Wnt3a/GSK3ß/ß-catenin Signalling Modulates Doxorubicin-associated Memory Deficits in Breast Cancer.

BACKGROUND: Chemobrain is widespread in breast cancer patients receiving chemotherapy. However, the exact mechanism, especially the associated signalling pathway, is not currently clear. This study was to evaluate the behavioural changes in breast cancer mice after chemotherapy and to further explore the role of Wnt3a/glycogen synthase kinase (GSK3ß)/ß-catenin signalling in chemobrain. METHODS: MMTV-PyMT(+) breast cancer mice were injected intraperitoneally with doxorubicin (4 mg/kg) once a week for three weeks to establish a chemobrain model. The Morris water maze (MWM) and novel object recognition (NOR) tests were performed to assess the learning and memory ability. Electron microscopy was used to observe the structural changes in the hippocampal CA1 region. The brain tissue of breast cancer mice after chemotherapy was taken out for mRNA-seq detection. Then, the expression levels and phosphorylation of key proteins in the Wnt3a/GSK3 ß/ß-catenin signalling pathway were evaluated through Western blotting (WB) and immunofluorescence. RESULTS: Doxorubicin-induced spatial and short-term memory impairment was observed in breast cancer mice, and obvious neuronal damage could be seen in the hippocampal CA1 region. Immunofluorescence staining for GSK3ß was increased. Wnt signalling pathway is highly enriched from mRNA-seq analysis, with GSK3ß genes at important nodes. The relative protein levels of p-PI3K, p-AKT, p-GSK3 ß, Wnt3a and TCF-1 were decreased significantly, while the p-ß-catenin level was increased. After injection of the GSK3ß inhibitor sb216763 (1 ng/0.5 µl/side), hippocampal neuronal injury was alleviated to some extent, and the changes in the expression of proteins upstream and downstream of this signalling pathway were reversed. CONCLUSION: Wnt3a/GSK3 ß/ß-catenin signalling is likely involved in doxorubicin-induced memory impairment. This result provides basic evidence for the further study of chemobrain in breast cancer.

Analysis of Immune Resistance Mechanisms in TNBC: Dual Effects Inside and Outside the Tumor.

Triple-negative breast cancer (TNBC) is a unique subtype of breast cancer characterized by the lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. TNBC exhibits a high degree of aggressiveness, metastatic potential, and a poor prognosis. Despite the limited success of conventional treatments, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutics for TNBC. Therefore, understanding the mechanisms underlying innate and acquired resistance to ICIs in TNBC is essential. Numerous studies suggest that intrinsic and extrinsic factors significantly contribute to the development of ICI resistance in TNBC. Intrinsic resistance may result from alterations in tumor-intrinsic signaling pathways, such as dysregulation of interferon (IFN) signaling or other signaling pathways. In contrast, extratumoral mechanisms may develop due to alterations in the tumor microenvironment, changes in T cell-related factors or adaptations within the immune system itself. In this paper, we endeavor to elucidate the underlying mechanisms of immune resistance by systematically examining immune mechanisms, the present state of immunotherapy, and the processes of immune resistance. Nonetheless, enhancing our understanding of the mechanisms underlying intratumoral and extratumoral resistance to ICIs in TNBC is crucial for optimizing patient outcomes in this challenging disease. Persistent efforts to identify novel targets for combination therapies, biomarkers that can predict the response to immunotherapy, and resistance mechanisms will be instrumental in achieving this objective.

GSK3ß rs3107669 polymorphism implicates chemotherapy-associated retrospective memory deficits in breast cancer survivors.

Glycogen synthase kinase-3ß (GSK-3ß) plays an important role in the development of neurodegenerative diseases. However, the underlying effect of GSK-3ß polymorphism on chemobrain in cancer survivors is unclear. This study aimed to evaluate the correlation between GSK-3ß polymorphism and chemotherapy-associated retrospective memory deficits in breast cancer survivors. The difference in GSK-3ß gene expression between breast cancer patients and healthy controls was confirmed using bioinformatics technology. All participants (197 with breast cancer and 40 healthy controls) underwent prospective and retrospective memory tests, and five single-nucleotide polymorphism loci of GSK-3ß (rs3107669, rs1154597, rs334543, rs334558 and rs3755557) were genotyped from peripheral blood. Breast cancer survivors had memory impairment after chemotherapy (P<0.0001). The expression difference of the GSK-3ß gene was determined through bioinformation analysis, and a genotype frequency difference of GSK-3ß rs3107669 was found between the breast cancer and healthy control groups. GSK-3ß rs3107669 was a genetic risk in comparison to the healthy controls (OR=0.382; 95% CI=0.186-0.786; P=0.009). Breast cancer with the GSK-3ß rs3107669 (C/A+A/A) genotype was a protective factor for chemobrain (Beta=-0.306; 95% CI=-5.556~-2.145; P<0.0001) from multiple linear regression. The C/A+A/A genotype carrier performed better on the retrospective memory test than the C/C genotype (z=-4.302, P<0.0001). Breast cancer patients with chemotherapy who also carried the GSK-3ß rs3107669 (C/C) genotype more easily presented cognitive deficits. The GSK-3ß rs3107669 polymorphism was a feasible genetic risk factor for chemotherapy-associated retrospective memory impairments in breast cancer survivors.

Psychological distress as a risk factor for the efficacy of chemotherapy in advanced gastric cancer patients.

AIM: To assess the relationship between psychological distress and quality of life (QoL), cancer-related fatigue (CRF), and chemotherapy efficacy in advanced gastric cancer patients. METHODS: Advanced gastric cancer patients (39 with psychological distress and 35 without psychological distress) completed the Distress Thermometer (DT), QoL, and CRF test before receiving chemotherapy and assessed the efficacy after completing 2 courses of chemotherapy. RESULTS: Psychological distress was a significant factor in the efficacy of chemotherapy in advanced gastric cancer patients (χ2 = 6.324; p = 0.042). Compared to advanced gastric cancer patients with no psychological distress, advanced gastric cancer patients with psychological distress had a poorer QoL (50.41 ± 6.17 vs. 60.01 ± 7.94, t = - 5.882, p < 0.01) and more pronounced CRF (5.75 ± 1.16 vs. 3.22 ± 0.75, t = 11.231, p < 0.01) while receiving chemotherapy. FACT-G (p = 0.0035, r = - 0.4568), as well as PFS (p < 0.0001, r = 0.6599), correlated significantly with efficacy for patients in the psychological distress group. The FACT-G (p = 0.0134, r = - 0.4139) of patients in the no psychological distress group correlated significantly with efficacy. CONCLUSION: Psychological distress has a negative impact on QoL, CRF, and efficacy and may be a potential risk for the efficacy of palliative chemotherapy in advanced gastric cancer patients.

Effects of the CALM intervention on resilience in Chinese patients with early breast cancer: a randomized trial.

OBJECTIVE: Resilience is an important regulating factor for anxiety and depression in breast cancer. The Managing Cancer and Living Meaningfully (CALM) intervention has been confirmed to improve anxiety and depression in patients, but the role of resilience is still unclear. This study explores this issue. METHODS: In this study, a cohort of 124 patients diagnosed with breast cancer was recruited and randomly assigned to either the intervention group (IG) or the control group (CG). In addition, we enrolled a group of cancer-free women (regular control group) and assessed their resilience. All patients were evaluated using the Connor-Davidson Resilience Scale (CD-RISC), Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Cancer Therapy (FACT-B) and Perceived Stress Scale (PSS) at different time points. The primary outcomes were resilience, quality of life, anxiety, depression, and perceived stress. A repeated measures ANOVA was used to compare the scores of the IG and CG groups. The relationship between resilience and quality of life was analyzed using Pearson's correlation test. The paired-sample t-test was used to compare the changes in each score at different time points. RESULTS: The intervention group showed significant differences in resilience, adamancy, optimism, tenacity, anxiety, depression, perceived stress and QOL scores before and after 6, 12, and 24 weeks (F = 17.411, F = 226.55, F = 29.096, F = 50.67, F = 82.662, F = 105.39, F = 62.66, F = 72.43, F = 34.561, respectively; P < 0.001). Compared to the control group, the intervention group demonstrated significant improvement in resilience and quality of life (t = -11.517, p < 0.001; t = - 4.929, p < 0.001), as well as a significant reduction in anxiety, depression, and perceived stress scores (t = 5.891, p < 0.001; t = 2.654, p < 0.001; t = 4.932, p < 0.001). In the intervention group, a significant positive correlation was observed between resilience in breast cancer survivors and quality of life (QOL) scores. (before CALM treatment: r = 0.3204, P = 0.0111; after 6 weeks: r = 0.3619, P = 0.0038; after 12 weeks: r = 0.3355, P = 0.0077; after 24 weeks: r = 0.2801, P = 0.0274). CONCLUSIONS: A positive impact of the CALM intervention can be seen in improved resilience and reduced anxiety and depression, supporting its use as an effective psychological management tool and intervention strategy in the early stages of long-term breast cancer recovery.

The role of the oxytocin system in the resilience of patients with breast cancer.

Breast cancer is a grave traumatic experience that can profoundly compromise patients' psychological resilience, impacting their overall quality of life. The oxytocin system represents one of the essential neurobiological bases of psychological resilience and plays a critical role in regulating resilience in response to social or traumatic events during adulthood. Oxytocin, through its direct interaction with peripheral or central oxytocin receptors, has been found to have a significant impact on regulating social behavior. However, the precise mechanism by which the activation of peripheral oxytocin receptors leads to improved social is still not completely comprehended and requires additional research. Its activation can modulate psychological resilience by influencing estrogen and its receptors, the hypothalamic-pituitary-adrenal axis, thyroid function, 5-hydroxytryptamine metabolism levels, and arginine pressure release in breast cancer patients. Various interventions, including psychotherapy and behavioral measures, have been employed to improve the psychological resilience of breast cancer patients. The potential effectiveness of such interventions may be underpinned by their ability to modulate oxytocin release levels. This review provides an overview of the oxytocin system and resilience in breast cancer patients and identifies possible future research directions and interventions.

Effects of autophagy inhibitor 3-methyladenine on a diabetic mice model.

AIM: To investigate the role of autophagy inhibitor 3-methyladenine (3-MA) on a diabetic mice model (DM) and the potential mechanism. METHODS: Male C57BL/6J mice were randomly divided into a normal control group (NC group) and an DM group. DM were induced by multiple low-dose intraperitoneal injection of streptozotocin (STZ) 60 mg/kg·d for 5 consecutive days. DM mice were randomly subdivided into untreated group (DM group), 3-MA (10 mg/kg·d by gavage) treated group (DM+3-MA group) and chloroquine (CQ; 50 mg/kg by intraperitoneal injection) treated group (DM+CQ group). The fasting blood glucose (FBG) levels were recorded every week. At the end of experiment, retinal samples were collected. The expression levels of pro-apoptotic proteins cleaved caspase-3, cleaved poly ADP-ribose polymerase 1 (PARP1) and Bax, anti-apoptotic protein Bcl-2, fibrosis-associated proteins Fibronectin and type 1 collagen α1 chain (COL1A1), vascular endothelial growth factor (VEGF), inflammatory factors interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, as well as autophagy related proteins LC3, Beclin-1 and P62 were determined by Western blotting. The oxidative stress indicators 8-hydroxydeoxyguanosine (8-OHdG) and malondialdehyde (MDA) were detected by commercial kits. RESULTS: Both 3-MA and CQ had short-term hypoglycemic effect on FBG and reduced the expression of VEGF and inflammatory factors IL-1ß and TNF-α in DM mice. 3-MA also significantly alleviated oxidative stress indicators 8-OHdG and MDA, decreased the expression of fibrosis-related proteins Fibronectin and COL1A1, pro-apoptotic proteins cleaved caspase-3, cleaved PARP1, as well as the ratio of Bax/Bcl-2. CQ had no significant impact on the oxidative stress indicators, fibrosis, and apoptosis related proteins. The results of Western blotting for autophagy related proteins showed that the ratio of LC3 II/LC3 I and the expression of Beclin-1 in the retina of DM mice were decreased by 3-MA treatment, and the expression of P62 was further increased by CQ treatment. CONCLUSION: 3-MA has anti-apoptotic and anti-fibrotic effects on the retina of DM mice, and can attenuate retinal oxidative stress, VEGF expression and the production of inflammatory factors in the retina of DM mice. The underlying mechanism of the above effects of 3-MA may be related to its inhibition of early autophagy and hypoglycemic effect.

Advances in the study of the molecular biological mechanisms of radiation-induced brain injury.

Radiation therapy is one of the most commonly used treatments for head and neck cancers, but it often leads to radiation-induced brain injury. Patients with radiation-induced brain injury have a poorer quality of life, and no effective treatments are available. The pathogenesis of this condition is unknown. This review summarizes the molecular biological mechanism of radiation-induced brain injury and provides research directions for future studies. The molecular mechanisms of radiation-induced brain injury are diverse and complex. Radiation-induced chronic neuroinflammation, destruction of the blood-brain barrier, oxidative stress, neuronal damage, and physiopathological responses caused by specific exosome secretion lead to radiation-induced brain injury.

Positive influence of managing cancer and living meaningfully (CALM) on fear of cancer recurrence in breast cancer survivors.

To evaluate the effectiveness and feasibility of managing cancer and living meaningfully (CALM), an intervention used to reduce the fear of cancer recurrence (FCR) in breast cancer survivors and improve their quality of life (QoL). A total of 103 breast cancer survivors were enrolled. Participants were randomly assigned to the CALM group or the care as usual (CAU) group. The participants completed a survey at baseline (T0) and after two (T1), four (T2), and six (T3) intervention sessions. The patients were assessed using the Cancer Worry Scale (CWS), Psychological Distress Thermometer (DT), Functional Assessment of Cancer Therapy-Breast (FACT-B) and Hospital Anxiety and Depression Scale (HADS). After the intervention, the CALM group showed a significant decrease in levels of FCR, distress, anxiety, and depression (χ2=154.353, χ2=130.292, χ2=148.879, and χ2=78.681; P<0.001, 0.001, 0.001, and 0.001, respectively) and an increased QoL (χ2=122.822, P<0.001). Compared with the CAU group, the CALM group showed significant differences in FCR, distress, QoL, anxiety and depression (F=292.431, F=344.156, F=11.115, F=45.124, and F=16.155; P<0.001, P<0.001, P=0.01, P<0.001, and P<0.001, respectively). Negative correlations were found between CWS and FACT-B scores in the CALM group (T0: r=-0.6345, P<0.001; T1: r=-0.4127, P=0.0017; T2: r=-0.2919, P=0.0306; and T3: r=-0.3188, P=0.0177) and in the CAU group (T0: r=-0.7714, P<0.0001; T1: r=-0.6549, P<0.0001; T2: r=-0.5060, P=0.0002; and T3: r=-0.3151, P=0.0291). Thus, the CALM intervention reduced FCR, distress, anxiety and depression in breast cancer survivors and improved QoL.

Effects of CALM intervention on neutrophil-to-lymphocyte ratio (NLR), fear of cancer recurrence and quality of life in patients with lung cancer.

PURPOSE: To evaluate the feasibility and practicability of Managing Cancer and Living Meaningfully (CALM) as a psychological intervention to reduce neutrophil to lymphocyte ratio (NLR), fear of cancer recurrence, general distress, and improve quality of life in lung cancer survivors. METHODS: Eighty lung cancer patients with FCRI severity subscale (≥13 points) were recruited and randomly assigned to CALM or usual care (UC). NLR was recorded before and after treatment. The Fear of Cancer Recurrence Inventory (FCRI), Quality of Life Questionnaire Core 30 (QLQ-C30) and Depression-Anxiety-Stress Scale (DASS-21) were used to evaluate patients at baseline (T0), immediately after treatment (T1), and at 2 (T2) and 4 (T3) months. RESULTS: Compared with UC, NLR was significantly different before and after CALM intervention (z=-5.498; P=0.000). There were significant differences in the scores of QLQ, FCR and general distress before and after the T1, T2 and T3 interventions (F=220.30, F=315.20, F=290.10, respectively; P<0.001). NLR was negatively correlated with QOL both before (r=-0.763; P<0.0001) and after the intervention (r=-0.810, P<0.0001). FCR and general distress were negatively correlated with QOL in CALM (T0: r=-0.726, r=-0.776, respectively; P<0.0001; T1: r=-0.664, r=-0.647, respectively; P<0.0001; T2: r=-0.678, r=-0.695, respectively; P<0.0001; T3: r=-0.511, P = 0.0008; r=-0.650, P<0.0001). CONCLUSION: CALM intervention can effectively reduce the NLR, alleviate the recurrence fear and general distress and improve the quality of life in patients. This study suggests that CALM may be an effective psychological intervention for reducing symptoms associated with lung cancer survivors.

Effects of fear of cancer recurrence on subjective physical and mental health in breast cancer patients: The intermediary role of heart rate variability.

BACKGROUND: Fear of cancer recurrence (FCR) and psychological distress are common psychological problems in breast cancer (BC) patients and ultimately affecting their health-related quality of life (HRQoL). Heart rate variability (HRV) can reflect the activity of the parasympathetic nervous system. However, the pathways through which HRV influences between FCR and HRQoL are unclear. This study preliminarily explored the intermediary role of HRV in FCR and HRQoL in BC patients. METHODS: A total of 101 BC patients participated in this study. HRV parameters were measured by a 5-min dynamic electrocardiogram. FCR, psychological distress and HRQoL were evaluated by the Fear of disease progression simplified scale (FOP-Q-SF), Distress thermometer and SF-36 concise health survey. The intermediary effect model was established to test the intermediary effect of high frequency-HRV (HF-HRV) on FCR and HRQoL. RESULTS: FCR and psychological distress were negatively correlated with HRV in the time domain, negatively correlated with HF-HRV in the frequency domain, and positively correlated with low frequency/high frequency (LF/HF). HF-HRV had a partial mediating effect on the FCR and physical health and mental health, with effects of 30.23% and 9.53%, respectively. CONCLUSION: FCR and psychological distress are correlated with HRV parameters in the time domain and the frequency domain, and we preliminarily believe that parasympathetic nerves play an important intermediary role between FCR and subjective physical and mental health. This may provide intervention information for improving the HRQoL of BC patients.

Effects of Managing Cancer and Living Meaningfully on Cancer-Related Fatigue and Cytokine Levels in Gastrointestinal Cancer Patients.

OBJECTIVE: To evaluate the effects of managing cancer and living meaningfully (CALM), a psychological intervention with semi-structured interviews, on cancer-related fatigue (CRF), quality of life (QOL), and sleep quality in patients with gastrointestinal (GI) cancer, which may be accompanied by changes in cytokine levels. METHODS: A total of 152 GI cancer patients with CRF were enrolled in the study during treatment. Patients were randomly assigned to CALM or usual care (UC) groups. Patients in the CALM group received 12 weeks of CALM plus usual care, and patients in the UC group received usual care plus usual health education. All study participants were evaluated at baseline and at 12 weeks using the Revised Piper Fatigue Scale, the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30, and the Pittsburgh Sleep Quality Index scale, while cytokine levels were measured. RESULTS: At 12 weeks, the differences in total CRF, QOL, sleep quality, IL-6, IL-4, and TNF-α levels were statistically significant not only in the CALM group compared to patients in the UC group (t = -7.902, t = 2.163, t = -2.187, t = 3.313, t = -4.120, t = -3.853, respectively; P < .05), but also in the CALM group compared to baseline (t = 11.331, t = -5.492, t = 5.450, t = -2.418, t = 2.186, t = 2.699, respectively; P < .05). Additionally, the total CRF at 12 weeks was correlated with IL-4, IL-6, and TNF-α levels (r = -.30, r = .31, r = .32, respectively; P < .001). CONCLUSIONS: CALM alleviated CRF and improved QOL and sleep quality in patients with GI cancer, and these improvements were accompanied by changes in IL-4, IL-6, and TNF-α levels.

Immunotherapy in combination with chemotherapy for Peutz-Jeghers syndrome with advanced cervical cancer: A case report.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder, and female patients may develop gynecologic tumours. The prognosis for such patients is poor and the specific pathogenesis remains uncertain. Therefore, there are currently no uniform treatment options. CASE SUMMARY: Herein, we introduce the case of a 45-year-old female who was diagnosed with PJS for 45 years and cervical cancer for 3 years. Postoperative pathological examination showed metastases in the right external iliac lymph nodes. The patient was initially treated with a combination of doxorubicin and carboplatin chemotherapy and pelvic magnetic resonance showed that the metastases had grown. Subsequently, we performed whole exome sequencing in this patient and identified the relevant causative gene. In addition to the chemotherapy regimen, sindilizumab was administered and the patient was followed up. After 4 cycles of treatment, the metastases were substantially reduced and were not enlarged after six months of follow-up. This case report suggests that patients with PJS combined with cervical cancer may have a sustained response to immune-combination chemotherapy regimens. CONCLUSION: Clinicians should be aware of the importance of immunotherapy in patients with PJS combined with advanced cervical cancer.

Psychological distress as risk factor for the efficacy of whole-brain radiotherapy in brain metastasis patients.

Aim: To evaluate the relationship between psychological distress and the efficacy of whole-brain radiotherapy (WBRT) in advanced brain metastasis patients. Methods: Brain metastasis patients (40 with psychological distress and 47 without psychological distress) completed distress thermometer tests before WBRT, and progression-free survival (PFS) was acquired during the follow-up period. Results: Psychological distress was a risk factor for poorer PFS in patients treated with WBRT (p < 0.01). The PFS of survivors who underwent WBRT was superior for those without psychological distress (hazard ratio: 0.295; 95% CI: 0.173-0.500; p < 0.01). Conclusion: The survival of brain metastasis patients receiving WBRT was influenced by psychological distress, which negatively affected the treatment outcome and is likely to be a potential risk indicator in advanced cancer patients receiving WBRT.

Distress thermometer tests were carried out 1 week before whole-brain radiotherapy to assess psychological distress in 87 brain metastasis patients. The results demonstrated that the progression-free survival of brain metastasis patients with psychological distress was obviously inferior to that of patients without psychological distress. The negative effects of psychological distress could be recognized in advanced patients with brain metastases after whole-brain radiotherapy. Psychological distress is likely to be a potential risk indicator for radiotherapy in brain metastasis patients.

Comparison of iodine nutritional status and disease monitoring results among children in water source high iodine areas of Henan Province in 2017 and 2019 / 中华地方病学杂志

Objective:To compare the coverage rate of non-iodized salts, children's iodine nutrition and the change trend of goiter rate between the original water source high iodine areas in Henan Province in 2017 and the newly designated water source high iodine areas in 2019.Methods:Using a cross-sectional survey method, household edible salt monitoring was conducted in all 20 counties (cities, districts) with high iodine content in Henan Province in 2017. Ten counties (cities, districts) were selected to monitor water iodine, urinary iodine and thyroid volume of children aged 8 to 10 years. A total of 4 430 salt samples and 1 012 urine samples were collected, and thyroid volume of 1 012 children were measured. In 2019, monitoring of household edible salt, water iodine, urinary iodine, and thyroid volume was carried out in all 55 newly designated counties (cities, districts) with high iodine village. A total of 9 835 salt samples and 9 830 urine samples were collected, and the thyroid volume of 8 896 children was measured. The monitoring results of two years were compared, and the relationship between children's urinary iodine and goiter rate was analyzed by univariate logistic regression.Results:In 2019, the water iodine content in newly designated high iodine areas decreased compared to the original high iodine areas in 2017 (119.8 to 191.0 μg/L), and the difference was statistically significant ( Z = - 2.48, P = 0.013). The rate of non-iodized salts in 2019 was only 35.5% (3 494/9 835), significantly lower than that in 2017 (96.2%, 4 263/4 430, χ 2 = 4 536.74, P < 0.001). The median urinary iodine of children in 2017 and 2019 were 338.2 and 317.8 μg/L, respectively, the difference between the two years was statistically significant ( Z = - 2.46, P = 0.014). In 2017 and 2019, the goiter rate of children aged 8 to 10 years was 1.5% (15/1 012) and 2.1% (187/8 896), respectively, and there was no significant difference between the two years (χ 2 = 1.76, P = 0.185). The results of univariate logistic regression analysis showed that, compared with the control group with urinary iodine < 100 μg/L, the risk of goiter rate (but the enlargement rate did not exceed 5%) increased with the increase of urinary iodine level (100 - 199, 200 - 299 and ≥300 μg/L groups), and the differences were statistically significant [odds ratio ( OR) = 8.64, 7.68, 10.69, P < 0.05]. Conclusion:After the implementation of the new demarcation standard for areas with excessive iodine in water sources, the supply of non-iodized salts in Henan Province is relatively lagging behind, and the iodine nutrition level of children is still high, but the goiter rate is relatively stable.

Analysis of iodine nutritional level of residents in iodine adequate areas of Henan Province in 2020 / 中华地方病学杂志

Objective:To investigate the iodine nutritional level of residents in iodine adequate areas in Henan Province, and provide basis for making policy of targeted guidance and rational iodine supplementation.Methods:In the 156 counties of Henan Province in 2020, one township was selected from each location (east, west, south, north and middle) in each county; one school was selected from each township; 40 children aged 8-10 years in the school and 20 pregnant women in the township were selected to collect their urine and salt samples to test urine and salt iodine levels. One third of the counties were selected to examine the thyroid gland of children. Individuals lived in villages with water iodine between 40 and 100 μg/L were included in the study.Results:In iodine adequate areas, a total of 2 097 salt samples were collected from children and tested, the consumption rate of qualified iodized salt was 93.6% (1 962/2 097). A total of 2 096 urine samples were collected from children and tested, and the median urinary iodine was 288.0 μg/L. The goiter rate of children was 0.7% (5/723). A total of 1 068 salt samples from pregnant women were tested, and the consumption rate of qualified iodized salt was 93.0% (993/1 068). A total of 1 068 urine samples from pregnant women were tested, with a median urinary iodine 232.7 μg/L. Stratified by water iodine (40-59, 60-79, 80-100 μg/L), the median urinary iodine of children was 273.8, 288.6, and 305.9 μg/L, respectively, statistically significantly different between groups ( H = 15.79, P < 0.001); the goiter rate of children was ≤2%, and the difference between groups was statistically significant (χ 2 = 7.31, P = 0.026); but the median urinary iodine of pregnant women was not significantly different ( H = 1.82, P = 0.402). Under different water iodine conditions, there was no significant difference in urinary iodine levels in children and pregnant women between the high salt iodine concentration group (≥21 mg/kg) and the low salt iodine concentration group (< 21 mg/kg, P > 0.05). Conclusions:The iodine nutrition level of children in iodine adequate areas in Henan Province is relatively high, and the iodine nutrition of pregnant women is appropriate. The goiter rate of children is at a relatively low level. Continuous surveillance should be conducted to comprehensively evaluate the iodine nutrition level. Various measures will be taken by regions and populations.

Bone Metastasis of Breast Cancer: Molecular Mechanisms and Therapeutic Strategies.

Bone metastasis is a common complication of many types of advanced cancer, including breast cancer. Bone metastasis may cause severe pain, fractures, and hypercalcemia, rendering clinical management challenging and substantially reducing the quality of life and overall survival (OS) time of breast cancer patients. Studies have revealed that bone metastasis is related to interactions between tumor cells and the bone microenvironment, and involves complex molecular biological mechanisms, including colonization, osteolytic destruction, and an immunosuppressive bone microenvironment. Agents inhibiting bone metastasis (such as bisphosphate and denosumab) alleviate bone destruction and improve the quality of life of breast cancer patients with bone metastasis. However, the prognosis of these patients remains poor, and the specific biological mechanism of bone metastasis is incompletely understood. Additional basic and clinical studies are urgently needed, to further explore the mechanism of bone metastasis and develop new therapeutic drugs. This review presents a summary of the molecular mechanisms and therapeutic strategies of bone metastasis of breast cancer, aiming to improve the quality of life and prognosis of breast cancer patients and provide a reference for future research directions.

MiR-191-5p Attenuates Tau Phosphorylation, Aß Generation, and Neuronal Cell Death by Regulating Death-Associated Protein Kinase 1.

Dysregulation of microRNAs has been implicated in diverse diseases, including Alzheimer's disease (AD). MiR-191-5p in plasma/serum has been identified as a novel and promising noninvasive diagnostic biomarker for AD. However, whether miR-191-5p is involved in AD pathogenesis is largely unknown, and its levels in human AD brains are undetermined. Herein, we demonstrated that miR-191-5p downregulated tau phosphorylation at multiple AD-related sites and promoted neurite outgrowth using immunoblotting, immunofluorescence, and neurite outgrowth assays. Moreover, immunoblotting and enzyme-linked immunosorbent assays indicated that miR-191-5p decreased amyloid precursor protein phosphorylation levels and beta-amyloid (Aß) generation. Furthermore, miR-191-5p reduced ceramide-induced neuronal cell death analyzed by trypan blue staining, the in situ cell death detection kit, and Annexin V-FITC/PI flow cytometry. Next, we verified that death-associated protein kinase 1 (DAPK1) was a direct target of miR-191-5p through the dual luciferase reporter assay and confirmed that the effects of miR-191-5p were antagonized by restoration of DAPK1 expression. Finally, the hippocampal miR-191-5p level was found to be decreased in humans with AD compared with controls and was inversely correlated with the DAPK1 expression level. Collectively, these findings suggest that miR-191-5p might exert inhibitory effects on tau phosphorylation, Aß secretion, and neuronal cell death by directly targeting DAPK1, providing an attractive therapeutic option for AD.

miR-143-3p Inhibits Aberrant Tau Phosphorylation and Amyloidogenic Processing of APP by Directly Targeting DAPK1 in Alzheimer's Disease.

The neuropathology of Alzheimer's disease (AD) is characterized by intracellular aggregation of hyperphosphorylated tau and extracellular accumulation of beta-amyloid (Aß). Death-associated protein kinase 1 (DAPK1), as a novel therapeutic target, shows promise for the treatment of human AD, but the regulatory mechanisms of DAPK1 expression in AD remain unclear. In this study, we identified miR-143-3p as a promising candidate for targeting DAPK1. miR-143-3p directly bound to the 3' untranslated region of human DAPK1 mRNA and inhibited its translation. miR-143-3p decreased tau phosphorylation and promoted neurite outgrowth and microtubule assembly. Moreover, miR-143-3p attenuated amyloid precursor protein (APP) phosphorylation and reduced the generation of Aß40 and Aß42. Furthermore, restoring DAPK1 expression with miR-143-3p antagonized the effects of miR-143-3p in attenuating tau hyperphosphorylation and Aß production. In addition, the miR-143-3p levels were downregulated and correlated inversely with the expression of DAPK1 in the hippocampus of AD patients. Our results suggest that miR-143-3p might play critical roles in regulating both aberrant tau phosphorylation and amyloidogenic processing of APP by targeting DAPK1 and thus offer a potential novel therapeutic strategy for AD.

Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy.

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not been determined. We assessed multiple electroencephalograms and seizure grades and performed biochemical and cell death analyses with cellular and animal models. We applied small molecules and peptides and knocked out and mutated genes to evaluate the therapeutic efficacy of kainic acid (KA), an analog of glutamate-induced neuronal damage. KA administration increased DAPK1 activity by promoting its phosphorylation by activated extracellular signal-regulated kinase (ERK). DAPK1 activation increased seizure severity and neuronal cell death in mice. Selective ERK antagonist treatment, DAPK1 gene ablation, and uncoupling of DAPK1 and ERK peptides led to potent anti-seizure and anti-apoptotic effects in vitro and in vivo. Moreover, a DAPK1 phosphorylation-deficient mutant alleviated glutamate-induced neuronal apoptosis. These results provide novel insight into the pathogenesis of epilepsy and indicate that targeting DAPK1 may be a potential therapeutic strategy for treating epilepsy.