Management and Mechanisms of Diarrhea Induced by Tyrosine Kinase Inhibitors in Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer.

Breast cancer has the highest incidence among female malignancies, significantly impacting women's health. Recently, numerous HER2-targeted therapies have achieved excellent clinical outcomes. Currently, anti-HER2 drugs are divided into three main categories: monoclonal antibodies, small-molecule tyrosine kinase inhibitors, and antibody-coupled drugs (ADCs). The main toxic side effects of small molecule TKI-based therapy are diarrhea, hand-foot syndrome, rash, nausea, and vomiting. Diarrhea is a potential predictor of tumor response, affecting up to 95% of cancer patients treated with TKIs. Severe gastrointestinal toxicity can result in the need for dose reductions and treatment interruptions. This not only compromises the efficacy of TKIs but also deteriorates human nutrition and quality of life. The majority of individuals develop diarrhea within 7 days of starting treatment, with approximately 30% developing grade 3 or higher diarrhea within 2-3 days of starting treatment. The severity of diarrhea typically correlates with the dosage of most TKIs. Current prevention and management strategies are primarily empirical, focusing on symptom alleviation rather than addressing the toxicological mechanisms underlying TKI-induced diarrhea. Consequently, anti-diarrheal drugs are often less effective in managing this condition in cancer patients receiving TKIs. Moreover, our understanding of the toxicological mechanisms responsible for such diarrhea remains limited, underscoring the urgent need to identify these mechanisms in order to develop effective anti-diarrheal medications tailored to this specific context. This review aims to elucidate management approaches and mechanisms for diarrhea induced by TKIs during HER2-positive breast cance.

Breast cancer has the highest incidence among female malignancies, significantly impacting women's health. In recent years, numerous HER2-targeted therapies have been developed, including lapatinib, neratinib, tucatinib, and pyrotinib. However, second-generation tyrosine kinase inhibitors (TKIs) often cause severe gastrointestinal toxicity, necessitating dose reduction and treatment interruption. This not only compromises the efficacy of TKIs but also deteriorates nutritional status and quality of life. Diarrhea is a potential predictor of tumor response and is the second most common adverse event, affecting up to 95% of cancer patients treated with TKIs. Approximately 30% of these patients experience grade 3 or higher diarrhea within just 2-3 days of initiating TKI treatment. The severity of diarrhea typically correlates with the dosage of most TKIs. Current prevention and management strategies are primarily empirical, focusing on symptom alleviation rather than addressing the toxicological mechanisms underlying TKI-induced diarrhea. Consequently, anti-diarrheal drugs are often less effective in managing this condition in cancer patients receiving TKIs. Moreover, our understanding of the toxicological mechanisms responsible for such diarrhea remains limited, underscoring the urgent need to identify these mechanisms to develop effective antidiarrheal medications tailored for this specific context. This review aims to elucidate management approaches for diarrhea induced by HER2 tyrosine kinase inhibitors during breast cancer treatment.

Development and validation of a nomogram integrating marital status for 5-year overall survival of chondrosarcoma: a population-based study.

OBJECTIVES: The objective of this study was to evaluate the influence of marital status on overall survival (OS) and develop a nomogram for predicting 5-year OS in chondrosarcoma (CHS) patients. METHODS: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify CHS patients diagnosed between 2010 and 2018. Survival rates were calculated using Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analyses. An independent cohort was used for external validation of the nomogram. Performance evaluation of the nomogram was conducted using Harrell's concordance index (C-index), calibration plot, and decision curve analysis (DCA). RESULTS: In the SEER cohort, Kaplan-Meier analysis showed significant differences in OS among CHS patients with different marital statuses (P < 0.001), with widowed patients having the lowest OS. In terms of gender, there were significant survival differences based on marital status in females (P < 0.001), but not in males (P = 0.067). The OS of married and single females is significantly higher than that of married (P < 0.001) and single male (P = 0.006), respectively. Kaplan-Meier curves showed no significant difference in OS between groups stratified by either gender or marital status in the external cohort. Univariate and multivariate analyses confirmed that age at diagnosis, gender, marital status, tumor size, histological type, tumor grade, SEER stage, and surgery were independent prognostic factors for OS. The nomogram demonstrated high internal and external validation C-indexes of 0.818 and 0.88, respectively. Calibration plots, DCA curve, and Kaplan-Meier curve (P < 0.001) confirmed the excellent performance and clinical utility of the nomogram. CONCLUSIONS: Marital status was an independent factor influencing OS in CHS patients, with widowed patients having the worst prognosis. The OS of both married and single females is significantly higher than that of their male counterparts. However, these findings require further validation in a large independent cohort. While the contribution of marital status on predicting OS appears modest, our nomogram accurately predicted 5-year OS and identified high-risk groups, providing a valuable tool for clinical decision-making.

PI3K/AKT/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.

Efficacy, safety, and predictive model of Palbociclib in the treatment of HR-positive and HER2-negative metastatic breast cancer.

PURPOSE: This research designeded to: 1. Analyze the efficacy and safety of Palbociclib treatment in HR-positive and HER2-negative (HR + /HER2-) metastatic breast cancer(MBC) patients. 2. Establish and validate a nomogram model for predicting the progression-free survival (PFS) rates of 6 months, 12 months, and 18 months in HR + /HER2- MBC patients after receiving Palbociclib plus endocrine therapy (ET). PATIENTS AND METHODS: 1. This research retrospectively analyzed the efficacy and safety of Palbociclib combined with ET in 214 patients with HR + /HER2- MBC. 2. A nomogram was designed and constructed with the retrospective clinical data of 214 patients with HR + /HER2- MBC who received Palbociclib plus ET at Zhejiang Cancer Hospital in China from August 2018 to August 2022. Among these patients, 161 were randomly assigned to the training cohort, while 53 to the validation cohort. The predictive accuracy of the nomogram was assessed through the analysis the area under the receiver operating characteristic(ROC) curve, calibration curve, and decision curve analysis(DCA). RESULTS: 1. Median PFS was 7.17 months (95% CI: 7.61-10.05 months), with an objective response rate (ORR) of 2.80% and a disease control rate (DCR) of 34.58%. The most prevalent grade 3-4 adverse event was neutropenia (38.79%). 2. Multiple variable analysis of the training set revealed that age < 60 years old, PR < 20%, Ki-67 ≥ 20%, luminal B molecular subtype, primary resistance to ET, receipt of late-stage chemotherapy, and presence of liver metastasis or ≥ 2 visceral metastases were independent prognostic factors associated with poor PFS (P < 0.05). Then, the predictive model underwent development and validation utilizing the aforementioned parameters. On the one hand, the area under the ROC curve (AUC) values of the training set at 6 months, 12 months, and 18 months were 0.771, 0.783, and 0.790, respectively, indicating a strong predictive ability of the developed model. On the other hand, the AUC of the validation set at 6 months, 12 months, and 18 months were 0.720, 0.766, and 0.754, respectively, suggesting the favorable discriminatory ability of the model. The calibration curves also exhibited a good fit with the ideal curves, and the DCA demonstrated the clinical applicability of the model. The nomogram's different scores could distinguish PFS. CONCLUSION: This retrospective study demonstrates the efficacy of Palbociclib in Chinese breast cancer patients. Moreover, the clinical parameters showed a significant association with the prognosis of HR + /HER2- MBC, and the prognostic models constructed based on these variables also displayed robust predictive power, which could offer more intuitive and convenient references for clinical doctors to formulate follow-up treatment plans.

Ginsenoside Rh4 inhibits inflammation-related hepatocellular carcinoma progression by targeting HDAC4/IL-6/STAT3 signaling.

This study aimed to investigate the effects of Ginsenoside Rh4 (Rh4) on inflammation-related hepatocellular carcinoma (HCC) progression and the underlying mechanism. HCC cells (HUH7 and LM3) were induced by lipopolysaccharide (LPS) to establish an inflammatory environment in the absence or presence of Rh4. CCK-8, wound healing and transwell assays were employed to analyze the viability, migration and invasion of HCC cells. Ki67 expression was detected by immunofluorescence method. Besides, the levels of glucose and lactic acid were tested by kits. The expression of proteins related to migration, glycolysis and histone deacetylase 4 (HDAC4)/IL-6/STAT3 signaling was measured with western blot. The transplantation tumor model of HCC in mice was established to observe the impacts of Rh4 on the tumor growth. Results indicated that Rh4 restricted the viability and Ki67 expression in HCC cells exposed to LPS. The elevated migration and invasion of HCC cells triggered by LPS were reduced by Rh4. Additionally, Rh4 treatment remarkably decreased the contents of glucose and lactic acid and downregulated LDHA and GLUT1 expression. The database predicated that Rh4 could target HDAC4, and our results revealed that Rh4 downregulated HDAC4, IL-6 and p-STAT3 expression. Furthermore, the enforced HDAC4 expression alleviated the effects of Rh4 on the proliferation, migration, invasion and glycolysis of HCC cells stimulated by LPS. Taken together, Rh4 could suppress inflammation-related HCC progression by targeting HDAC4/IL-6/STAT3 signaling. These findings clarify a new anti-cancer mechanism of Rh4 on HCC and provide a promising agent to limit HCC development.

Ginsenosides: changing the basic hallmarks of cancer cells to achieve the purpose of treating breast cancer.

In 2021, breast cancer accounted for a substantial proportion of cancer cases and represented the second leading cause of cancer deaths among women worldwide. Although tumor cells originate from normal cells in the human body, they possess distinct biological characteristics resulting from changes in gene structure and function of cancer cells in contrast with normal cells. These distinguishing features, known as hallmarks of cancer cells, differ from those of normal cells. The hallmarks primarily include high metabolic activity, mitochondrial dysfunction, and resistance to cell death. Current evidence suggests that the fundamental hallmarks of tumor cells affect the tissue structure, function, and metabolism of tumor cells and their internal and external environment. Therefore, these fundamental hallmarks of tumor cells enable tumor cells to proliferate, invade and avoid apoptosis. Modifying these hallmarks of tumor cells represents a new and potentially promising approach to tumor treatment. The key to breast cancer treatment lies in identifying the optimal therapeutic agent with minimal toxicity to normal cells, considering the specific types of tumor cells in patients. Some herbal medicines contain active ingredients which can precisely achieve this purpose. In this review, we introduce Ginsenoside's mechanism and research significance in achieving the therapeutic effect of breast cancer by changing the functional hallmarks of tumor cells, providing a new perspective for the potential application of Ginsenoside as a therapeutic drug for breast cancer.

Clinical outcomes and biomarkers of phyllodes tumors of the breast: A single-center retrospective study.

PURPOSE: Phyllodes tumors (PTs) are rare neoplasms with a certain risk of recurrence and/or metastasis. In clinical practice, there is a lack of high-quality clinical studies and unified guidelines to guide the treatment. MATERIALS AND METHODS: All malignant and recurrence/metastasis PTs were retrospectively collected, which were diagnosed from 2008 to 2022. RESULTS: A total of 82 patients were enrolled, including 69 malignant and 13 borderline tumors. 96.3% (79/82) received surgical treatment. During a median follow-up of 55.5 months, 20 patients (20/82, 24.4%) had distant metastasis (DM), while 32 (32/82, 39.0%) had local recurrence (LR). Univariate analysis showed the survival of PTs was associated with surgical methods (p < 0.001), tumor size (p = 0.026), and biological behavior (p = 0.017), but not age at diagnosis. In relapsed borderline PTs, we did not find deaths due to disease progression. Patients with DM were all malignant PTs, with disease-progression occurring within 3 years in more than 80% of patients. Among salvage treatments, the combination of antiangiogenic drugs improved the prognosis to some extent, with a significant increase in mPFS (2.77 vs. 1.53 months), but no significant statistical results were obtained (p = 0.168). Lactate dehydrogenase (LDH) was an independent predictor of the prognosis for malignant PTs (p = 0.001, HR = 1.203, 95%CI, 1.082-1.336). CONCLUSION: Borderline PTs rarely metastasize, and even if LR occurs, surgical resection can lead to long-term survival. In metastatic phyllodes tumors (MPT), systemic therapy is not effective, but antiangiogenic drugs may prolong survival. LDH is an independent prognostic factor for malignant PTs to identify high-risk tumors.

LCZ method is more effective than traditional LUCC method in interpreting the relationship between urban landscape and atmospheric particles.

Landscape classification methods significantly impact the exploration of the mechanism of the relationship between landscapes and atmospheric particulate matter. This study compared the local climate zones (LCZs) and traditional land use/cover change (LUCC) landscape classification methods in explaining spatial differences in concentrations of atmospheric particulate matter (PM2.5 and PM10) and explored the mechanisms involved in how landscape elements affect atmospheric particulate matter. This was done by establishing a PM2.5 and PM10 land use regression (LUR) model of LCZ and LUCC landscapes under low, typical, and high particle concentration gradients in urban and suburban areas. The results show that under an LCZ classification system, the number of patches in the urban area of Shanghai was 548 times higher than that of a LUCC system. Moreover, LCZs were successfully established for LUR models in 12 scenarios, while only five models were established for LUCC, all of which were suburban models. The R2 of the LUR model based on the LCZ landscape and atmospheric particulate matter was mostly higher than that of the LUCC. For unnatural landscapes, the LUCC demonstrated that an urbanized environment positively affects the concentration of atmospheric particles. However, the LCZ analysis found that areas with high-density buildings have a positive effect on atmospheric particles, while most areas with low-density buildings significantly reduced the number of atmospheric particles present. Generally, compared with the traditional LUCC landscape classification method, LCZ integrates Shanghai's physical structure and classifies the urban landscape more accurately, which is closely related to the urban atmospheric particulate matter, especially in the urban area. Because the low-density building area has the same effect on the particulate matter as the natural landscape, the use of low-density buildings is recommended when planning new towns.

Effects of revetments on soil ecosystems in the urban river-riparian interface.

By altering material and energy exchange between river and riparian, the city revetments have an unknown impact on the service function of river-riparian interface (RRI) ecosystems. This study analyzes the differences in natural, permeable (PR), and impervious revetment (IR). We found that the water-filled porosity of revetment increased from 20% to 100%, which coincided with an increase in soil potassium, air-filled porosity, the surface soil of moisture and organic matter (SOM), and a decrease in soil nitrogen, phosphorus nutrients, and in the middle and deep soil SOM. The changes affected the abundance of dominant bacterial and fungi genera. Compared with the PR, surface soil moisture, pH, and underground biomass were lower in IR surface soils, while surface soil SOM and middle soil moisture were higher. This research provides a development direction and theoretical basis for future urban planning and environmental governance.

BuFeiXiaoJiYin ameliorates the NLRP3 inflammation response and gut microbiota in mice with lung cancer companied with Qi-yin deficiency.

INTRODUCTION: NLRP3 inflammasome responses and gut microbiota have been shown an important role in lung cancer, however, the relationship between gut microbiota and NLRP3 inflammasome responses in lung cancer with Qi-yin deficiency remains elusive. METHODS: To investigate the effect of the traditional Chinese medicine BuFeiXiaoJiYin (BFXJY) on NLRP3 inflammasome responses and dysbiosis in lung cancer with Qi-yin deficiency, the female BALB/cA-nu mice were treated with LPS and ATP to induce inflammation, and were intragastrically treated with warm Chinese medicine and smoked with shavings to induce Qi-yin deficiency, as well as were injected with 1 × 107/ml A549 cells to simulate lung cancer. Then the three different doses of BuFeiXiaoJiYin (BFXJY) and positive control (CRID3) were used for intervention in mice for 27 consecutive days. Then, we estimated the protection effect of BFXJY on lung cancer mice with Qi-yin deficiency, through deterring tumor growth, NLRP3 inflammasome, PKC signaling, and homeostasis of gut microbiota. RESULTS: In this study, we found that BFXJY could inhibit the tumor growth in lung cancer with Qi-yin deficiency by reducing the production of IL-1ß and IL-18 and inhibiting NLRP3 inflammasome activation, which might be associated with the inhibition of PKC signaling. Furthermore, BFXJY could promote microbial diversity and balance the microbial composition changes induced by inflammation and Qi-yin deficiency in lung cancer. CONCLUSION: BuFeiXiaoJiYin ameliorates the NLRP3 inflammation response and gut microbiota in mice with lung cancer companied with Qi-yin deficiency. Our study provides a theoretical basis for the clinical development of therapeutic drugs targeting to treat lung cancer.

Freeze-thaw cycle frequency affects root growth of alpine meadow through changing soil moisture and nutrients.

Alpine meadows grow in alpine regions and play an important role in the production and life of alpine regions. As a unique feature of alpine regions, freeze-thaw cycles (FTCs) affect the growth of alpine meadows. However, with climate change, the change in the freeze-thaw cycle frequency (FTCF) has become obvious. These changes affect the content and distribution of soil moisture and nutrients, as well as the growth of roots in the alpine meadow. Therefore, based on the analysis of FTCF in the Nagqu River Basin, the characteristics of soil moisture, nutrients, and alpine meadow roots are analyzed, thus revealing the influence mechanism of FTCF on the root growth of alpine meadows. The results highlight three major findings. (1) Compared with the low-frequency mode (LFM), the moisture at 0-20, 20-40, and 40-60 cm in the high-frequency mode (HFM) has decreased by 30.74%, 52.89%, and 47.52%, respectively. Additionally, in HFM the contents of soil hydrolysable nitrogen (HN), available K (AK), and microbial biomass carbon (MBC) at the same depth are lower than those in LFM. (2) The original distribution of soil moisture at 0-60 cm has gradually increased from the surface to the bottom. However, with the increase in FTCF, the distribution of the soil moisture now means that the soil moisture at the surface (0-20 cm) and the deeper layers (40-60 cm) is higher than that in the middle (20-40 cm). (3) With the increase in FTCF, the growth mode of alpine meadow roots has changed from vertical extension to horizontal divergence; the distribution range of roots has changed from 0-40 cm to 0-20 cm; the length, surface area, and volume of 0-0.5 mm roots have increased by 20.95 cm, 1.90 cm2, and 0.014 cm3; and the corresponding specific gravity has increased by 9.09%, 13.50%, and 12.14%, respectively. This study provides a theoretical basis for predicting the growth mode of alpine meadow roots in the Nagqu River Basin under the influence of climate change and provides guidance for protecting the ecology of alpine regions and mitigating and solving global climate change.

Effect of Climate Change on CO2 Flux in Temperate Grassland, Subtropical Artificial Coniferous Forest and Tropical Rain Forest Ecosystems.

The interactions between CO2 flux, an important component of ecosystem carbon flux, and climate change vary significantly among different ecosystems. In this research, the inter-annual variation characteristics of ecosystem respiration (RE), gross ecosystem exchange (GEE), and net ecosystem exchange (NEE) were explored in the temperate grassland (TG) of Xilinhot (2004-2010), the subtropical artificial coniferous forest (SACF) of Qianyanzhou (2003-2010), and the tropical rain forest (TRF) of Xishuangbanna (2003-2010). The main factors of climate change affecting ecosystem CO2 flux were identified by redundancy analysis, and exponential models and temperature indicators were constructed to consider the relationship between climate change and CO2 flux. Every year from 2003 to 2010, RE and GEE first increased and then decreased, and NEE showed no significant change pattern. TG was a carbon source, whereas SACF and TRF were carbon sinks. The influence of air temperature on RE and GEE was greater than that of soil temperature, but the influence of soil moisture on RE and GEE was greater than that of air moisture. Compared with moisture and photosynthetically active radiation, temperature had the greatest impact on CO2 flux and the exponential model had the best fitting effect. In TG and SACF, the average temperature was the most influential factor, and in TRF, the accumulated temperature was the most influential factor. These results provide theoretical support for mitigating and managing climate change and provide references for achieving carbon neutrality.

Effects of revetments on soil denitrifying communities in the urban river-riparian interface.

The river-riparian interface plays an important role in removal of nitrogen pollution. Many revetments have been built in urban riparian zones, which has affected soil denitrification function of river-riparian interface. However, the impacts of revetments on denitrifying communities of soil in the river-riparian interface are still unclear. In this study, in the case of eliminating the influence of plants, three modes of revetments (No Revetments (NR), Impervious Masonry Revetments (IR), and Permeable Concrete Imitation Pile Revetments (PR)) were employed to determine the influence of revetments on denitrifying communities of soil among three distances from revetments (1.0, 0.6 and 0.3 m). It was shown in comparison with IR and NR, PR promoted the abundance, diversity and relative abundance of major strains in nirS and nirK denitrifying bacteria (P < 0.05), but these effects decreased as distances increased. Compared with the IR (2.95 ± 1.15 × 105 copies g-1) and NR (4.13 ± 2.14 × 105 copies g-1), abundances of nirK denitrifying bacteria adjacent to PR (6.19 ± 1.89 × 105 copies g-1) were significantly higher (P < 0.05). Rubrivivax and Bradyrhizobium were the dominant bacterial genera, accounting for 16.02-23.94% and 29.25%-38.25% of nirS- and nirK- denitrifying bacteria, respectively. SOC and nitrogen availability were the primary factors which influence the gene richness of nirK and nirS, while soil bulk density, sand content and WFPS as the major elements were impacting compositions of nirK and nirS communities. The results will improve the comprehension of theoretical process of denitrification affected by revetment types.

[Determination of target compounds in cefoperazone sodium and tazobactam sodium for injection by capillary electrophoresis].

A capillary zone electrophoresis (CZE) method was developed for the simultaneous determination of cefoperazone sodium and tazobactam sodium in the injectable powder of cefoperazone sodium and tazobactam sodium with hydrochlorothiazide as the internal standard. The operation was carried out on a quartz capillary (75 cm x 75 microm i. d. , 63 cm effective length). The electrophoretic conditions were as follows: 40 mmol/L borax solution as the back ground electrolyte (BGE), 12. 0 kV applied voltage, 220 nm as the detection wavelength; the sample solution was injected by hydraulic pressure for 10 s at the height of 10 cm. The cefoperazone and tazobactam showed good linear relationship in the ranges of 0.25-3.96 g/L and 0.062-0.99 g/L with the correlation coefficients of 0.999 5 and 0.999 6, respectively. The relative standard deviations of relative peak areas were less than 3%. The preparation was stable in 208 min. The recovery results met the methodology requirements. The method is simple, rapid, reproducible, and suitable to control the quality of cefoperazone sodium and tazobactam sodium injectable powder.