Bacteria-driven nanosonosensitizer delivery system for enhanced breast cancer treatment through sonodynamic therapy-induced immunogenic cell death.

BACKGROUND: Sonodynamic therapy (SDT) has shown promise as a non-invasive cancer treatment due to its local effects and excellent tissue penetration. However, the limited accumulation of sonosensitizers at the tumor site hinders its therapeutic efficacy. Although nanosonosensitizers have improved local tumor accumulation through passive targeting via the enhanced permeability and retention effect (EPR), achieving sufficient accumulation and penetration into tumors remains challenging due to tumor heterogeneity and inaccurate targeting. Bacteria have become a promising biological carrier due to their unique characteristic of active targeting and deeper penetration into the tumor. METHODS: In this study, we developed nanosonosensitizers consisting of sonosensitizer, hematoporphyrin monomethyl ether (HMME), and perfluoro-n-pentane (PFP) loaded poly (lactic-co-glycolic) acid (PLGA) nanodroplets (HPNDs). These HPNDs were covalently conjugated onto the surface of Escherichia coli Nissle 1917 (EcN) using carbodiimine chemistry. EcN acted as an active targeting micromotor for efficient transportation of the nanosonosensitizers to the tumor site in triple-negative breast cancer (TNBC) treatment. Under ultrasound cavitation, the HPNDs were disrupted, releasing HMME and facilitating its uptakes by cancer cells. This process induced reactive oxygen species (ROS)-mediated cell apoptosis and immunogenic cell death (ICD) in vitro and in vivo. RESULTS: Our bacteria-driven nanosonosensitizer delivery system (HPNDs@EcN) achieved superior tumor localization of HMME in vivo compared to the group treated with only nanosonosensitizers. This enhanced local accumulation further improved the therapeutic effect of SDT induced-ICD therapeutic effect and inhibited tumor metastasis under ultrasound stimulation. CONCLUSIONS: Our research demonstrates the potential of this ultrasound-responsive bacteria-driven nanosonosensitizer delivery system for SDT in TNBC. The combination of targeted delivery using bacteria and nanosonosensitizer-based therapy holds promise for achieving improved treatment outcomes by enhancing local tumor accumulation and stimulating ICD.

Establishment of ultrasound-responsive SonoBacteriaBot for targeted drug delivery and controlled release.

Bacteria-driven biohybrid microbots have shown great potential in cancer treatment. However, how precisely controlling drug release at the tumor site is still an issue. To overcome the limitation of this system, we proposed the ultrasound-responsive SonoBacteriaBot (DOX-PFP-PLGA@EcM). Doxorubicin (DOX) and perfluoro-n-pentane (PFP) were encapsulated in polylactic acid-glycolic acid (PLGA) to form ultrasound-responsive DOX-PFP-PLGA nanodroplets. Then, DOX-PFP-PLGA@EcM is created by DOX-PFP-PLGA amide-bonded to the surface of E. coli MG1655 (EcM). The DOX-PFP-PLGA@EcM was proved to have the characteristics of high tumor-targeting efficiency, controlled drug release capability, and ultrasound imaging. Based on the acoustic phase change function of nanodroplets, DOX-PFP-PLGA@EcM enhance the signal of US imaging after ultrasound irradiation. Meanwhile, the DOX loaded into DOX-PFP-PLGA@EcM can be released. After being intravenously injected, DOX-PFP-PLGA@EcM can efficiently accumulate in tumors without causing harm to critical organs. In conclusion, the SonoBacteriaBot has significant benefits in real-time monitoring and controlled drug release, which has significant potential applications for therapeutic drug delivery in clinical settings.

Effects of a online brief modified mindfulness-based stress reduction therapy for anxiety among Chinese adults: A randomized clinical trial.

The COVID-19 pandemic has exacerbated anxiety and related symptoms among the general population. In order to cope with the mental health burden, we developed an online brief modified mindfulness-based stress reduction (mMBSR) therapy. We performed a parallel-group randomized controlled trial to evaluate the efficacy of the mMBSR for adult anxiety with cognitive-behavioral therapy (CBT) as an active control. Participants were randomized to mMBSR, CBT or waitlist group. Those in the intervention arms performed each therapy for 6 sections in 3 weeks. Measurements were conducted at baseline, post-treatment and 6 months post-treatment by Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, Patient Health Questionnaire-15, reverse scored Cohen Perceived Stress scale, Insomnia Severity Index, and Snaith-Hamilton Pleasure Scale. 150 participants with anxiety symptoms were randomized to mMBSR, CBT or waitlist group. Post intervention assessments showed that mMBSR improved the scores of all the six mental problem dimensions (anxiety, depression, somatization, stress, insomnia, and the experience of pleasure) significantly compared to the waitlist group. During 6-month post treatment assessment, the scores of all six mental problem dimensions in the mMBSR group still showed improvement compared to baseline and showed no significant difference with the CBT group. Our results provide positive evidence for the efficacy and feasibility of an online brief modified MBSR program to alleviate anxiety and related symptoms of individuals from the general population, and the therapeutic benefits of mMBSR persisted for up to six months. This low resource-consuming intervention could facilitate the challenges of supplying psychological health therapy to large scale of population.

Acute psychological impact on COVID-19 patients in Hubei: a multicenter observational study.

We conducted a multicentre cross-sectional survey of COVID-19 patients to evaluate the acute psychological impact on the patients with coronavirus disease 2019 (COVID-19) during isolation treatment based on online questionnaires from 2 February to 5 March 2020. A total of 460 COVID-19 patients from 13 medical centers in Hubei province were investigated for their mental health status using online questionnaires (including Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Patient Health Questionnaire-15, and Insomnia Severity Index scales). Among all 460 COVID-19 patients, 187 (40.65%) of them were healthcare workers (HCWs). 297 (64.57%) of them were females. The most common psychological problems were somatization symptoms (66.09%, n = 304), followed by depression (53.48%, n = 246), anxiety (46.30%, n = 213), problems of insomnia (42.01%, n = 171), and then self-mutilating or suicidal thoughts (23.26%, n = 107). Of all the patients, 15.65% (n = 72) had severe somatization symptoms, and 2.83% (n = 13) had severe (almost every day) self-mutilating or suicidal thoughts. The most common psychological problems for HCWs were somatization symptoms (67.84%, n = 125), followed by depression (51.87%, n = 97), anxiety (44.92%, n = 84), problems of insomnia (36.18%, n = 55), and then self-mutilating or suicidal thoughts (20.86%, n = 39). Patients with lower education levels were found to be associated with higher incidence of self-mutilating or suicidal thoughts (odds ratio [OR], 2.68, 95% confidence interval [95% CI], 1.66-4.33 [P < 0.001]). Patients with abnormal body temperature were found to be associated with higher incidence of self-mutilating or suicidal thoughts (OR, 3.97, 95% CI, 2.07-7.63 [P < 0.001]), somatic symptoms (OR, 2.06, 95% CI, 1.20-3.55 [P = 0.009]) and insomnia (OR, 1.66, 95% CI, 1.04-2.65 [P = 0.033]). Those with suspected infected family members displayed a higher prevalence of anxiety than those without infected family members (OR, 1.61, 95% CI, 1.1-2.37 [P = 0.015]). Patients at the age of 18-44 years old had fewer somatic symptoms than those aged over 45 years old (OR, 1.91, 95% CI, 1.3-2.81 [P = 0.001]). In conclusion, COVID-19 patients tended to have a high prevalence of adverse psychological events. Early identification and intervention should be conducted to avoid extreme events such as self-mutilating or suicidal impulsivity for COVID-19 patients, especially for those with low education levels and females who have undergone divorce or bereavement.

Comparative liver function models for ruptured hepatocellular carcinoma: A 10-year single center experience.

BACKGROUND/OBJECTIVE: Previous studies have proposed several objective means for liver function assessment in hepatocellular carcinoma (HCC) patients; however, their efficiency in predicting survival of HCC rupture is unknown. Our study aims to confirm which is a better liver function model for ruptured HCC. METHODS: A total of 230 patients with HCC ruptures at our center were included. Kaplan-Meier and Cox regression analyses were performed to compare long-term survival and short-term mortality. The 90-day mortality was compared with the area under the receiver characteristic curve. Logistic regression was used to determine the risk factors for 90-day deaths, and the discriminant ability of the model was measured. RESULTS: There were significant differences in predicting OS of the Child-Pugh (CP) score in all patients, the non-surgical subgroup, and the surgical subgroup (all P < 0.0001). But no statistical significance was shown of the ALBI score in the surgical (P = 0.8985) or non-surgical subgroup (P = 0.0634). The CP score yielded a better performance among all patients (AUC = 0.746 vs. 0.712), the surgical subgroup (AUC = 0.558 vs. 0.530), and the non-surgical subgroup (AUC = 0.715 vs. 0.634) compared to ALBI score in predicting ninety-day mortality. A similar result can be found in the subgroup of surgical and non-surgical treatment group. Moreover, the logistic model that included CP or MELD had a better discriminatory ability than ALBI in predicting ninety-day mortality. CONCLUSION: The CP or MELD rather than ALBI score should be used as a liver function classification criterion for HCC rupture. CLINICAL TRIAL NUMBER: NCT03534843 (retrospectively).

Changes in the serum levels of inflammatory cytokines in antidepressant drug-naïve patients with major depression.

Major depressive disorder (MDD) is a common condition that afflicts the general population across a broad spectrum of ages and social backgrounds. The inflammatory hypothesis of depression posits that immune hyperactivation and dysregulated cytokine production are involved in depression. To investigate cytokine profiles in patients with MDD, we examined the levels of the pro-inflammatory cytokines interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor (TNF)-α, and those of the anti-inflammatory cytokines IL-10 and transforming growth factor (TGF)-ß1 in antidepressant drug-naïve patients with MDD. Compared to healthy controls, patients with MDD had significantly higher levels of IL-1ß, IL-10, and TNF-α, but significantly lower levels of IL-8. There were no significant differences in the levels of IL-6 or TGF-ß1. We found linear correlations between IL-1ß, TNF-α, and IL-8, and the severity of depression, as well as between IL-8 and anxiety level in patients with comorbid anxiety disorder. In addition, higher IL-1ß and TNF-α levels were associated with higher Hamilton Depression Rating Scale (HAMD) scores, while higher IL-8 levels were associated with lower HAMD and Hamilton Anxiety Rating Scale scores. Here we present evidence of changes in cytokine levels in antidepressant drug-naïve patients with MDD. Abnormal expression of inflammatory cytokines in patients with depression suggests that depression activates an inflammatory process. Immunological abnormalities may be involved in the pathophysiology of depression.

A new tumor-associated antigen prognostic scoring system for spontaneous ruptured hepatocellular carcinoma after partial hepatectomy.

OBJECTIVE: Spontaneous hepatocellular carcinoma (HCC) rupture can be fatal, and hepatic resection could achieve a favorable long-term survival among all strategies of tumor rupture. However, there is no available prognostic scoring system for patients with ruptured HCC who underwent partial hepatectomy. METHODS: From January 2005 to May 2015, 129 patients with spontaneous HCC rupture underwent partial hepatectomy. Preoperative clinical data were collected and analyzed. Independent risk factors affecting overall survival (OS) were used to develop the new scoring system. Harrell's C statistics, Akaike information criterion (AIC), the relative likelihood, and the log likelihood ratio were calculated to measure the homogeneity and discriminatory ability of a prognostic system. RESULTS: In the multivariable Cox regression analysis, three factors, including tumor size, preoperative α-fetoprotein level, and alkaline phosphatase level, were chosen for the new tumor-associated antigen (TAA) prognostic scoring system. The 1-year OS rates were 88.1%, 43.2%, and 30.2% for TAA scores of 0-5 points (low-risk group), 6-9 points (moderate-risk group), and 10-13 points (high-risk group), respectively. The TAA scoring system had superior homogeneity and discriminatory ability (Harrell's C statistics, 0.693 vs. 0.627 and 0.634; AIC, 794.79 vs. 817.23 and 820.16; relative likelihood, both < 0.001; and log likelihood ratio, 45.21 vs. 22.77 and 21.84) than the Barcelona Clinic Liver Cancer staging system and the Cancer of the Liver Italian Program in predicting OS. Similar results were found while predicting disease-free survival (DFS). CONCLUSIONS: The new prognostic scoring system is simple and effective in predicting both OS and DFS of patients with spontaneous ruptured HCC.

Global climate change: impact of heat waves under different definitions on daily mortality in Wuhan, China.

BACKGROUND: There was no consistent definition for heat wave worldwide, while a limited number of studies have compared the mortality effect of heat wave as defined differently. This paper aimed to provide epidemiological evidence for policy makers to determine the most appropriate definition for local heat wave warning systems. METHODS: We developed 45 heat wave definitions (HWs) combining temperature indicators and temperature thresholds with durations. We then assessed the impact of heat waves under various definitions on non-accidental mortality in hot season (May-September) in Wuhan, China during 2003-2010. RESULTS: Heat waves defined by HW14 (daily mean temperature ≥ 99.0th percentile and duration ≥ 3 days) had the best predictive ability in assessing the mortality effects of heat wave with the relative risk of 1.63 (95% CI: 1.43, 1.89) for total mortality. The group-specific mortality risk using official heat wave definition of Chinese Meteorological Administration was much smaller than that using HW14. We also found that women, and the elderly (age ≥ 65) were more susceptible to heat wave effects which were stronger and longer lasting. CONCLUSION: These findings suggest that region specific heat wave definitions are crucial and necessary for developing efficient local heat warning systems and for providing evidence for policy makers to protect the vulnerable population.

The Short-Term Effect of Ambient Temperature on Mortality in Wuhan, China: A Time-Series Study Using a Distributed Lag Non-Linear Model.

Less evidence concerning the association between ambient temperature and mortality is available in developing countries/regions, especially inland areas of China, and few previous studies have compared the predictive ability of different temperature indictors (minimum, mean, and maximum temperature) on mortality. We assessed the effects of temperature on daily mortality from 2003 to 2010 in Jiang'an District of Wuhan, the largest city in central China. Quasi-Poisson generalized linear models combined with both non-threshold and double-threshold distributed lag non-linear models (DLNM) were used to examine the associations between different temperature indictors and cause-specific mortality. We found a U-shaped relationship between temperature and mortality in Wuhan. Double-threshold DLNM with mean temperature performed best in predicting temperature-mortality relationship. Cold effect was delayed, whereas hot effect was acute, both of which lasted for several days. For cold effects over lag 0-21 days, a 1 °C decrease in mean temperature below the cold thresholds was associated with a 2.39% (95% CI: 1.71, 3.08) increase in non-accidental mortality, 3.65% (95% CI: 2.62, 4.69) increase in cardiovascular mortality, 3.87% (95% CI: 1.57, 6.22) increase in respiratory mortality, 3.13% (95% CI: 1.88, 4.38) increase in stroke mortality, and 21.57% (95% CI: 12.59, 31.26) increase in ischemic heart disease (IHD) mortality. For hot effects over lag 0-7 days, a 1 °C increase in mean temperature above the hot thresholds was associated with a 25.18% (95% CI: 18.74, 31.96) increase in non-accidental mortality, 34.10% (95% CI: 25.63, 43.16) increase in cardiovascular mortality, 24.27% (95% CI: 7.55, 43.59) increase in respiratory mortality, 59.1% (95% CI: 41.81, 78.5) increase in stroke mortality, and 17.00% (95% CI: 7.91, 26.87) increase in IHD mortality. This study suggested that both low and high temperature were associated with increased mortality in Wuhan, and that mean temperature had better predictive ability than minimum and maximum temperature in the association between temperature and mortality.

[Association between ambient air pollution and stroke mortality in Wuhan, China: A time-series analysis].

OBJECTIVE: Using time-series analyses to determine the association between ambient air pollution and stroke mortality in Jiang'an District of Wuhan, China from 2003 to 2010. METHODS: Data on daily stroke mortality for the period 2003 January 1 to 2010 December 31 was obtained from Jiang'an District Center for Disease Control and Prevention, Wuhan and data on relevant air pollution and meteorological factors from the local municipal environmental monitoring center and meteorology bureau of Wuhan, respectively. Application of a time-series analysis in generalized additive model was applied to evaluate the association between air pollution and stroke mortality. RESULTS: Annual average concentrations of PM10, SO(2) and NO(2) during the study period were (115.0 ± 60.0), (50.2 ± 33.7), and (57.6 ± 25.3) µg/m³ respectively. The total stroke death was 9 204, including 4 495 women, and 7 628 people aged over 65-years old. In single-pollutant model, a 10 µg/m³ increase in previous day (lag 1 d) ambient pollutants was associated with 0.67% (95% CI: 0.25%-1.10%) excess risk in stroke mortality for PM10, 0.87% (95% CI: 0.13%-1.63%) excess risk for SO(2) and 2.07% (95% CI: 1.08%-3.07%) excess risk for NO(2), respectively. When co-pollutants were involved into the models, only NO(2) remained strongly associated with stroke mortality (ß = 2.07, 95% CI: 1.08-3.07, P < 0.001). A 10 µg/m³, increase of NO(2) in lag 1 d was associated with 1.77% (95% CI: 0.54%-3.01%), 2.27% (95% CI: 0.98%-3.57%) and 2.00% (95% CI: 0.59%-3.43%) excess risk in stroke mortality, respectively, after adjusting for PM10, SO(2)th PM10 and SO(2) e-specific and gender-specific analyses showed that the association between ambient air pollution and stroke mortality was stronger in the elderly (≥ 65 years old) people and women. A 10 µg/m, increase of PM10, SO(2) NO(2) in lag 1 d was associated with excess stroke mortality of 0.97% (95% CI: 0.37%-1.57%), 1.73% (95% CI: 0.69%-2.78%) and 2.98% (95% CI: 1.59%-4.39%) for women, respectively and 0.94% (95% CI: 0.47%-1.42%), 1.06% (95% CI: 0.23%-1.90%) and 2.50% (95% CI: 1.40%-3.62%) for the elderly people (> 65 years old), respectively. CONCLUSION: PM10 and gaseous pollutants (SO(2), NO(2)) were significant risk factors for acute stroke death, and people aged over 65-years old and women were more susceptible to the effect of ambient pollutants on stroke mortality.