Mesoporous polydopamine Targeting CDK4/6 Inhibitor toward Brilliant Synergistic Immunotherapy of Breast Cancer.

Immunotherapy utilizing anti-PD-L1 blockade has achieved dramatic success in clinical breast cancer management but is often hampered by the limited immune response. Increasing evidence shows that immunogenic cell death (ICD) recently arises as a promising strategy for enlarging tumor immunogenicity and eliciting systemic anti-tumor immunity effectively. However, developing simple but versatile, highly efficient but low-toxic, biosafe, and clinically available transformed ICD inducers remains a huge demand and is highly desirable. Herein, a multifunctional ICD inducer is purposefully developed A6-MPDA@PAL by integrating photothermal therapy (PTT) nanoplatforms mesoporous polydopamine (MPDA), CDK4/6 inhibitor palbociclib (PAL), and CD44-specific targeting A6 peptide in a simple way for augmenting the immune antitumor efficacy of anti-PD-L1 therapy. Remarkably, the light-inducible nanoplatforms exhibit multiple favorable therapeutic features ensuring a superior and biosafe PTT/chemotherapy efficacy. Together with stronger accumulative ICD induction, single administration of A6-MPDA@PAL can trigger robust systemic antitumor immunity and abscopal effect with the assistance of anti-PD-L1 blockade by fascinating the intratumoral infiltration of T lymphocytes and reversing the immunosuppressive tumor microenvironment simultaneously, therapy achieving brilliant synergistic immunotherapy with effective tumor ablation. This study presents a simple and smart ICD inducer opening up attractive clinical possibilities for reinforcing the anti-PD-L1 therapy against breast cancer.

Predicting Persistent Acute Respiratory Failure in Acute Pancreatitis: The Accuracy of Two Lung Injury Indices.

BACKGROUND/AIMS: Early and accurate identification of patients with acute pancreatitis (AP) at high risk of persistent acute respiratory failure (PARF) is crucial. We sought to determine the accuracy of simplified Lung Injury Prediction Score (sLIPS) and simplified Early Acute Lung Injury (sEALI) for predicting PARF in ward AP patients. METHODS: Consecutive AP patients in a training cohort from West China Hospital of Sichuan University (n = 912) and a validation cohort from The First Affiliated Hospital of Nanchang University (n = 1033) were analyzed. PARF was defined as oxygen in arterial blood/fraction of inspired oxygen < 300 mmHg that lasts for > 48 h. The sLIPS was composed by shock (predisposing condition), alcohol abuse, obesity, high respiratory rate, low oxygen saturation, high oxygen requirement, hypoalbuminemia, and acidosis (risk modifiers). The sEALI was calculated from oxygen 2 to 6 L/min, oxygen > 6 L/min, and high respiratory rate. Both indices were calculated on admission. RESULTS: PARF developed in 16% (145/912) and 22% (228/1033) (22%) of the training and validation cohorts, respectively. In these patients, sLIPS and sEALI were significantly increased. sLIPS ≥ 2 predicted PARF in the training (AUROC 0.87, 95% CI 0.84-0.89) and validation (AUROC 0.81, 95% CI 0.78-0.83) cohorts. sLIPS was significantly more accurate than sEALI and current clinical scoring systems in both cohorts (all P < 0.05). CONCLUSIONS: Using routinely available clinical data, the sLIPS can accurately predict PARF in ward AP patients and outperforms the sEALI and current existing clinical scoring systems.

Elevated Interleukin-37 Associated with Dengue Viral Load in Patients with Dengue Fever.

Dengue remains a public health issue worldwide. Similar to chronic infectious diseases, stimulation of cytokine production is not enough to drive immune effector cells for effective virus clearance. One possible mechanism is the virus induces a large number of negative stimulatory cytokines inhibiting immune response. Interleukin 37 (IL-37) plays a crucial regulatory role in infection and immunity, inhibits innate and adaptive immunity as an anti-inflammatory cytokine by inhibiting proinflammatory mediators and pathways. To date, there are few studies reporting correlations between dengue fever (DF) and IL-37. In this study we found that the serum IL-37b and IL-37b-producing monocytes in patients were significantly increased in DF patients. A majority of the IL-37b produced by DF patients was produced by monocytes, not lymphocytes. Increased levels of IL-6, IL-10, and IFN-α were also found in DF patients. However, we failed to detect IL-1ß, IL-17A and TNF-α in plasma, because of off-target. In our study, there was no relation between IL-6, IL-10, and IFN-α expressions and IL-37b in serum (P > 0.05). The IL-37b-producing monocytes were negatively correlated with the level of IFN-α in serum and platelet count, and positively correlated with lymphocytes percentage (P < 0.05, respectively). Additionally, serum DENV nonstructural protein 1 levels were positively correlated with monocytes percentages (P < 0.05). Our data represents findings for IL-37b expression and its potential mechanisms in DF patients' immune response.

Rod-like hybrid nanomaterial with tumor targeting and pH-responsive for cancer chemo/photothermal synergistic therapy.

The development of chemo/photothermal nanotherapeutic systems with excellent photothermal performance, stable drug loading, tumor targeting and strong membrane penetration still remains a challenge. To address this problem, herein a rod-like nanocomposite system (AuNR@FA-PR/PEG) forming from folic acid (FA) terminated carboxylated cyclodextrin (CD) pseudopolyrotaxane (FA-PR) and polyethylene glycol (PEG) modifying gold nanorods (AuNR) was reported. Cisplatin (CDDP) was loaded in AuNR@FA-PR/PEG via coordination bonds to prepare a rod-like pH-responsive nanosystem (AuNR@FA-PR/PEG/CDDP) with chemotherapy/photothermal therapy. The rod-like morphology of AuNR@FA-PR/PEG was characterized by transmission electron microscope. In vitro drug release experiments showed the pH-responsive of AuNR@FA-PR/PEG/CDDP. In vivo real-time imaging assays proved AuNR@FA-PR/PEG/CDDP could rapidly enrich in the tumor area and stay for a long time because of folate targeting and their rod-like morphology. In vivo photothermal imaging assays showed AuNR@FA-PR/PEG/CDDP excellent photothermal performance, the average temperature of tumor region could reach 63.5 °C after 10 min irradiation. In vitro and in vivo experiments also demonstrated that the combined therapy of chemotherapy and photothermal therapy had an outstandingly synergistic effect and improved the therapeutic efficacy comparing with chemotherapy and photothermal therapy alone. Therefore, the prepared rod-like AuNR@FA-PR/PEG/CDDP will provide a new strategy for the effective treatment of cancer.

Hollow mesoporous polydopamine nanospheres: synthesis, biocompatibility and drug delivery.

Various polydopamine (PDA) nanospheres were synthesized by utilizing triblock copolymer Pluronic F127 and 1,3,5-trimethylbenzene (TMB) as soft templates. Precise morphology control of polydopamine nanospheres was realized from solid polydopamine nanospheres to hollow polydopamine nanospheres, mesoporous polydopamine nanospheres and hollow mesoporous polydopamine nanospheres (H-MPDANSs) by adjusting the weight ratio of TMB to F127. The inner diameter of the prepared H-MPDANSs can be controlled in the range of 50-100 nm, and the outer diameter is about 180 nm. Furthermore, the thickness of hollow mesoporous spherical shell can be adjusted by changing the amount of dopamine (DA). The H-MPDANSs have good biocompatibility, excellent photothermal properties, high drug loading capacity, and outstanding sustainable drug release properties. In addition, both NIR laser irradiation and acid pH can facilitate the controlled release of doxorubicin (DOX) from H-MPDANSs@DOX.

Uncertainties in estimating SARS-CoV-2 prevalence by wastewater-based epidemiology.

Wastewater-based epidemiology (WBE) is a promising approach for estimating population-wide COVID-19 prevalence through detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in wastewater. However, various methodological challenges associated with WBE would affect the accuracy of prevalence estimation. To date, the overall uncertainty of WBE and the impact of each step on the prevalence estimation are largely unknown. This study divided the WBE approach into five steps (i.e., virus shedding; in-sewer transportation; sampling and storage; analysis of SARS-CoV-2 RNA concentration in wastewater; back-estimation) and further summarized and quantified the uncertainties associated with each step through a systematic review. Although the shedding of SARS-CoV-2 RNA varied greatly between COVID-19 positive patients, with more than 10 infected persons in the catchment area, the uncertainty caused by the excretion rate became limited for the prevalence estimation. Using a high-frequency flow-proportional sampling and estimating the prevalence through actual water usage data significantly reduced the overall uncertainties to around 20-40% (relative standard deviation, RSD). And under such a scenario, the analytical uncertainty of SARS-CoV-2 RNA in wastewater was the dominant factor. This highlights the importance of using surrogate viruses as internal or external standards during the wastewater analysis, and the need for further improvement on analytical approaches to minimize the analytical uncertainty. This study supports the application of WBE as a complementary surveillance strategy for monitoring COVID-19 prevalence and provides methodological improvements and suggestions to enhance the reliability for future studies.

Porphyrin-terminated nanoscale fluorescent polyrotaxane as a biodegradable drug carrier for anticancer research.

Drug delivery carriers hold tremendous promise for improving cancer treatment, and polyrotaxane (PR) has shown excellent drug-carrying properties. However, there have been some reports that, when used as a drug carrier, water-soluble PR is not easily labeled with organic fluorescent dyes. Herein, we synthesized a drug-loaded fluorescent porphyrin-terminated PR (PR-COOH) which can be used as a tracer material in drug and gene delivery. The structure, morphology and zeta potential of PR-COOH were characterized by nuclear magnetic resonance, high-resolution transmission electron microscopy and zeta potentiometry. In this research, cisplatin (CDDP) is used as a model drug. The zeta potential, drug encapsulation efficiency and drug release of CDDP-loaded PR (PR-COOH-Pt) were studied. Confocal laser scanning microscopy showed that PR-COOH could be internalized by HeLa and CT26 cells. The antitumor efficacy of PR-COOH-Pt was investigated in vitro by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and in vivo by a xenograft tumor model. The results showed that PR-COOH-Pt could significantly inhibit tumor growth; thus PR-COOH-Pt has a promising role in cancer therapy.

Nitric Oxide and Cyclic Guanosine Monophosphate Signaling Mediates the Antidepressant Effects of Acupuncture in the Rat Model of Chronic Unpredictable Mild Stress.

BACKGROUND Depression is a major mood disorder. Some patients have been reported to improve following acupuncture. This study aimed to investigate the effects of acupuncture on behaviors associated with depression in the chronic unpredictable mild stress (CUMS) rat model. The expression of signaling pathway components of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in the rat hippocampus and plasma were also measured. MATERIAL AND METHODS Male Sprague-Dawley rats (N=40) were divided into the control group (N=10), the model group (N=10), the acupuncture group (N=10), and the non-acupuncture group (N=10). The rat model was established by orphaning combined with chronic unpredictable mild stress (CUMS) for six weeks. The acupuncture group was given 21 days of treatment using acupoints (AP) or non-acupoints (NP). Rat behaviors associated with depression were tested using the sucrose preference test (SPT), the open field test (OFT), and the elevated plus maze (EPM) test. Enzyme-linked immunoassay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) were used to detect the expression of inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor subunits, NR1, NR2A, and NR2B in the rat plasma and hippocampus. RESULTS Acupuncture reversed the behaviors associated with depression in the CUMS rat model and reduced the expression of components of the NO and cGMP pathway in the rat hippocampus and plasma. CONCLUSIONS In the CUMS rat model, treatment with acupuncture reduced behaviors associated with depression, and these effects were associated with changes in the NO and cGMP signaling pathway.

Association between estimated plasma volume status and acute kidney injury in patients who underwent coronary revascularization: A retrospective cohort study from the MIMIC-IV database.

BACKGROUND: Acute kidney injury (AKI) remains a common complication of coronary revascularization and increases poor outcomes in critically ill surgical patients. Compared to the plasma volume status (PVS), estimated plasma volume status (ePVS) has the advantages of being noninvasive and simple and has been shown to be associated with worse prognosis in patients undergoing coronary revascularization. This study was to evaluate the association of ePVS with the risk of AKI in patients who underwent coronary revascularization. METHODS: In this retrospective cohort study, data of patients who underwent coronary revascularization were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database (2008-2019). The outcome was the occurrence of AKI after ICU admission. The covariates were screened via the LASSO regression method. Univariate and multivariate Logistic regression models were performed to assess the association of ePVS and PVS and the odds of AKI in patients who underwent coronary revascularization, with results shown as odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses of age, surgery, and anticoagulation agents and sequential organ failure assessment (SOFA) score were performed to further explore the association of ePVS with AKI. RESULTS: A total of 3,961 patients who underwent coronary revascularization were included in this study, of whom 2,863 (72.28%) had AKI. The high ePVS was associated with the higher odds of AKI in patients who received coronary revascularization (OR = 1.06, 95%CI: 1.02-1.10), after adjusting for the covariates such as age, race, SAPS-II score, SOFA score, CCI, weight, heart rate, WBC, RDW-CV, PT, BUN, glucose, calcium, PH, PaO2, mechanical ventilation, vasopressors, and diuretic. Similar results were found in patients who underwent the CABG (OR = 1.07, 95%CI: 1.02-1.11), without anticoagulation agents use (OR = 1.07, 95%CI: 1.03-1.12) and with high SOFA score (OR = 1.10, 95%CI: 1.04-1.17). No relationship was found between PVS and the odds of AKI in patients who underwent the coronary revascularization. CONCLUSION: The ePVS may be a promising parameter to evaluate the risk of AKI in patients undergoing coronary revascularization, which provides a certain reference for the risk stratification management of ICU patients who underwent coronary revascularization.

Inverse metabolic engineering based on metabonomics for efficient production of hydroxytyrosol by Saccharomyces cerevisiae.

Metabolic engineering provides a powerful approach to efficiently produce valuable compounds, with the aid of emerging gene editing tools and diverse metabolic regulation strategies. However, apart from the current known biochemical pathway information, a variety of unclear constraints commonly limited the optimization space of cell phenotype. Hydroxytyrosol is an important phenolic compound that serves various industries with prominent health-beneficial properties. In this study, the inverse metabolic engineering based on metabolome analysis was customized and implemented to disclose the hidden rate-limiting steps and thus to improve hydroxytyrosol production in Saccharomyces cerevisiae (S. cerevisiae). The potential rate-limiting steps involved three modules that were eliminated individually via reinforcing and balancing metabolic flow, optimizing cofactor supply, and weakening the competitive pathways. Ultimately, a 118.53 % improvement in hydroxytyrosol production (639.84 mg/L) was achieved by inverse metabolic engineering.

Injectable Therapeutic Hydrogel with H2O2 Self-Supplying and GSH Consumption for Synergistic Chemodynamic/Low-Temperature Photothermal Inhibition of Postoperative Tumor Recurrence and Wound Infection.

Postoperative tumor recurrence and wound infection remain significant clinical challenges in surgery, often requiring adjuvant therapies. The combination treatment of photothermal therapy (PTT) and chemodynamic therapy (CDT) has proven to be effective in cancer treatment and wound infection. However, the hyperthermia during PTT increases the risk of normal tissue damage, severely impeding its application. Moreover, the efficacy of CDT is limited by insufficient hydrogen peroxide (H2O2) and excessive glutathione (GSH) levels at tumor or infection sites. Herein, an injectable and multifunctional CuO2@Au hydrogel system (CuO2@Au Gel) is developed for synergistic CDT and low-temperature PTT (LTPTT) to prevent tumor recurrence and bacterial wound infections. CuO2@Au Gel is constructed by embedding therapeutic CuO2@Au into low-melting point agarose hydrogel. In vitro and in vivo experiments confirm that the CuO2@Au in CuO2@Au Gel is capable of self-supplying H2O2 and depleting GSH, exhibiting effective CDT effect in acidic tumor or bacterial infected microenvironment. Additionally, it exhibits favorable photothermal conversion ability, inducing localized temperature elevation and synergistically enhancing CDT efficiency. The prepared CuO2@Au Gel demonstrates efficient tumor ablation capability in post-surgery recurrence mouse models and exhibits promising anti-infective efficiency in bacterial infection wound models, indicating significant potential in adjuvant therapy for post-surgical treatment and recovery.

Copper(II)-infused porphyrin MOF: maximum scavenging GSH for enhanced photodynamic disruption of bacterial biofilm.

Bacterial biofilm infection is a serious obstacle to clinical therapeutics. Photodynamic therapy (PDT) plays a dynamic role in combating biofilm infection by utilizing reactive oxygen species (ROS)-induced bacterial oxidation injury, showing advantages of mild side effects, spatiotemporal controllability and little drug resistance. However, superfluous glutathione (GSH) present in biofilm and bacteria corporately reduces ROS levels and seriously affects PDT efficiency. Herein, we have constructed a Cu2+-infused porphyrin metal-organic framework (MOF@Cu2+) for the enhanced photodynamic combating of biofilm infection by the maximum depletion of GSH. Our results show that the released Cu2+ from porphyrin MOF@Cu2+ could not only oxidize GSH in biofilm but also consume GSH leaked from ROS-destroyed bacteria, thus greatly weakening the antioxidant system in biofilm and bacteria and dramatically improving the ROS levels. As expected, our dual-enhanced PDT nanoplatform exhibits a strong biofilm eradication ability both in vitro and in an in vivo biofilm-infected mouse model. In addition, Cu2+ can promote biofilm-infected wound closing by provoking cell immigration, collagen sediment and angiogenesis. Besides, no apparent toxicity was detected after treatment with MOF@Cu2+. Overall, our design offers a new paradigm for photodynamic combating biofilm infection.

The pH-controlled morphology transition of polyaniline from nanofibers to nanospheres.

To explore the dependences of polyaniline (PANI) morphology on the oxidant and the initial pH value (referred to as 'pH-initial') of the reaction system, a series of oxidative polymerization experiments on aniline using chloroaurate acid (HAuCl4) as the oxidant are carried out in aqueous solutions with different values of pH-initial. The smooth morphology transition of PANI nanostructures from nanofibers to solid and hollow nanospheres can be controlled by simply changing pH-initial for the reaction solution using HAuCl4 as the oxidant. In aqueous solutions with different values of pH-initial, the anilinium ions and neutral aniline molecules coexist in different proportions, leading to different PANI nanostructures under different nucleation mechanisms. In strongly acidic media (pH-initial < 2), the homogeneous nucleation of PANI will result in PANI nanofibers. When pH-initial is raised to 2 or above, the heterogeneous nucleation will lead to solid or hollow PANI nanospheres. The solid PANI nanospheres are obtained in mildly acidic media (pH-initial=2-4) and the diameter decreases as the initial pH value of the reaction solution increases from 2 to 4. However, in weakly acidic and neutral media (pH-initial=5-7), hollow PANI nanospheres are formed and the diameter increases with the increase of pH-initial for the solution from 5 to 7.

Constructing a self-healing injectable SABA/Borax/PDA@AgNPs hydrogel for synergistic low-temperature photothermal antibacterial therapy.

Infections caused by bacteria are one of the biggest challenges humans face around the world. Photothermal therapy (PTT) has been regarded as a promising strategy in combating pathogenic infection, however the high temperatures (55-65 °C) required during a single PTT process can induce injury to healthy tissues nearby. Combination therapy could overcome this problem by reducing the photothermal temperature. Here, we developed a self-healing and injectable hydrogel to realize low-temperature PTT (LT-PTT, ≤45 °C) for antisepsis with high-efficiency. The hybrid hydrogel is prepared by incorporating borax into a mixture of 3-aminophenylboronic acid grafted sodium alginate and nano-silver decorated polydopamine nanoparticles. Our results showed that the SABA/Borax/PDA@AgNPs hydrogel possesses satisfactory mechanical properties and self-healing capacity, and as a result, it can repair itself after being damaged mechanically, retaining its integrality and recovering its initial functionalities. Furthermore, through utilizing the photothermal property of polydopamine nanoparticles and broad-spectrum antibacterial activity of nano-silver, the hybrid hydrogel achieves excellent LT-PTT for sterilization both in vitro as well as in an in vivo mice skin wound model with no distinct injury to normal tissues. Overall, our prepared hydrogel is expected to be an excellent candidate for treating bacterial infections.

Association between acculturation and physician trust for internal migrants: A cross-sectional study in China.

BACKGROUND: Physician trust is a critical determinant of the physician-patient relationship and is necessary for an effective health system. Few studies have investigated the association between acculturation and physician trust. Thus, this study analyzed the association between acculturation and physician trust among internal migrants in China by using a cross-sectional research design. METHODS: Of the 2000 adult migrants selected using systematic sampling, 1330 participants were eligible. Among the eligible participants, 45.71% were female, and the mean age was 28.50 years old (standard deviation = 9.03). Multiple logistic regression was employed. RESULTS: Our findings indicated that acculturation was significantly associated with physician trust among migrants. The length of stay (LOS), the ability of speaking Shanghainese, and the integration into daily life were identified as contributing factors for physician trust when controlling for all the covariates in the model. CONCLUSION: We suggest that specific LOS-based targeted policies and culturally sensitive interventions can promote acculturation among Shanghai's migrants and improve their physician trust.

Healthy immigration effect among internal migrants in megacities: a cross-sectional study in Shanghai, China.

Objectives: To verify the healthy immigration effect on self-rated health (SRH) among Chinese internal migrants, identify the determinants of SRH, and provide recommendations for the Chinese government to formulate effective intervention strategies to improve population governance and health management in megacities. Methods: A sample comprising 1,147 white-and blue-collar migrant workers was randomly selected through an online survey conducted in Shanghai from August to December 2021. Multivariate logistic regression models were used to verify the healthy immigration effect as well as determinants of the effect among internal migrants in Shanghai. Results: Among 1,024 eligible internal migrants, 864 (84.4%) were aged between 18 and 59 years, 545 (53.2%) were men, and 818 (79.9%) were married. When confounders in the logistic regression models were adjusted, the odds ratio of SRH for internal migrants who had lived in Shanghai for 5-10 years was 2.418 (p < 0.001), whereas the odds ratio for those who had lived there for ≥10 years was not statistically significant. Additionally, marital status, a postgraduate or higher degree, income level, number of physical examinations in the past 12 months, and the number of critical diseases they were suffering from, were significant contributing factors for favorable SRH among the internal migrants. Furthermore, a cross-sectional analysis revealed that SRH demonstrated a healthy immigration effect among blue-collar internal migrants from the manufacturing industry but not among white-collar internal migrants. Conclusion: A healthy immigration effect was observed among internal migrants in Shanghai. The migrant population that had lived in Shanghai for 5-10 years had more health advantages than the locals, whereas those who had lived there for ≥10 years did not. The Chinese government should understand this effect and enact measures accordingly, such as implementing physical examinations, improving acculturation, addressing individual characteristics, and improving socioeconomic conditions to improve the physical and mental health of internal migrants. Enacting such changes could facilitate the integration of migrants into the local culture of megacities.

A nanozyme-reinforced injectable photodynamic hydrogel for combating biofilm infection.

Bacterial biofilm-associated infectious diseases remain serious menaces to human health. Recently, photodynamic therapy (PDT) has become a prospective strategy for combating biofilm infection. However, anaerobic conditions in a biofilm greatly inhibit its therapeutic efficacy. Here, a nanozyme-reinforced injectable hydrogel is prepared using Ca2+-crosslinked sodium alginate incorporated with photosensitizer-loaded MnO2 nanosheets and CaO2 nanoparticles for O2 self-sufficient PDT to eradicate biofilm infection. In our design, CaO2 reacts with water to produce locally concentrated H2O2, which could be catalyzed by MnO2 nanosheets (catalase-mimic nanozymes) to generate O2 and greatly relieve the hypoxic conditions in the biofilm, thus significantly strengthening PDT efficacy. In vitro assays confirmed that the hybrid hydrogel not only exhibits high-performance bactericidal activity in combating both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli but also shows great efficacy in eliminating biofilm infection. Moreover, benefiting from its good syringeability, the hybrid hydrogel is prone to fit irregular wounds and exhibits high efficiency in promoting wound healing in a biofilm-infected mice model. Besides, no obvious toxicity is detected in the hybrid hydrogel. Overall, we envision that our designed hydrogel could provide a prospective solution for combating biofilm-associated infections.

Corrigendum: Fetoplacental transmission and placental response to SARS-CoV-2: evidence from the literature.

[This corrects the article DOI: 10.3389/fmed.2022.962937.].

Photosensitive pro-drug nanoassemblies harboring a chemotherapeutic dormancy function potentiates cancer immunotherapy.

Immunotherapy combined with effective therapeutics such as chemotherapy and photodynamic therapy have been shown to be a successful strategy to activate anti-tumor immune responses for improved anticancer treatment. However, developing multifunctional biodegradable, biocompatible, low-toxic but highly efficient, and clinically available transformed nano-immunostimulants remains a challenge and is in great demand. Herein, we report and design of a novel carrier-free photo-chemotherapeutic nano-prodrug COS-BA/Ce6 NPs by combining three multifunctional components-a self-assembled natural small molecule betulinic acid (BA), a water-soluble chitosan oligosaccharide (COS), and a low toxic photosensitizer chlorin e6 (Ce6)-to augment the antitumor efficacy of the immune adjuvant anti-PD-L1-mediated cancer immunotherapy. We show that the designed nanodrugs harbored a smart and distinctive "dormancy" characteristic in chemotherapeutic effect with desired lower cytotoxicity, and multiple favorable therapeutic features including improved 1O2 generation induced by the reduced energy gap of Ce6, pH-responsiveness, good biodegradability, and biocompatibility, ensuring a highly efficient, synergistic photochemotherapy. Moreover, when combined with anti-PD-L1 therapy, both nano-coassembly based chemotherapy and chemotherapy/photodynamic therapy (PDT) could effectively activate antitumor immunity when treating primary or distant tumors, opening up potentially attractive possibilities for clinical immunotherapy.

Effects of sewer biofilms on the degradability of carbapenems in wastewater using laboratory scale bioreactors.

Carbapenems are last-resort antibiotics used to treat bacterial infections unsuccessfully treated by most common categories of antibiotics in humans. Most of their dosage is secreted unchanged as waste, thereby making its way into the urban water system. There are two major knowledge gaps addressed in this study to gain a better understanding of the effects of their residual concentrations on the environment and environmental microbiome: development of a UHPLC-MS/MS method of detection and quantification from raw domestic wastewater via direct injection and study of their stability in sewer environment during the transportation from domestic sewers to wastewater treatment plants. The UHPLC-MS/MS method was developed for four carbapenems: meropenem, doripenem, biapenem and ertapenem, and validation was performed in the range of 0.5-10 µg/L for all analytes, with limit of detection (LOD) and limit of quantification (LOQ) values ranging from 0.2-0.5 µg/L and 0.8-1.6 µg/L respectively. Laboratory scale rising main (RM) and gravity sewer (GS) bioreactors were employed to culture mature biofilms with real wastewater as the feed. Batch tests were conducted in RM and GS sewer bioreactors fed with carbapenem-spiked wastewater to evaluate the stability of carbapenems and compared against those in a control reactor (CTL) without sewer biofilms, over a duration of 12 h. Significantly higher degradation was observed for all carbapenems in RM and GS reactors (60 - 80%) as opposed to CTL reactor (5 - 15%), which indicates that sewer biofilms play a significant role in the degradation. First order kinetics model was applied to the concentration data along with Friedman's test and Dunn's multiple comparisons analysis to establish degradation patterns and differences in the degradation observed in sewer reactors. As per Friedman's test, there was a statistically significant difference in the degradation of carbapenems observed depending on the reactor type (p = 0.0017 - 0.0289). The results from Dunn's test indicate that the degradation in the CTL reactor was statistically different from that observed in either RM (p = 0.0033 - 0.1088) or GS (p = 0.0162 - 0.1088), with the latter two showing insignificant difference in the degradation rates observed (p = 0.2850 - 0.5930). The findings contribute to the understanding about the fate of carbapenems in urban wastewater and the potential application of wastewater-based epidemiology.