Cardiotoxicity of HER2-Targeted Drugs When Combined with Other Drugs: A Systematic and Meta-analysis of Randomized Controlled Trials.

The development and use of HER2-targeted drugs has improved the prognosis of HER2-positive cancer patients. However, in addition to improved survival rates, treatment-induced adverse events and nontumor-related deaths have increased. We sought to assess the incidence of cardiovascular adverse events when HER2-targeted drugs are combined with other drugs. We systematically searched the literature on the cardiotoxicity of anti-HER2 drugs in electronic databases, including PubMed, Web of Science, Cochrane Library, OVID and CNKI, from their inception to April 2022. The Cochrane Collaboration's tool for assessing risk of bias and the Jadad scale were used to evaluate the risk of bias and quality of the studies, respectively. For each included trial, we calculated the incidence of cardiovascular adverse effects (CAEs) and 95% confidence intervals (95% CIs) and performed a meta-analysis using a random effects model (REM). The meta-analysis was performed using R 4.2.1. We included 41 randomized clinical trials (RCTs) in the meta-analysis, consisting of 56 groups and 31,934 patients. The meta-analysis revealed the following: (1) The incidence of cardiotoxicity in groups given monoclonal antibody treatment was 14% for single therapy (95% CI: 2-34%) and 10%, 11%, and 12% for adjuvant therapy combined with combined therapy (95% CI: 6-13%), chemotherapy (95% CI: 8-13%) and endocrine therapy (95% CI: 7-18%), respectively. However, in the groups treated with the antibody‒drug conjugates (ADCs), the percentage of patients treated with the combination therapy was 1% (95% CI: 0-2%) and 5% (95% CI: 4-7%), respectively, with a significant difference (P < 0.01). The heterogeneity among the included studies was significant (I2 = 94%, p < 0.01). (2) When monoclonal antibodies were combined with chemotherapy, the incidence of cardiotoxicity under anthracycline-containing therapy (10.3%) was significantly greater than that under nonanthracycline-containing therapy (8.8%). (3) Significant differences were found between subgroups, except for the endocrine group versus some others, although this difference might result from the different inclusion criteria of the original trials. (1) When anti-HER2 drugs are administered in combination with anthracycline-containing chemotherapy, the incidence of cardiotoxicity is greater than with other drugs. (2) Safety benefits can be achieved by replacing traditional monoclonal antibodies with ADCs. The comprehensive use of these drugs necessitates collaboration between oncologists and cardiologists.

FAM189A2 plays a tumour suppressor role in lung adenocarcinoma by influencing cell apoptosis, CXCR4 expression and tight junction proteins.

Transmembrane proteins play key roles in the development of lung cancer. The family with sequence similarity 189 member A2 (FAM189A2) gene encodes a transmembrane structural protein, yet its involvement in lung adenocarcinoma remains largely unexplored. This study elucidated its role in lung adenocarcinoma and its possible molecular mechanism. Our findings revealed diminished expression levels of FAM189A2 in LUAD tissues. Additionally, the activity of LUAD cells was significantly inhibited by overexpression of FAM189A2. Following FAM189A2 overexpression, the expression of OCLN and TJP2 was upregulated in LUAD cells, while CXCR4 expression experiences a notable decrease. Moreover, the coimmunoprecipitation experiment confirmed the direct interaction between FAM189A2 and CXCR4. The infiltration levels of T cells (CD4+ memory resting, CD8+, regulatory), NK cells, B memory cells, endothelial cells and cancer-associated fibroblasts were significantly correlated with FAM189A2 expression. These results indicate FAM189A2 may act as a tumour suppressor in LUAD through tight junction protein (TJP) and CXCR4 regulation. Moreover, FAM189A2 is significantly correlated with the immune microenvironment of LUAD, which may be involved in prognosis and immunotherapeutic efficacy.

Improving structural damage tolerance and fracture energy via bamboo-inspired void patterns.

Bamboo has a functionally-graded microstructure that endows it with a combination of desirable properties, such as high failure strain, high toughness, and a low density. As a result, bamboo has been widely used in load-bearing structures. In this work, we study the use of bamboo-inspired void patterns to geometrically improve the failure properties of structures made from brittle polymers. We perform finite element analysis and experiments on 3D-printed structures to quantify the effect of the shape and spatial distribution of voids on the fracture behavior. The introduction of periodic, uniformly distributed voids in notched bend specimens leads to a 15-fold increase in the fracture energy relative to solid specimens. Adding a gradient to the pattern of voids leads to a cumulative 55-fold improvement in the fracture energy. Mechanistically, the individual voids result in crack blunting, which suppresses crack initiation, while neighboring voids redistribute stresses throughout the sample to enable large deformation before failure. In addition, we conduct qualitative, low-energy impact experiments on PMMA plates with laser-cut void patterns, illustrating the broader potential for this strategy to improve damage tolerance and energy absorption in a wide range of materials systems.

The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer.

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial ß oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/ß-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.

Network crafting, goal attainment, and work-to-family facilitation among hotel employees: the mediating roles of positive affect and information exchange.

Background: The hospitality industry is experiencing new developmental opportunities after the coronavirus pandemic, such as the expansion of digital presence, the introduction of wellness offerings to cater to health-conscious guests, and a growing focus on local and sustainable tourism. However, despite these positive changes, we still lack knowledge on how hospitality workers can proactively adjust their work conditions to excel in their professional domain while also flourishing in their family domain. Thus, the current study proposed and examined how network crafting behaviors can have positive effects on hotel employees' work goal attainment and work-to-family facilitation. Based on the affectivity theories and the social cognitive theory, we examined the mediating roles of positive affect and information exchange on the relationship between network crafting behaviors and work goal attainment and work-to-family facilitation. Methods: We collected data from three 5-star hotels in Jinan, China. We sent out the surveys in three waves to avoid the common method bias. We obtained 199 valid responses in total in three waves and entered them into the data analysis. Structural equation modeling was conducted to examine our hypotheses. Results: We found that network crafting was positively related to hotel employees' work goal attainment and work-to-family facilitation. We also confirmed the mediating roles of positive affect and information exchange in this relationship. Conclusion: We revealed a dual process of network crafting - that is, a positive affective process and an information exchange process. We contribute to the social network and networking literature by highlighting an optimization-oriented networking strategy, rather than one simply maximizing networks. We enrich the work-family enrichment literature by suggesting an effective behavioral strategy that can transmit the resources and gains from one domain to the other domain.

Managing the negative impact of workforce diversity: The important roles of inclusive HRM and employee learning-oriented behaviors.

The workforce has become more diverse than it used to be. Although organizations actively capitalize on workforce diversity to enhance team innovation and organizational performance, it is found that workforce diversity also has potential risks, among which interpersonal conflict is the most salient one. However, we still know relatively less about why workforce diversity may link to higher interpersonal conflict and, more importantly, how to mitigate the negative impact of workforce diversity. Based on the workplace diversity theories (e.g., the categorization-elaboration model), this study examined how workforce diversity was positively related to interpersonal conflict through impacting one's affective states, and to what extent this indirect effect can be weakened by organization-initiated practices (i.e., the inclusive human resources management (HRM) practices) and employee-initiated behaviors (i.e., employee learning-oriented behaviors). Using two-wave surveys from 203 employees from various organizations in China, we confirmed our hypotheses. Our results showed that perceived workforce diversity was positively related to interpersonal conflict through increasing negative affect (after we controlled for the objective diversity level calculated by the Blau index), and this indirect effect was weakened when the levels of inclusive HRM practices and employee learning-oriented behaviors were high. Our study suggests that it is important for organizations to be aware of the detrimental impact of workforce diversity. In addition, it is essential to use both the top-down (e.g., inclusive HRM practices) and bottom-up (e.g., employee learning-oriented behaviors) approaches to managing the challenges presented by diversity so as to unlock more potential of diversity in the workplace.

RT-RPA-Cas12a-based assay facilitates the discrimination of SARS-CoV-2 variants of concern.

Timely and accurate detection of SARS-CoV-2 variants of concern (VOCs) is urgently needed for pandemic surveillance and control. Great efforts have been made from a mass of scientists in increasing the detection sensitivity and operability, and reducing the turn-around time and cost. Here, we report a nucleic acid testing-based method aiming to detect and discriminate SARS-CoV-2 mutations by combining RT-RPA and CRISPR-Cas12a detecting assays (RRCd). With a detection limit of 10 copies RNA/reaction, RRCd was validated in 194 clinical samples, showing 89% positive predictive agreement and 100% negative predictive agreement, respectively. Critically, using specific crRNAs, representatives of single nucleotide polymorphisms and small deletions in SARS-CoV-2 VOCs including N501Y, T478K and ΔH69-V70 were discriminated by RRCd, demonstrating 100% specificity in clinical samples with C t < 33. The method completes within 65 min and could offer visible results without using any electrical devices, which probably facilitate point-of-care testing of SARS-CoV-2 variants and other epidemic viruses.

Efficacy and safety of the combination of glucosamine and chondroitin for knee osteoarthritis: a systematic review and meta-analysis.

AIMS: Though glucosamine and chondroitin have become common practices for treating knee osteoarthritis, the clinical value of these two drugs in combination are still questionable. To evaluate the efficacy and safety of the combination of glucosamine (GS) and chondroitin (CS) in knee osteoarthritis (KOA) treatment. METHODS: We searched electronic databases, including PubMed, Embase, Web of Science, SCOPUS, The Cochrane Central Register of Controlled Trials (CENTRAL), OVID, Chinese Clinical Trial Registry (ChiCTR), CBM, CNKI, WanFang and VIP from their inception to August 20, 2020, for literature concerning the combination of glucosamine and chondroitin in knee osteoarthritis treatment. The Cochrane Collaboration's tool for assessing risk of bias and Jadad scale were used to evaluate the risk of bias and quality of literature. The meta-analysis was performed using Review Manager 5.3 software. RESULTS: Eight randomized controlled trials (RCTs) were included, including 7 studies in English and 1 study in Chinese. While the number of included papers was quite limited, the number of participants was decent, and quality appraisal result is acceptable. The total number of patients was 3793, with 1067 patients receiving a combination of glucosamine and chondroitin and 2726 patients receiving other treatments. The meta-analysis results revealed the following: (1) Regarding the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, compared with the placebo group, the combination group showed a statistically significant advantage [MD = - 12.04 (- 22.33 ~ - 1.75); P = 0.02], while the other groups showed no significance. (2) Regarding the VAS score, none of the comparisons showed significance. (3) In the secondary outcomes, except the comparison of JSN between the combination and placebo groups (MD = - 0.09 (- 0.18 ~ - 0.00); P = 0.04) and the comparison of the WOMAC stiffness score between the combination and CS groups [MD = - 4.70 (- 8.57 ~ - 0.83); P = 0.02], none of the comparisons showed a significant difference. (4)Safety analysis results show that none of the comparisons have significant differences. CONCLUSION: Our study confirmed that the combination of glucosamine and chondroitin is effective and superior to other treatments in knee osteoarthritis to a certain extent. It is worthwhile to popularize and apply the combination in KOA treatment considering the point of effect, tolerability and economic costs. Additionally, regarding the limited number of studies and uneven trial quality, more high-quality trials are required to investigate the accurate clinical advantages of the combination. PROSPERO REGISTRATION ID: CRD42020202093.

Masked face is looking at me: Face mask increases the feeling of being looked at during the COVID-19 pandemic.

Background: As the COVID-19 global pandemic unfolded, governments recommended wearing face masks as a protective measure. Recent studies have found that a face mask influences perception; but how it affects social perception, especially the judgment of being looked at, is still unknown. This study investigated how wearing a mask influences the judgment of gaze direction by conducting a cone of direct gaze (CoDG) task. Methods: In Experiment 1, three types of masked faces were considered to investigate whether the effect of masks on CoDG is modulated by mask types. Experiment 2 was to further validate the results of Experiment 1 by adding a learning phase to help participants better distinguish N95 and surgical masks. Furthermore, to investigate whether the effect of masks derives from its social significance, a face with only the eye-region (a mouth-cut face) was used as the stimuli in Experiment 3. Results: The results of Experiment 1 found that wearing masks widens the CoDG, irrespective of the mask type. Experiment 2 replicated the results of Experiment 1. Experiment 3 found that the CoDG of N95-masked faces was wider than the mouth-cut and non-masked faces, while no significant difference existed between the CoDG of mouth-cut and non-masked faces, illustrating that the influence of wearing masks on CoDG was due to high-level social significance rather than low-level facial feature information. Conclusion: The results show that face mask increases the feeling of being looked at during the COVID-19 Pandemic. The present findings are of significance for understanding the impact of wearing masks on human social cognition in the context of COVID-19.

The effect of director-deputy director promotion focus congruence on team knowledge creation: A social identification perspective.

As a new leadership style, promotion-focused leadership has attracted the attention of theorists and practitioners. Existing research emphasizes the positive value of director personal promotion focus on team creative behavior while overlooking director-deputy director promotion focus fit. Based on Regulatory Fit Theory and Social Identity Theory, this study explored the effect of director-deputy director promotion focus fit on team knowledge creation and the mediating role of team identification. We used polynomial regression and response surface analysis to analyze the data from 674 questionnaires. The results demonstrate that: (1) director-deputy director congruence in promotion focus is positively related to team identification; (2) under the condition of director-deputy director promotion focus congruence, the level of team identification does not significantly increase when director-deputy director promotion focus rises from "low-low" to "high-high"; (3) team identification plays a mediating role in the relationship between director-deputy director promotion focus congruence and team knowledge creation.

A Prediction Model of Human Resources Recruitment Demand Based on Convolutional Collaborative BP Neural Network.

This paper presents an in-depth study and analysis of the prediction model of force resource recruitment demand using a convolutional neural network combined with a BP neural network algorithm. BP neural network technology is introduced to be applied to enterprise management talent assessment activities. Using BP neural network has strong parallel processing characteristics, as well as unique adaptive learning and feedback adjustment capabilities while combining the traditional enterprise talent assessment system, to build a business management talent assessment model based on BP neural network technology, to circumvent the possible influence of subjective factors in talent assessment, reduce assessment errors, and improve the accuracy and validity of the assessment. The first layer of convolutional layers may only extract some low-level features such as edges, lines, and corners, and more layers of the network can iteratively extract more complex features from low-level features. The constructed applicant reputation evaluation model based on multiplicative long- and short-term recurrent neural network and the hybrid project recommendation model based on conditional variational self-encoder were experimented on Freelancer's dataset for effectiveness, respectively, and the experimental results showed that the proposed employer hiring decision model, reputation analysis model, and applicant project recommendation model have more reliable performance compared with the existing models. The research results achieve more efficient matching of labor supply and demand in the online labor market and provide technical support for the online labor market platform to realize personalized, intelligent, and accurate services for both employers and applicants.

Microbial community day-to-day dynamics during a spring algal bloom event in a tributary of Three Gorges Reservoir.

The microbial food-loop is critical to energy flow in aquatic food webs. We tested the hypothesis that species composition and relative abundance in a microbial community would be modified by the development of toxic algal blooms either by enhanced carbon production or toxicity. This study tracked the response of the microbial community with respect to composition and relative abundance during a 7-day algal bloom event in the Three Gorges Reservoir in May 2018. Chlorophyll a biomass, microscopic identification and cell counting of algae and algal abundance (ind. L-1) and carbon, nutrient concentrations (total phosphorus and nitrogen, dissolved total phosphorus and nitrogen), and DNA high throughput sequencing were measured daily. Algal density (1.2 × 109 ind. L-1) and Chlorophyll a (219 µg L-1) peaked on May 20th-21st, when the phytoplankton community was dominated by Chlorella spp. and Microcystis spp. The concentrations of both dissolved total nitrogen and phosphorus declined during the bloom period. Based on DNA high throughput sequencing data, the relative abundance of eukaryotic phytoplankton, microzooplankton (20-200 µm), mesozooplankton (>200 µm), and fungal communities varied day by day while the prokaryotic community revealed a more consistent structure. Enhanced carbon production during the bloom was closely associated with increased heterotrophic microbial composition in both the prokaryotic and eukaryotic communities. A storm event, however, that caused surface cooling and deep mixing of the water column greatly modified the composition and relative abundance of species in the microbial loop. The high temporal variability and dynamics observed in this study suggest that many factors, and not just algal blooms, were interacting to determine the composition and relative abundance of species of the microbial loop.

Activating cryptic biosynthetic gene cluster through a CRISPR-Cas12a-mediated direct cloning approach.

Direct cloning of biosynthetic gene clusters (BGCs) from microbial genomes facilitates natural product-based drug discovery. Here, by combining Cas12a and the advanced features of bacterial artificial chromosome library construction, we developed a fast yet efficient in vitro platform for directly capturing large BGCs, named CAT-FISHING (CRISPR/Cas12a-mediated fast direct biosynthetic gene cluster cloning). As demonstrations, several large BGCs from different actinomycetal genomic DNA samples were efficiently captured by CAT-FISHING, the largest of which was 145 kb with 75% GC content. Furthermore, the directly cloned, 110 kb long, cryptic polyketide encoding BGC from Micromonospora sp. 181 was then heterologously expressed in a Streptomyces chassis. It turned out to be a new macrolactam compound, marinolactam A, which showed promising anticancer activity. Our results indicate that CAT-FISHING is a powerful method for complicated BGC cloning, and we believe that it would be an important asset to the entire community of natural product-based drug discovery.

Urban Metabolism of Food-Sourced Nitrogen among Different Income Households: A Case Study Based on Large Sample Survey in Xiamen City, China.

Food consumption is fundamental for urban households if they are to sustain production and daily life. Nitrogen resulting from food consumption has significantly contributed to pollutant emissions in urban ecosystems. Taking Xiamen city, a rapid urbanizing area of southeast China as a case study, we evaluated the food-sourced nitrogen consumption of households based on a large simple onsite questionnaire survey, as well as differences between households in the consumption of plant-based and animal-based foods. A material flow analysis (MFA) was conducted to simulate the urban metabolism of food-sourced nitrogen and environmental emissions among different income groups. The impacts of household attributes, plant-based food consumption, and animal-based food consumption on environmental nitrogen emissions were examined with a structural equation model (SEM). Our results show that the surveyed households' diets were more plant-based and less animal-based. Aquatic products and livestock were the source of 43.7% of food-sourced nitrogen, and 84.5% of the food-sourced nitrogen was discharge into the environment through direct discharge and waste treatment. Soil, water, and air emissions accounted for 62.8%, 30.1%, and 7.1% of the food-sourced nitrogen, respectively. Household income, household size, and household area are all associated with accelerating increases of nitrogen emissions released into the environment, though middle-income group households have the highest food-sourced environmental nitrogen emissions. On this basis, we discuss how to better manage the urban metabolism of food-sourced nitrogen, so as to improve urban household consumption, lower nitrogen emissions, and improve food security.

A versatile biosensing platform coupling CRISPR-Cas12a and aptamers for detection of diverse analytes.

Rapid and sensitive detection of various analytes is in high demand. Apart from its application in genome editing, CRISPR-Cas also shows promises in nucleic acid detection applications. To further exploit the potential of CRISPR-Cas for detection of diverse analytes, we present a versatile biosensing platform that couples the excellent affinity of aptamers for broad-range analytes with the collateral single-strand DNA cleavage activity of CRISPR-Cas12a. We demonstrated that the biosensors developed by this platform can be used to detect protein and small molecule in human serum with a complicated background, i.e., the tumor marker alpha fetoprotein and cocaine with the detection limits of 0.07 fmol/L and 0.34 µmol/L, respectively, highlighting the advantages of simplicity, sensitivity, short detection time, and low cost compared with the state-of-the-art biosensing approaches. Altogether, this biosensing platform with plug-and-play design show great potential in the detection of diverse analytes.

A CRISPR-Cas12a-derived biosensing platform for the highly sensitive detection of diverse small molecules.

Besides genome editing, CRISPR-Cas12a has recently been used for DNA detection applications with attomolar sensitivity but, to our knowledge, it has not been used for the detection of small molecules. Bacterial allosteric transcription factors (aTFs) have evolved to sense and respond sensitively to a variety of small molecules to benefit bacterial survival. By combining the single-stranded DNA cleavage ability of CRISPR-Cas12a and the competitive binding activities of aTFs for small molecules and double-stranded DNA, here we develop a simple, supersensitive, fast and high-throughput platform for the detection of small molecules, designated CaT-SMelor (CRISPR-Cas12a- and aTF-mediated small molecule detector). CaT-SMelor is successfully evaluated by detecting nanomolar levels of various small molecules, including uric acid and p-hydroxybenzoic acid among their structurally similar analogues. We also demonstrate that our CaT-SMelor directly measured the uric acid concentration in clinical human blood samples, indicating a great potential of CaT-SMelor in the detection of small molecules.

iCatch: a new strategy for capturing large DNA fragments using homing endonucleases.

Natural genetic materials contain many biosynthetic gene clusters encoding potentially valuable natural products, many of which can be used directly without codon optimization or other manipulations. With the development of synthetic biology, several DNA assembly standards have been proposed, conveniently facilitating the reuse of natural materials. Among these standards, the iBrick assembly standard was developed by our laboratory to manipulate large DNA fragments, employing two homing endonucleases. Considering the difficulty of cloning large iBrick parts using conventional endonuclease-mediated restriction and ligation methods, we herein present a new method, known as iCatch, which readily captures biosynthetic gene clusters. As the clusters cloned by iCatch have the prefix and suffix of the iBrick standard, they serve as new iBrick parts and are therefore conducive to further editing and assembly with the iBrick standard. iCatch employs the natural homologous recombination system to flank the region of interest with I-SceI and PI-PspI recognition sites, after which the genome is digested with I-SceI or PI-PspI and the fragments are then self-ligated to clone the target DNA fragments. We used this method to successfully capture the actinorhodin biosynthetic cluster from Streptomyces coelicolor and then heterologously expressed this cluster in a thermophilic Streptomyces strain. We propose that iCatch can be used for the cloning of DNA sequences that are dozens of kilobases in length, facilitating the heterologous expression of microbial natural products. Moreover, this cloning methodology can be a complementary tool for the iBrick standard, especially in applications requiring the manipulation of large DNA fragments.

CADS: CRISPR/Cas12a-Assisted DNA Steganography for Securing the Storage and Transfer of DNA-Encoded Information.

Because DNA has the merit of high capacity and complexity, DNA steganography, which conceals DNA-encoded messages, is very promising in information storage. The classical DNA steganography method hides DNA with a "secret message" in a mount of junk DNA, and the message can be extracted by polymerase chain reaction (PCR) using specific primers (key), followed by DNA sequencing and sequence decoding. As leakage of the primer information may result in message insecurity, new methods are needed to better secure the DNA information. Here, we develop a pre-key by either mixing specific primers (real key) with nonspecific primers (fake key) or linking a real key with 3'-end redundant sequences. Then, the single-stranded DNA (ssDNA) trans cleavage activity of CRISPR/Cas12a is employed to cut a fake key or remove the 3'-end redundant sequences, generating a real key for further information extraction. Therefore, with the Cas12a-assisted DNA steganography method, both storage and transfer of DNA-encoding data can be better protected.