, which was validated using IHC, in both tissue microarray and xenografted tumor tissues, western blot analysis, and cell function experiments. Conclusions Increased expression of IRF-2 can inhibit tumor growth and affect the prognoses of patients by directly regulating AMER-1 transcription in GC and inhibiting the Wnt/β-catenin signaling pathway.

Background There is limited data on the clinical outcome, long‐term survival and tolerability of sequential therapy of first‐line crizotinib followed by alectinib in a real‐world setting for Chinese patients with advanced ALK+ NSCLC. Methods The medical records of patients who received sequential therapy with first‐line crizotinib followed by alectinib (no intermittent systemic therapy was allowed between the two ALK‐TKIs) were collected from six centers in China. Combined time treatment to failure (C‐TTF) was defined as the period from the start of crizotinib to the complete discontinuation of alectinib due to any cause. Results A total of 61 patients were included in our study. Fifty‐two patients were switched to alectinib due to disease progression, seven as a result of toxicity, and two due to patient preference. At the time of data cutoff, alectinib treatment was discontinued in 31 patients on account of disease progression while severe adverse events resulted in cessation of alectinib in another two patients. Rebiopsy was conducted in 21 patients following disease progression on alectinib in whom ALK secondary mutation was found in 13 patients. Patients with ALK secondary mutation demonstrated better PFS during treatment with subsequent ALK‐TKIs compared with those without (10.4 vs. 3.1 m, p = 0.0018, HR = 0.08). With a median follow‐up of 34.3 months, C‐TTF was 39.2 months and estimated 5‐year OS was 68.6% in the overall population. Conclusion Sequential therapy with first‐line crizotinib followed by alectinib demonstrated long‐term benefits. Different efficacy in subsequent ALK‐TKI between patients with or without ALK secondary mutation further emphasized the importance of rebiopsy to guide targeted therapy more precisely., Sequential therapy with first‐line crizotinib followed by alectinib demonstrated long‐term benefits in a Chinese population. Different efficacy in subsequent ALK‐TKI between patients with or without ALK secondary mutation further emphasized the importance of rebiopsy to guide targeted therapy more precisely.

Background For lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) sensitive mutation and synchronous brain metastasis (syn‐BM), when and how to apply radiotherapy (RT) during first‐line tyrosine kinase inhibitor (TKI) treatment remains debatable. Methods From a real‐world multicenter database, EGFR‐mutant patients with syn‐BM diagnosed between 2010–2020 and treated with first‐line TKIs were enrolled and divided into upfront TKI + RT and upfront TKI groups. Median intracranial progression‐free survival (mIC‐PFS), median overall survival (mOS), and their risk factors were estimated. Results There were 60 and 186 patients in the upfront TKI + RT group and upfront TKI group, respectively. Their mIC‐PFS were 28.9 months (m) and 17.5 m (p = 0.023), and mOS were 42.7 m and 40.1 m (p = 0.51). Upfront brain RT improved mIC‐PFS in patients ≤60‐year‐old (p = 0.035), with symptomatic BM (p = 0.002), and treated with first‐generation TKIs (p = 0.012). There was no significant difference in mOS in any subgroup. Upfront brain stereotactic radiosurgery (SRS) showed a trend of better mIC‐PFS and mOS. mIC‐PFS was independently correlated with symptomatic BM (HR = 1.54, p = 0.030), EGFR L858R mutation (HR = 1.57, p = 0.019), and upfront brain RT (HR = 0.47, p = 0.001). mOS was independently correlated with being female (HR = 0.54, p = 0.007), ECOG 3–4 (HR = 10.47, p 3 (HR = 2.19, p = 0.002), and third‐generation TKI (HR = 0.54, p = 0.044) or antiangiogenic drugs (HR = 0.11, p = 0.005) as first/second‐line therapy. Conclusions Upfront brain RT based on first‐line EGFR‐TKI might improve IC‐PFS but not OS in EGFR‐mutant lung adenocarcinoma patients, indicating potential survival benefit from brain SRS and early application of drugs with higher intracranial activity., To our best knowledge, this is the most extensive multicenter real‐world study (Fig.1) on epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma with synchronous brain metastasis (BM) and treated with first‐line EGFR targeting tyrosine kinase inhibitor (TKI). On the basis of first‐line EGFR‐TKI therapy, additional upfront brain radiation therapy (RT) could improve intracranial progression free survival (PFS) (Fig.2a), particularly for patients with BM symptom and 1st‐generation EGFR‐TKI (Fig.4a). With no OS improvement (Fig.2d, Fig.3b, Fig.4b), upfront whole‐brain irradiation could be deferred during the first‐line EGFR‐TKI treatment; however, upfront brain stereotactic radio‐surgery (SRS) might have potential OS benefit (Fig.3d).

Fibroblast growth factor receptors (FGFRs) play key roles in promoting cancer cell proliferation, differentiation, and migration. However, acquired resistance to FGFR inhibitors has become an emerging challenge in long-term cancer therapies, especially for hepatocellular carcinoma (HCC). Gatekeeper (GK) mutations are the main mechanism of resistance. Herein, we describe the discovery of a series of reversible FGFR inhibitors, particularly for GK mutations with the 2-amino-7-sulfonyl-7

Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.

Background Tumor-associated macrophages (TAMs) are key regulators of the complex interplay between cancer and the immune microenvironment. Tumor cell-derived spondin 2 (SPON2) is an extracellular matrix glycoprotein that has complicated roles in recruitment of macrophages and neutrophils during inflammation. Overexpression of SPON2 has been shown to promote tumor cell migration in colorectal cancer (CRC). However, the mechanism by which SPON2 regulates the accumulation of TAMs in the tumor microenvironment (TME) of CRC is unknown. Methods Immunohistochemistry was used to examine SPON2 expression in clinical CRC tissues. In vitro migration assays, transendothelial migration assays (iTEM), and cell adhesion assays were used to investigate the effects of SPON2 on monocyte/macrophage migration. Subcutaneous tumor formation and orthotopic implantation assays were performed in C57 BL/6 mice to confirm the effects of SPON2 on TAM infiltration in tumors. Results SPON2 expression is positively correlated with M2-TAM infiltration in clinical CRC tumors and poor prognosis of CRC patients. In addition, SPON2 promotes cytoskeletal remodeling and transendothelial migration of monocytes by activating integrin β1/PYK2 axis. SPON2 may indirectly induce M2-polarization through upregulating cytokines including IL10, CCL2 and CSF1 expression in tumor cells. Blocking M2 polarization and Macrophage depletion inhibited the SPON2-induced tumors growth and invasion. Furthermore, blocking the SPON2/integrin β1/PYK2 axis impairs the transendothelial migration of monocytes and cancer-promoting functions of TAMs in vivo. Conclusions Our findings demonstrate that SPON2-driven M2-TAM infiltration plays an important role during CRC tumor growth and metastasis. SPON2 may be a valuable biomarker guiding the use of macrophage-targeting strategies and a potential therapeutic target in advanced CRC.

Background Orthostatic tremor (OT) is a type of postural tremor of the lower extremities that has not been described in either phenylketonuria (PKU) or hyperphenylalaninemia (HPA). Because little is known about the clinical features and therapeutic responses of OT in mild HPA, we describe a mild HPA patient who presented with OT as an initial symptom. Case presentation A 22-year-old male was admitted for bilateral leg tremor while standing, with symptom onset eight months prior. One month before admission, the tremor disappeared in the left leg but persisted in the right leg. Electromyography recorded from the right gastrocnemius revealed a 6–8 Hz tremor, which appeared when the patient was standing and disappeared when he was resting or walking. Blood screening showed a phenylalanine/tyrosine ratio of 2.06 and a phenylalanine level of 140 μmol/L. Urine metabolic screening was negative. Whole-exome sequencing confirmed the presence of a compound heterozygous mutation, c.158G > A and c.728G > A, in phenylalanine hydroxylase (PAH) gene. After three months of levodopa/benserazide tablets (250 mg, tid) and a low-phenylalanine diet treatment, the tremor disappeared. Conclusions Young-onset mild HPA is a relatively rare autosomal recessive metabolic disease, and slow OT is a rare clinical feature. Metabolic screening and genetic testing are the keys to early diagnosis and treatment. For adolescents and young adults, appropriate medication and long-term dietary therapy remain important treatments. This case expanded the disease spectrum of slow OT.

BackgroundSince the delivery of sex education is not standardized across local and international secondary schools in Hong Kong, this study aims to assess and compare the knowledge level of sexually transmitted infections (STIs) between university students who attended local and international secondary schools in Hong Kong.MethodsFrom January to March 2019, we conducted a cross-sectional survey among undergraduates at the University of Hong Kong. The primary outcome was STI knowledge as measured by a 29-item quiz. A higher quiz score meant a better STI knowledge level. Students' attitude toward sexual health and their sex education history was collected. Bivariate and multivariate analyses were conducted to evaluate the association factor with a better STI knowledge level.ResultsThree hundred and ninety six students were included in the analysis. Three hundred thirty three (85.35%) students attended local secondary schools and 58 (14.65%) students attended international secondary schools in Hong Kong; 200 (50.51%) students were male and 196 (49.49%) students were female. Compared with students from local secondary school, those from international secondary schools had a significantly higher STI quiz score (18.19 vs. 15.4, p = 0.003). The results of multiple linear regression revealed that students in a higher year of study (β = 1.07, p < 0.001), from medical faculties (β = 6.96, p < 0.001), and from international secondary schools (β = 2.27, p = 0.003) achieved a higher STI quiz score.ConclusionUniversity students who attended international secondary schools in Hong Kong possess a significantly higher knowledge level of STIs compared with those who attended local secondary schools. Nonetheless, the overall STI awareness among university students is inadequate. The inadequacy of STI awareness calls for the need to plan and implement satisfactory, comprehensive, and standardized sex education across the overall education system in Hong Kong.

Recently, the incidence of diseases caused by nontuberculous mycobacteria (NTM) has been increasing worldwide, especially in immunocompromised patients and those with potential chronic lung disease. Vitek MS v3.0 matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a rapid and reliable method for identifying mycobacteria in clinical laboratories. This study aimed to evaluate the performance of Vitek MS v3.0 by isolating NTM directly from automated liquid medium systems using patient samples. A total of 855 Mycobacterium growth indicator tube (MGIT)-positive liquid cultures were investigated. Among them, 658 (77.0%) liquid cultures were correctly identified to the species, group, or complex level, 192 (23.0%) resulted in no identification, and 5 (0.6%) were misidentified at the species level. DNA sequencing identified 855 NTM isolates from liquid cultures, comprising 316 isolates of rapidly growing mycobacteria (RGM) and 539 isolates of slow-growing mycobacteria (SGM). Using the Vitek MS system, the RGM integral identification rate (276/316 [87.34%]) was higher than the SGM rate (381/539 [70.69%]) (

Changes in diastolic blood pressure (DBP) are common in patients with acute myocardial infarction (AMI). The relationship between the dynamic change of DBP and in-hospital mortality among patients with AMI remains unclear. This study aimed to explore the importance of DBP during disease development among patients with AMI. We performed a retrospective cohort study involving patients from the Medical Information Mart for Intensive Care III database, which included40,000 patients admitted to the intensive care unit (ICU). Overall, 3209 adult AMI admissions were identified. We extracted the clinical and laboratory information in the patients with AMI. Cox proportional hazards models were used to evaluate the prognostic values of baseline DBP. We used the generalized additive mixed model (GAMM) to compare trends in DBP over time among survivors and non-survivors, after adjusting for potential confounders. During the ICU stay, 189 patients died (mortality rate, 6.36%). The age of each non-survivor together with the variations in DBP over time from admission to the time of death is of great importance to the scientific community. Cox multivariable regression analysis displayed that after adjusting for confounding factors, ascended baseline DBP was an important hazard factor for hospital deaths (hazard ratio, 1.02; 95% confidence interval, 1.01-1.03; P = .003). Based on GAMM, DBP in the death group was markedly lower than that of the surviving group. Moreover, the difference between the two groups showed an increasing trend within 3 days after ICU admission. After adjusting for various variables, the results were stable. DBP significantly contributed to in-hospital mortality among patients with AMI. There was a nonlinear correlation between baseline DBP and in-hospital mortality among patients with AMI, and the DBP of the non-survivors decreased within the first 3 days after ICU admission. However, the causality cannot be deduced from our data.

To examine the prevalence of suicide-related behaviors among junior middle school students, and to explore the mediating role of depression in the relationship between suicide-related behaviors and family function.A total of 2572 junior middle school students from three middle schools in Chengdu were interviewed face-to-face by using suicide-related items from Youth Risk Behavior Surveillance System (YRBSS), Chinese Family Assessment Instrument (C-FAI), and Center for Epidemiologic Studies Depression Scale for Children (CES-DC). The mediating role of depression was analyzed with structural equation model.The prevalence of suicide-related behaviors was 26.01% among the respondents. The prevalence of suicide ideation, suicide plan and suicide attempt were 24.38%, 13.49% and 10.77%, respectively. Depression played a partial mediating role in how family function impacted on suicide-related behaviors, presenting a direct effect value of 0.170 (95%Poor family function may increase the risk of suicide-related behaviors, and this effect is produced mostly through the impact on children's mental health. Improving family function will not only improve children's psychological status, but also reduce suicide-related behaviors.

Hematological metastasis was the main metastatic method of colorectal cancer and the main reason for failure of radical surgery. Vascular endothelial cells played an important role in tumor hematologic metastasis. We previously performed RNA-Seq on primary and metastatic colorectal carcinoma (CRC) tissues and then identified GPR63 as a potential metastasis-promoting gene, but its role and mechanisms in the interaction between cancer cells and vascular endothelial cells were still unknown. In this study, GPR63 was significantly elevated in CRC tissues compared with paracarcinoma tissues. GPR63 expression was closely related to lymph node metastasis and distant metastasis in 147 CRC tissues. GPR63 promoted cell migration and stemness. Moreover, endothelial cell-derived S1P enhanced the migration and sphere-forming ability of CRC through activation of GPR63. Mechanistically, S1P promoted GPR63 binding to Src to activate JAK2/STAT3 pathway, and therefore promoted CRC cell migration. Our study revealed a novel mechanism by which endothelial cells promoted metastasis of CRC cells, which might have potential as a promising target for CRC therapy.

The lockdown due to COVID-19 created a rare opportunity to examine the nonlinear responses of secondary aerosols, which are formed through atmospheric oxidation of gaseous precursors, to intensive precursor emission reductions. Based on unique observational data sets from six supersites in eastern China during 2019-2021, we found that the lockdown caused considerable decreases (32-61%) in different secondary aerosol components in the study region because of similar-degree precursor reductions. However, due to insufficient combustion-related volatile organic compound (VOC) reduction, odd oxygen (Ox = O3 + NO2) concentration, an indicator of the extent of photochemical processing, showed little change and did not promote more decreases in secondary aerosols. We also found that the Chinese provinces and international cities that experienced reduced Ox during the lockdown usually gained a greater simultaneous PM2.5 decrease than other provinces and cities with an increased Ox. Therefore, we argue that strict VOC control in winter, which has been largely ignored so far, is critical in future policies to mitigate winter haze more efficiently by reducing Ox simultaneously.

Self-compassion has been shown to be protective against stress. Whether its stress buffering effect differs between cancer caregivers and non-caregivers is unknown. This study examined the moderating effect of self-compassion among cancer caregivers relative to non-caregivers by recruiting cancer caregivers from the hospital and a community sample matching on sex and age. Participants completed a questionnaire which comprised the self-reported anxiety (STAI-6) and self-compassion (SCS-SF) measures, and administered cortisol sample collections with Salivette tubes at home. Whereas caregivers experienced higher diurnal cortisol level, the differential protective effects of self-compassion were only present against anxiety symptoms but not physiological stress.

Solute carrier (SLC) transporters are primarily known for their function in the transportation of various exogenous/endogenous substances via influx/efflux mechanisms. In addition to their diverse role in several tumor-modulating functions, such as proliferation, migration, angiogenesis, epithelial-mesenchymal transition (EMT), epigenetic modification, chemoresistance, immunoregulation, and oncometabolism, influx/efflux-independent contributions of SLCs in the activation of various signaling network cascades that might drive metastatic tumor formation have also been uncovered. Disappointingly, even after two decades and the discovery of >450 SLCs, many of their members remain orphans in terms of cancer pathogenesis. In this review, we summarize the current understanding of the tumor-modulating functions, mechanisms, and complexity of SLCs, as well as their potential as targets for cancer therapy.

Background Depression is a common, easily ignored, accompanied disease of gastric cancer (GC) patients and is often observed with elevated plasma catecholamine levels. Depression frequently promotes GC progression and leads to poor clinical outcomes; however, the molecular mechanisms underlying depression‐induced GC progression remain poorly understood. We aimed to study the effects of depression on GC progression and explore possible mechanisms mediating the action of depression‐associated catecholamines on GC. Methods Depression states of GC patients were graded using the Patient Health Questionnaire‐9, and plasma catecholamine levels were examined by high performance liquid chromatography coupled with tandem mass spectrometry. Migrative and invasive GC cells were examined using transwell assays, and metastatic GC niches were imaged using bioluminescence technology in a depression mouse model established with chronic unpredictable mild stress. Mouse depression‐like behaviors were assessed through sucrose preference, forced swimming, and tail suspension tests. Characteristics of the neuroendocrine phenotype were observed via RT‐PCR, Western blotting, flow cytometry, and transmission electron microscopy. Results Fifty‐one GC patients (age: 53.61 ± 1.79 years; cancer duration: 3.71 ± 0.33 months; depression duration: 2.37 ± 0.38 months; male‐to‐female ratio: 1.55:1) were enrolled in the study. Depression grade was significantly higher in GC patients showing higher plasma levels of catecholamines (epinephrine: P = 0.018; noradrenaline: P = 0.009), higher oncogene metastasis‐associated in colon cancer‐1 (MACC1) level (P = 0.018), and metastasis (P < 0.001). Further, depression‐associated catecholamine specifically bound to the beta‐2 adrenergic receptor (β2‐AR) and upregulated MACC1 expression, and thus promoting neuroendocrine phenotypic transformation through direct binding between MACC1 and synaptophysin. Eventually, the neuroendocrine phenotypic transformation accelerated GC invasion in vitro and metastasis in vivo. However, β2‐AR antagonist ICI‐118,551 or MACC1 silencing effectively blocked the catecholamine‐induced neuroendocrine phenotypic transformation and eliminated depression‐enhanced GC migration and invasion. Moreover, β2‐AR blocking or MACC1 silencing prevented GC metastasis attributed to a neuroendocrine phenotype in a depression mouse model. Conclusions Catecholamine‐induced neuroendocrine phenotypes of GC cells led to depression‐accelerated GC invasion and metastasis via the β2‐AR/MACC1 axis, while β2‐AR antagonist or MACC1 silencing could reverse it, showing promising potential therapeutic strategies for improving the outcome of GC patients with comorbid depression.

Penile squamous cell carcinoma (PSCC) is a rare disease. The treatment options for advanced penile cancer are often limited, and the prognosis remains poor. We reported a 52-year-old male recurrent and metastatic PSCC patient with high PD-L1 expression (90%) and TMB (14.4 muts/Mb). He had undergone penectomy, bilateral inguinal lymph node dissection, and excision of the abdominal wall mass. Despite cisplatin-based concurrent chemoradiotherapy and sequential chemotherapy with docetaxel plus cisplatin then being carried out, the carcinoma still progressed. The patient then obtained progression-free survival with continuous sintilimab, although he experienced the new onset of ICI-induced diabetes after 24 cycles of sintilimab and required sustained insulin treatment. He had negative type 1 diabetes-associated autoantibodies and the susceptible HLA genotype DR3-DQ2 haplotype. This is the first patient with radiation and multichemorefractory PSCC who has obtained the remarkable anti-tumor effect of partial regression exceeding 32 months during continuous sintilimab and anlotinib treatment.