Antitumor Activity and Mechanistic Insights of a Mitochondria-Targeting Cu(I) Complex.

Using copper-ionophores to translocate extracellular copper into mitochondria is a clinically validated anticancer strategy that has been identified as a new type of regulated cell death termed "cuproptosis." This study reports a mitochondria-targeting Cu(I) complex, Cu(I)Br(PPh3)3 (CBP), consisting of a cuprous ion coordinated by three triphenylphosphine moieties and a Br atom. CBP exhibited antitumor and antimetastatic efficacy in vitro and in vivo by specifically targeting mitochondria instigating mitochondrial dysfunction. The cytotoxicity of CBP could only be reversed by a copper chelator rather than inhibitors of the known cell death, indicating copper-dependent cytotoxicity. Furthermore, CBP induced the oligomerization of lipoylated proteins and the loss of Fe-S cluster proteins, consistent with characteristic features of cuproptosis. Additionally, CBP induced remarkable intracellular generation of reactive oxygen species (ROS) through a Fenton-like reaction, indicating a complex antitumor mechanism. This is a proof-of-concept study exploiting the antitumor activity and mechanism of the Cu(I)-based mitochondria-targeting therapy.

[Characteristics of Secondary Inorganic Ions in PM2.5 and Its Influencing Factors in Summer in Zhengzhou].

Nitrate (NO3-), sulfate (SO42-), and ammonium (NH4+) are important components of PM2.5, and studying their characteristics and influencing factors is essential for the continuous improvement of air quality. A series of online instruments were used to analyze the chemical components of PM2.5 in Zhengzhou in the summer of 2020. The results showed that the average ρ(PM2.5) was (28 ±13) µg·m-3, showing a daily variation characteristic of high at night and low during the day. The main concentrations of NO3-, SO42-, and NH4+ were (7.8 ±6.7), (7.2 ±3.7), and (5.5 ±3.1) µg·m-3, accounting for 22%, 21%, and 16% in PM2.5, respectively. The proportions of NO3- (27%) and SO42- (23%) in PM2.5, respectively, increased with the increase in PM2.5 and O3 concentration. In addition, the proportions of NO3- and NH4+ increased under low wind speed, high humidity, low temperature, and rainfall conditions. Moreover, the proportion of NO3- showed a daily variation characteristic of high at night and low during the day, whereas the opposite was true for SO42-. The gas-particle partitioning process of NH4NO3 was the main factor affecting the concentrations of NO3- and NH4+ in PM2.5. Low temperature, high humidity, and high aerosol water content concentrations favored the partitioning of HNO3 and NH3 to the particulate phase. High pH also favored the partitioning of gas-phase HNO3 to NO3-; however, it was not conducive to the partition of NH3 to NH4+. These trends partially explained the increase in the concentration and proportion of NO3- in PM2.5 under different scenarios.

Preoperative systemic inflammation response index: Clinicopathologic predictor of pathological complete response in HER2-positive breast cancer patients receiving neoadjuvant systemic therapy.

BACKGROUND: Multiple pretreatment systemic inflammatory markers (SIMs) have been reported as predictors of pathological complete response (pCR) after neoadjuvant systemic therapy (NST) in patients with breast cancer (BC). However, the most significant SIM remains to be conclusively identified, and variations among different molecular subtypes remain unknown. The objective of the study was to identify the most significant SIM in patients with human epidermal growth factor receptor 2 (HER2) positive BC, to construct a pCR-predictive nomogram combining it with other clinicopathologic factors, and to evaluate its prognostic value on survival. METHODS: We retrospectively reviewed the findings for 240 patients with stage I-III HER2-positive BC who underwent NST and subsequent surgery at Kaohsiung and Taichung Veterans General Hospital from 2011 to 2021. Clinicopathologic factors were analyzed by stepwise logistic regression with backward selection. The data were used to construct a nomogram plot for determining the pCR probability. Kaplan-Meier curves and log-rank test were used to evaluate disease-free survival (DFS) and overall survival (OS). RESULTS: Among the pretreatment SIMs, only the systemic inflammation response index (SIRI) was significantly related to pCR, with an optimal cutoff value of 1.27 × 10 9 /L. Stepwise logistic analyses indicated that clinical N stage, HER2 immunohistochemistry score, hormone receptor status, targeted therapy regimen, and SIRI were independent predictors of pCR, with an area under the curve of 0.722. The Hosmer-Lemeshow test and calibration curve revealed that the predictive ability was a good fit to actual observations. A nomogram was constructed based on the logistic model. The external validation of the model also revealed satisfactory discrimination and calibration. Kaplan-Meier analysis showed that patients with SIRI <1.27 had longer DFS and OS. CONCLUSION: Pretreatment SIRI <1.27 is predictive of pCR, DFS, and OS in HER2-positive BC. Our nomogram could efficiently predict pCR and facilitate clinical decision-making before neoadjuvant treatment.

F-box protein 43 promoter methylation as a novel biomarker for hepatitis B virus-associated hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) has a high prevalence and poor prognosis worldwide. Therefore, it is urgent to find effective and timely diagnostic markers. The objective of this study was to evaluate the diagnostic value of F-box protein 43 promoter methylation in peripheral blood mononuclear cells (PBMCs) for HCC. Method: A total of 247 participants were included in this study, comprising individuals with 123 hepatitis B virus-associated HCC, 79 chronic hepatitis B, and 45 healthy controls. F-box protein 43 methylation and mRNA levels in PBMCs were detected by MethyLight and quantitative real-time PCR. Result: F-box protein 43 promoter methylation levels were significantly lower in HCC PBMCs than the chronic hepatitis B (P < 0.001) and healthy control PBMCs (P < 0.001). Relative mRNA expression levels of F-box protein 43 in HCC PBMCs were significantly higher than those in chronic hepatitis B (P < 0.001) and healthy control PBMCs (P < 0.001). Receiver operating characteristic analysis of F-box protein 43 promoter methylation levels yielded an area under curve (AUC) of 0.793 with 76.42% sensitivity and 68.35% specificity when differentiating HCC from chronic hepatitis. These values for the F-box protein 43 promoter methylation level were superior to those of the alpha-fetoprotein serum (AFP) level (AUC: 0.780, sensitivity: 47.97%, and specificity: 96.20%), with increments in values for the combination of F-box protein 43 promoter methylation AFP levels (AUC: 0.888, sensitivity: 76.42%, and specificity: 86.08%). Conclusion: Hypomethylation of the F-box protein 43 promoter in PBMCs is a promising biochemical marker for HBV-associated HCC.

Comparison of overall survival after neoadjuvant and adjuvant chemotherapy in patients with early breast cancer with immediate breast reconstruction after mastectomy: A retrospective, matched case-control study.

Immediate breast reconstruction after mastectomy combined with chemotherapy is the preferred option for patients with early-stage breast cancer who require both superior clinical and aesthetic outcomes. The present study aimed to determine the survival benefits of neoadjuvant and adjuvant chemotherapy for patients with early-stage breast cancer who have undergone immediate breast reconstruction after mastectomy in Taiwan. The present study compared overall survival (OS) following neoadjuvant or adjuvant chemotherapy in 139 patients with early-stage breast cancer who underwent immediate breast reconstruction after mastectomy. Patient data were used retrospectively as an unmatched cohort. Next, 37 neoadjuvant cases were matched with 37 adjuvant controls through 1:1 age-, clinical stage-, and molecular subtype-matching. OS differences between the cases and controls were determined using Kaplan-Meier survival curve analyses. Here, 77.7 and 81.1% of the unmatched and matched cohort patients were aged <50 years, respectively. Of the matched neoadjuvant cases, 10 (15.6%) reached pathologic complete response after neoadjuvant chemotherapy, whereas 5 (13.5%) neoadjuvant cases succumbed during the study period. The neoadjuvant matched cases demonstrated a significantly poor OS with their adjuvant matched controls (P=0.044); nevertheless, the stratification analysis results demonstrated that the survival differences between the neoadjuvant and the adjuvant controls decreased after matching. Targeted therapy demonstrated the same OS benefits for both the neoadjuvant matched cases and adjuvant matched controls (P=1.000). This study provided matched case-control evidence for the feasibility of neoadjuvant chemotherapy combined with targeted therapy for patients with early-stage breast cancer with immediate breast reconstruction after mastectomy in a Taiwanese female population.

IL-6 Promoter Hypomethylation Acts As a Diagnostic Biomarker in Hepatitis B Virus-Associated Hepatocellular Carcinoma.

Background: New biomarkers are needed to detect hepatocellular carcinoma at an earlier stage and to individualize treatment strategies. IL-6 has been proven to be associated with liver cancer in numerous studies. Aim: To evaluate the value of the IL-6 promoter methylation level as a noninvasive biomarker for the diagnosis of liver cancer. Methods: A retrospective analysis of 165 patients with HBV-associated hepatocellular carcinoma (HCC), 198 patients with chronic hepatitis B (CHB) and 31 healthy controls were involved. The methylight was detected the methylation level of the IL-6 promoter in peripheral blood mononuclear cells (PBMCs), clinical and laboratory parameters were obtained. Results: IL-6 promoter methylation levels were significantly lower in patients with HCC (median 53.59%, interquartile range 52.01-54.75%) than in those with CHB (median 56.05%, interquartile range 54.65-57.67%; P<0.001). The level of IL-6 mRNA in patients with HCC (median 0.371, interquartile range 0.173-0.671) was significantly higher than that in patients with CHB (median 0.203, interquartile range 0.108-0.354; P<0.001) and HCs (median 0.189, interquartile range 0.140-0.262; P=0.001). Meanwhile, the PMR value of IL-6 was notably negatively correlated with the mRNA expression level (Spearman's R=-0.201, P<0.001). The IL-6 PMR value of HCC patients in age (Spearman's R=0.193, P=0.026) and TBIL (Spearman's R=0.186, P=0.032) were very weak correlated. At the same time, the level of IL-6 promoter methylation was also an independent factor in the development of liver cancer. When the IL-6 promoter methylation level was used to diagnose HCC, its detective value was superior to AFP [area under the receiver operating characteristic curve (AUC) 0.773 vs. 0.686, P=0.027], And the combined use of AFP and IL-6 methylation level can improve the area under the receiver operating characteristic curve (p=0.011). Conclusion: IL-6 promoter hypomethylation is present in hepatocellular carcinoma, and it may be used as a noninvasive biomarker to detect early liver cancer.

[Concentration, Source, and Health Risk Assessment of PM1 Heavy Metals in Typical Pollution Processes in Zhengzhou].

Heavy metal elements in particulate matter can cause adverse effects on human health, and the smaller the particle size, the greater the harm. A total of 16 heavy metal elements (Al, Si, K, Ca, V, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Ba, Pb, and Cd) in PM1 were continuously determined by an online heavy metal observation instrument in Zhengzhou city from January 7 to 25, 2021. The results showed that ρ(K) concentration was the highest during the observation period (0.62 µg·m-3). According to pollutant concentration and meteorological characteristics, the observation period was divided into clean days, dust days, and haze days. The contribution of heavy metal pollution characteristics and health risk assessment in atmospheric PM1 was different under different pollution processes. The US EPA health risk assessment method was used to assess the health risks of heavy metals, and the enrichment factor method and positive matrix factorization (PMF) were used to analyze the sources of heavy metals. The influence of the transmission was evaluated by using the concentration-weighted trajectory (CWT) method and the backward trajectory method. The results show that the enrichment factors of Zn, As, Se, Pb, and Cd were more than 100 under different pollution processes, which were greatly affected by human activities. During the sampling period, the main sources of heavy metals were industrial sources, coal/biomass sources, motor vehicle sources, and dust sources. The results of the health risk assessment were substituted into PMF analysis, and it was found that industrial sources were the main contributing sources of carcinogenic and non-carcinogenic health risks during cleaning days, dust days, and haze days, and the carcinogenic risk of heavy metal elements in PM1 in this region for adults exceeded that for children. CWT and backward trajectory methods revealed that regional transmission was one of the main factors affecting local health risks.

[Chemical Components and Sources of PM2.5 and Their Evolutive Characteristics in Zhengzhou].

To explore the main sources of PM2.5 and the characteristics of seasonal differences in Zhengzhou, PM2.5 sampling was conducted in 2019 and the concentrations of inorganic water-soluble ions, carbon components, and various elements were analyzed. Results showed that the average mass concentration of PM2.5 in 2019 was (67.0±37.2) µg ·m-3 with the highest concentration in winter and the lowest in summer. The main components of PM2.5 were nitrate, ammonium, sulfate, organic matter, crustal matter, and elemental carbon. In spring and autumn, PM2.5 was greatly affected by crustal matter and elemental carbon, and In summer, concentrations were mainly affected by sulfate. In winter, the concentrations of organic matter and nitrate increased significantly, produced by photochemical reactions in summer and aqueous-phase reactions under high humidity in winter. Carbonaceous aerosols were greatly influenced by automobile exhaust emission, coal combustion, and biomass combustion. Source apportionment showed that secondary sources were the greatest contributors in all four seasons, particularly in in winter (56.5%). Among the primary sources, the proportion of dust in spring (15.2%) and autumn (11.4%) was slightly higher, and the contribution of motor vehicle pollution was the largest (12.3%) in summer. In winter, PM2.5was greatly affected by coal combustion (13.2%). From 2014 to 2019, PM2.5 in Zhengzhou increased annually under the influence of secondary sources. The contribution of industrial sources, biomass combustion sources, and coal combustion sources exhibited a downward trend over this period.

Hypermethylation of secreted frizzled related protein 2 gene promoter serves as a noninvasive biomarker for HBV-associated hepatocellular carcinoma.

For patients with hepatocellular carcinoma (HCC), early detection is critical to improve survival. Secreted frizzled-related protein 2 (SFRP2) is a candidate tumor suppressor as Wnt antagonist and SFRP2 promoter has been found hypermethylated in various malignancies. This study aimed to investigate the methylation status of SFRP2 promoter in hepatitis B virus (HBV) associated HCC and estimate its diagnostic value as a non-invasive biomarker. A total of 293 patients, including 132 patients with HBV-associated HCC, 121 with chronic hepatitis B (CHB) and 40 healthy controls (HCs) were enrolled. SFRP2 methylation level in peripheral mononuclear cells (PBMCs) was quantitatively detected by MethyLight. SFRP2 methylation level was significantly higher in patients with HBV-associated HCC than in those with CHB (p < 0.001) and HCs (p < 0.001) while mRNA level of SFRP2 was significantly lower in HCC group than the other two groups (p < 0.05). In HCC subgroup, SFRP2 methylation level markedly increased in patients >50 years old, female, with negative HBeAg, negative HBV-DNA and poor differentiation compared with the remaining groups (P < 0.05). Furthermore, SFRP2 methylation level showed a significantly better diagnostic value than alpha-fetoprotein (AFP) and the combination of AFP and methylation levels of SFRP2 markedly improved the area under the receiver operating characteristic curve (p < 0.05). In conclusion, hypermethylation of SFRP2 promoter exists in HBV-associated HCC. The combination of SFRP2 methylation level in PBMCs and AFP could significantly improve the diagnostic ability of AFP in discriminating HBV-associated HCC from CHB and SFRP2 methylation level had the potential to serve as a non-invasive biomarker for HCC diagnosis.

RIPK3 mRNA level acts as a diagnostic biomarker in hepatitis B virus-associated hepatocellular carcinoma.

HBV-associated hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and non-invasive early detection of HBV-associated HCC requires to be improved. To determine the alteration and clinical relevance of necroptosis and its key regulator receptor-interacting protein kinase 3 (RIPK3) in HBV-associated HCC, we detected the mRNA level of RIPK3 in peripheral blood mononuclear cells (PBMCs) and analyzed its correlation with clinical parameters. Here, we demonstrate that the expression of RIPK3 is elevated in patients with HBV-associated HCC compared to patients with chronic hepatitis B (CHB) and patients with HBV-related liver cirrhosis (LC). The mRNA level of RIPK3 is positively correlated with the severity of clinical manifestations and TNM stages. Moreover, the serum levels of RIPK3-asssocited cytokines are altered in consistent with the change of RIPK3 expression. The diagnostic accuracy of RIPK3 mRNA level is comparable to AFP test in discriminating HBV-associated HCC from LC and is better than AFP test in discriminating HBV-associated HCC from CHB. The combination of RIPK3 mRNA level and AFP test significantly improves the diagnosis of HBV-associated HCC. These data suggest that RIPK3 mRNA level is a biomarker in the onset and progression of HBV-associated HCC and may provide novel diagnostic strategies combined with the AFP test.

The Efficacy of Pegylated Liposomal Doxorubicin-Based Neoadjuvant Chemotherapy in Breast Cancer: A Retrospective Case-Control Study in Taiwan.

Breast cancer is a global issue regarding women's health, and high incident rates remain in the Taiwanese female population. Chemotherapy, using anthracycline-based chemotherapeutic agents in neoadjuvant settings, has been introduced as a promising new therapeutic option for treatment of invasive breast cancer. Set apart from conventional anthracycline regimens such as epirubicin, pegylated liposomal doxorubicin (Lipo-Dox®, PLD) was introduced for providing a justifiable treatment effect, while offering a favorable toxicity profile for breast cancer patients in a metastatic setting. However, the efficacy of PLD in neoadjuvant settings for breast cancer patients has not yet been sufficiently reported. This study aims to investigate the efficacy of PLD-based neoadjuvant chemotherapy in breast cancer patients using a retrospective matched case-control study. A total of 183 PLD cases and 183 epirubicin-based controls were included after a 1 : 1 ratio case-control matching procedure was held, according to the matching criteria. These criteria included the patient's preoperative clinical stage, molecular subtype, chemotherapy regimen with taxanes prior to surgery, and histological grade. All data were collected according to an institutional review board approved protocol. The study results reported that the PLD and epirubicin groups both obtained similar outcomes in pathologic complete response (pCR), recurrence, and overall survival rate with no statistically significant differences. Overall, the study results demonstrate that PLD-based neoadjuvant chemotherapy offers a similar effect of treatment with a favorable toxicity profile within the study follow-up duration, when compared with conventional epirubicin-based neoadjuvant chemotherapy.

Accuracy augmentation of body composition measurement by bioelectrical impedance analyzer in elderly population.

Bioelectrical impedance analysis (BIA) is currently the most commonly used method in clinical practice to measure body composition. However, the bioelectrical impedance analyzer is not designed according to different countries, races, and elderly populations. Because different races may have different body compositions, a prediction model for the elderly population in Taiwan should be developed to avoid population bias, thereby improving the accuracy of community evaluation surveys.Dual energy X-ray absorptiometry (DXA) was used as a standard method for comparison, and impedance analysis was used for the development of a highly accurate predictive model that is suitable for assessing the body composition of elderly people.This study employed a cross-sectional design and recruited 438 elderly people who were undergoing health examinations at the health management center in the Tri-Service General Hospital as study subjects. Basic demographic variables and impedance analysis values were used in four predictive models, namely, linear regression, random forest, support vector machine (SVM), and eXtreme Gradient Boosting (XGBoost) models, to predict DXA body composition. The data from 354 study subjects were used to develop the predictive model, while the data from 84 study subjects were used to validate the accuracy of the predictive model.The body composition of elderly people as estimated by InBody 720 was highly correlated with that estimated by DXA. The correlation coefficient between InBody 720 and DXA for muscle mass was 0.969, and that for fat mass was 0.935. Consistency analysis results showed that InBody 720 tends to underestimate muscle mass and fat mass. A comparison of the accuracy of the linear regression, random forest, SVM, and XGBoost models showed that the linear regression has the highest accuracy. The correlation coefficient between the new model and DXA for muscle mass and fat mass were 0.977 and 0.978, respectively.The new predictive model can be used to monitor the nutrition status of elderly people and identify people with sarcopenia in the community.

Everolimus-associated cytomegalovirus colitis in a patient with metastasized breast cancer: a case report.

PURPOSE: Anti-cancer therapy put patients in an immunocompromised status. Reactivation of cytomegalovirus (CMV) in immunocompromised patient can cause a severe disease. Thus, we presented a case who had recurrent CMV colitis which complicate with rectovaginal fistula. METHODS: We present a case of everolimus-associated cytomegalovirus colitis on a patient receiving everolimus and exemestane therapy for the treatment of metastasized breast cancer. RESULTS: The patient presented septic shock and acute peritonitis at first. Emergency exploratory laparotomy was performed. However, only edematous changes were observed over the terminal ileum, sigmoid colon and rectum. Four weeks after operation, we found feces coming out from her vagina. Colonoscopy was done and revealed rectovaginal fistula. Colonic and rectal mucosa moderate inflammation with multiple ulcer was also noted. Biopsy was done and the pathology proved CMV colitis. After treatment with ganciclovir, her symptoms improved. Everolimus was stopped for 12 weeks and was added back with a decreasing dose paradigm for breast cancer treatment. However, another episode of CMV colitis occurred again after resuming the everolimus. After anti-virus treatment, she was discharged. Due to adverse effects, everolimus therapy was discontinued. CONCLUSION: The standard treatment of hormone receptor positive and HER-2 negative metastatic breast cancer is everolimus together with exemestane. Due to the immunosuppressive effects of everolimus, the medication may cause invasive fungal infection or other opportunistic infections. Such infections are serious and may even be fatal. In this case, we did not consider CMV infection until rectovaginal fistula formation. Thus, for solid cancer patients presented with fever of unknown origin, clinicians should consider potential complications of CMV infection.

Human cancer cells retain modest levels of enzymatically active matriptase only in extracellular milieu following induction of zymogen activation.

The type 2 transmembrane serine protease matriptase is broadly expressed in human carcinomas and hematological cancers. The proteolytic activity of matriptase is a potential target of drugs and imaging probes. We assessed the fate of active matriptase following the induction of matriptase zymogen activation. Exposing eight human carcinoma cells to pH 6.0 buffer induced robust matriptase zymogen activation followed by rapid inhibition of the nascent active matriptase by hepatocyte growth factor activator inhibitor (HAI)-1. Consequently, no enzymatically active matriptase was detected in these cells. Some active matriptase is, however, rapidly shed to the extracellular milieu by these carcinoma cells. The lack of cell-associated active matriptase and the shedding of active matriptase were also observed in two hematological cancer lines. Matriptase shedding is correlated closely with the induction of matriptase activation, suggesting that matriptase activation and shedding are kinetically coupled. The coupling allows a proportion of active matriptase to survive HAI-1 inhibition by rapid shedding from cell surface. Our study suggests that cellular free, active matriptase is scarce and might not be an effective target for in vivo imaging and drug development.