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Targeted therapy has been standardized in front-line therapies for metastatic colorectal cancer (mCRC), while explicit recommendations for third- or later-line are still lacking. This study evaluated the efficacy and safety of combining targeted therapy with chemotherapy in the third- or later-line treatment for mCRC via meta-analysis, providing evidence-based guidance for clinical or research practice. Comprehensive retrieval of related studies was conducted according to the PRISMA guideline. Studies were stratified with patient characteristics and pharmacological classification of the drugs. For the data available for quantitative analysis, pooled overall response rate, disease control rate, hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and adverse events rate with respective 95% confidence intervals (CIs) were calculated. A total of 22 studies (1,866 patients) were included in this meta-analysis. Data from 17 studies (1,769 patients) involving targets of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) were extracted for meta-analyses. The overall response rates for monotherapy and combined therapy were 4% (95% CI: 3%, 5%) and 20% (95% CI: 11%, 29%). The pooled HRs (combined therapy vs. mono) for OS and PFS were 0.72 (95% CI: 0.53, 0.99) and 0.34 (95% CI: 0.26, 0.45). Another five studies were included in narrative depiction, involving targets of BRAF, HER-2, ROS1, and NTRK. The findings of this meta-analysis indicate that VEGF and EGFR inhibitors manifest promising clinical response rates and prolonged survival in the treatment of mCRC with acceptable adverse events. [ABSTRACT FROM AUTHOR]

Background: Gastric intestinal metaplasia (IM) is the key link of gastric precancerous lesions. Ferroptosis is a novel form of programmed cell death. However, its impact on IM is unclear. The focus of this study is to identify and verify ferroptosis-related genes (FRGs) that may be involved in IM by bioinformatics analysis. Materials and methods: Differentially expressed genes (DEGs) were obtained from microarray dataset GSE60427 and GSE78523 downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed ferroptosisrelated genes (DEFRGs) were obtained from overlapping genes of DEGs and FRGs got from FerrDb. DAVID database was used for functional enrichment analysis. Protein-protein interaction (PPI) analysis and Cytoscape software were used to screen hub gene. In addition, we built a receiver operating characteristic (ROC) curve and verified the relative mRNA expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, the CIBERSORT algorithm was used to analyze the immune infiltration in IM. Results: First, a total of 17 DEFRGs were identified. Second, a gene module identified by Cytoscape software was considered as hub gene: PTGS2, HMOX1, IFNG, and NOS2. Third, ROC analysis showed that HMOX1 and NOS2 had good diagnostic characteristics. qRT-PCR experiments confirmed the differential expression of HMOX1 in IM and normal gastric tissues. Finally, immunoassay showed that the proportion of T cells regulatory (Tregs) and macrophages M0 in IM was relatively higher, while the proportion of T cells CD4 memory activated and dendritic cells activated was lower. Conclusion: We found significant associations between FRGs and IM, and HMOX1 may be diagnostic biomarkers and therapeutic targets for IM. These results may enhance our understanding of IM and may contribute to its treatment. [ABSTRACT FROM AUTHOR]

Background: Gastric intestinal metaplasia (IM) is the key link of gastric precancerous lesions. Ferroptosis is a novel form of programmed cell death. However, its impact on IM is unclear. The focus of this study is to identify and verify ferroptosis-related genes (FRGs) that may be involved in IM by bioinformatics analysis. Materials and methods: Differentially expressed genes (DEGs) were obtained from microarray dataset GSE60427 and GSE78523 downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed ferroptosisrelated genes (DEFRGs) were obtained from overlapping genes of DEGs and FRGs got from FerrDb. DAVID database was used for functional enrichment analysis. Protein-protein interaction (PPI) analysis and Cytoscape software were used to screen hub gene. In addition, we built a receiver operating characteristic (ROC) curve and verified the relative mRNA expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, the CIBERSORT algorithm was used to analyze the immune infiltration in IM. Results: First, a total of 17 DEFRGs were identified. Second, a gene module identified by Cytoscape software was considered as hub gene: PTGS2, HMOX1, IFNG, and NOS2. Third, ROC analysis showed that HMOX1 and NOS2 had good diagnostic characteristics. qRT-PCR experiments confirmed the differential expression of HMOX1 in IM and normal gastric tissues. Finally, immunoassay showed that the proportion of T cells regulatory (Tregs) and macrophages M0 in IM was relatively higher, while the proportion of T cells CD4 memory activated and dendritic cells activated was lower. Conclusion: We found significant associations between FRGs and IM, and HMOX1 may be diagnostic biomarkers and therapeutic targets for IM. These results may enhance our understanding of IM and may contribute to its treatment. [ABSTRACT FROM AUTHOR]

A major issue in telomere research is to understand how the integrity of chromosome ends is controlled. The fact that different types of nucleoprotein complexes have been described at the telomeres of different organisms raises the question of whether they have in common a structural identity that explains their role in chromosome protection. We will review here how telomeric nucleoprotein complexes are structured, comparing different organisms and trying to link these structures to telomere biology. It emerges that telomeres are formed by a complex and specific network of interactions between DNA, RNA and proteins. The fact that these interactions and associated activities are reinforcing each other might help to guarantee the robustness of telomeric functions across the cell cycle and in the event of cellular perturbations. We will also discuss the recent notion that telomeres have evolved specific systems to overcome the DNA topological stress generated during their replication and transcription. This will lead to revisit the way we envisage the functioning of telomeric complexes since the regulation of topology is central to DNA stability, replication, recombination and transcription as well as to chromosome higher-order organization. [ABSTRACT FROM AUTHOR]

Background: To determine potential social, psychological, and environmental-structural factors that may result in motivating female sex workers (FSWs), who are rural-to-urban migrants, and their paying partners in Shanghai, China to promote consistent condom use (CCU). Methods: A cross-sectional study was conducted in five districts of Shanghai, including three suburbs and two downtown locales. We adopted a cluster randomized sampling method to obtain 20 geographic sites, which consisted of 1 or more communities/villages proximal to a location where FSWs were accessible. Five hundred four FSWs from 132 Xitou Fang (shampoo wash rooms), massage parlors, and hair salons who explicitly provided sexual services were enrolled in the study. Each participant completed a questionnaire survey and interview aimed to collect information on the perceptions and behaviors of individuals associated with a risk for human immunodeficiency virus/acquired immunodeficiency syndrome(HIV/AIDS),self-efficacy at negotiating safe sex, and the physical, social, and policy environment of the establishments where they worked. Results: The percentage of FSWs who reported consistent condom use with their paying partners was 63.3%. Controlling for socio-demographic characteristics in multivariate analyses, environmental-structural support (OR, 3.96; CI, 2.52-6.22) for condom use was the most significant positive predictor of CCU among FSWs and their regular paying partners. A high perception of susceptibility and risk of HIV/AIDS (OR, 1.96; CI, 1.25-3.01), a high perception of benefits on condom use to protect themselves (OR, 2.06; CI, 1.32-3.22), and high safe sex self-efficacy (OR, 2.52; CI, 1.64-3.85) also play important roles on CCU based on multivariate analyses. Conclusions: Environmental-structural factor support for condom use, in addition to social, psychological, and individual cognitive factors are significant predictors of CCU among FSWs, which should be assessed and addressed in research and interventions related to HIV/AIDS prevention among FSWs in China. [ABSTRACT FROM AUTHOR]

Background: China is currently facing a rapid and widespread increase in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The activities of female sex workers (FSWs) have contributed to the mounting epidemic of HIV/AIDS and other sexually transmitted diseases (STDs). Therefore, this study aimed to assess the HIV/AIDS-related knowledge, attitude and risk behaviors among FSWs operating in Shanghai China.Methods: A cross-sectional study was conducted in five districts of Shanghai, including three suburbs and two downtown locales. We adopted a cluster randomized sampling method to obtain ten geographic sites which consisted of one or more communities/villages proximal to a location where FSWs were accessible. A total of 324 FSWs from 109 Xitou Fang, massage parlors and hair salons who explicitly provided sexual services were enrolled in the study. Each participant completed a questionnaire survey and interview aimed to collect information on the individual's knowledge, attitude, and behaviors associated with risk for HIV/AIDs.Results: The overall correct answer rate of HIV/AIDS-related knowledge was 60.8%, and the knowledge of FSWs from downtown areas was significantly higher than those from suburban areas (P < 0.05). The percentage of FSWs who reported having experiences in commercial sexual services without the use of condoms was 33.6%. Condom slippage or breakage was reported as having occurred at least once by 51.2% of the FSWs. FSWs from suburban areas were found to more often engage in high-risk behaviors, including oral and anal sex, than those from downtown areas (P < 0.001). Many of the FSWs (65.7%) reported having non-client sexual partners (most were identified as boyfriends or husbands); however, condom usage with these partners were lower (34.3%).Conclusions: Based on the findings from our survey, we advise that promotion of HIV/AIDS-related knowledge be targeted towards FSWs in Shanghai, especially those operating in the suburbs. HIV prevention efforts, such as urging constant condom usage with both clients and steady partners, should be sustained and reinforced among the female sex workers population. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to investigate the relationship between the distribution of the analgesic area when different intensities of stimulation were applied to homotopic and heterotopic acupoints. The experiments were performed on volunteers; the left sural nerve was stimulated by a volley of eight rectangular pulses delivered at a frequency of 400 Hz. Electromyographic reflex responses (EMGs) were recorded from the ipsi-lateral biceps femoris muscle. Electroacupuncture stimuli were given on the skin overlying the Zusanli point (St 36), and the strengths chosen were times of the threshold eliciting a nociceptive reflex (T[sub RIII]) response (0.6, 0.8, 1.0, T[sub RIII] and T[sub supra-RIII], respectively). The effects of homotopic and heterotopic stimuli applied to St 36 on the pain sensation and the R[sub III] reflex elicited by stimulation of the left sural nerve were observed to explore the pain-relief and R[sub III] reflex-inhibition produced by stimulation of the St 36 point with different intensities. Both the nociceptive reflex and painful sensation evoked by stimulating the sural nerve were similarly inhibited by electroacupuncture at less than T[sub RIII] applied to the ipsi-lateral acupoint. In other words, acupuncture with an innocuous intensity can produce homotopic pain-alleviating effects and reflex suppression. With contra-lateral electroacupuncture at the St 36 acupoint, innocuous intensities cannot produce heterotopic pain-relieving effects; these inhibitions were only observed at electroacupuncture intensities similar to the T[sub RIII] threshold. These results suggest that local acupuncture-induced analgesia is effective with activation of large afferent fibers, whereas heterotopic acupuncture-induced analgesia is only effective with intensities strong enough to excite small afferent fibers. Local analgesic effects of acupoint stimulation involve segmental inhibition, whereas systemic analgesic effects of acupoint stimulation are involved in contra-lateral effects. The latter may recruit the diffuse noxious inhibitory controls (DNIC) system. The specific function of an acupoint is determined by the anatomical relationship between the disease focus and the segmental location of the acupoint. [ABSTRACT FROM AUTHOR]

The transition metal cadmium (Cd) has been shown to induce apoptosis in a variety of cell lines and tissues. Caspase activation of the tumor suppressor gene p53 and mitogen-activated protein kinase (MAPK) signaling cascades have been reported to be involved in Cd-induced apoptosis. However, the underlying pathways of Cd-induced apoptosis have not been clearly elucidated in the in vivo systems, primarily for the lack of appropriate animal models. The nematode Caenorhabditis elegans has been shown to be a good model to study basic biological processes, including apoptosis. In this study, we used the mutated alleles of C. elegans homologs of known mammalian genes that are involved in regulation of apoptosis. Sublethal doses of Cd exposure increased C. elegans germline apoptosis in a dose- and time-dependent manner. The loss-of-function mutations of DNA damage response (DDR) genes HUS1 and p53 exhibited significant increase in germline apoptosis under Cd exposure, and the depletion of p53 antagonist ABL1 significantly enhanced apoptosis. Cd-induced apoptosis was blocked in the loss-of-function alleles of both c-Jun N-terminal kinase (JNK) and p38 MAPK cascades, which behaved normally under γ-irradiation. Our findings implicate that both JNK and p38 MAPK cascades participate in Cd-induced apoptosis. Together, the results of this study suggest the nonessential roles of the DDR genes hus1 and p53 in Cd-induced germline apoptosis and that the apoptosis occurs through the ASK1/2-MKK7-JNK and ASK1/2-MKK3/6-p38 signaling pathways in a caspase-dependent manner. Finally, our study demonstrates that C. elegans is a mammalian in vivo substitute model to study the mechanisms of Cd-induced apoptosis. [ABSTRACT FROM AUTHOR]