Fabrication and structural and magnetic properties of spark plasma sintered group-IV diluted magnetic semiconductor Fe-doped SiGe alloys.

Fe-doped SiGe bulk alloys are fabricated using non-equilibrium spark plasma sintering (SPS) and their structure and ferromagnetic and magneto-transport properties are investigated. X-ray diffraction and high-resolution transmission electron microscope measurements show that the obtained alloys are composed of SiGe polycrystals. Magnetization measurements reveal that the Fe-doped SiGe alloys exhibit ferromagnetism up to 259 K, and their Curie temperature increases with Fe doping concentration up to 8%. Moreover, transport measurements of the Fe-doped SiGe alloys show typical metal-insulator transition characteristics of doped semiconductors as well as anomalous Hall effect and intriguing positive-to-negative magnetoresistance, indicating that the obtained alloys are diluted magnetic semiconductors (DMSs). Our results provide insight into the SPS-prepared Fe-doped SiGe bulk alloys and may be useful for the design, fabrication, and application of group-IV DMSs.

Long-term survival outcome of locally advanced gastric cancer patients who achieved a pathological complete response to neoadjuvant chemotherapy.

BACKGROUND: Long-term outcome of patients with locally advanced gastric cancer (LAGC) who achieved a pathological complete response (pCR) was scarcely discussed, and never had the factors affecting the prognosis of pCR patients been investigated. METHODS: We retrospectively reviewed all patients who achieved a pCR to neoadjuvant chemotherapy (NAC) in Jinling Hospital. The 3- and 5-year overall survival (OS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method. Meanwhile, univariate and multivariate COX regression analysis was applied to identify prognostic factors affecting patients' survival. RESULTS: A total of 37 consecutive LAGC patients with pCR were included. The 3- and 5-year OS rates were 88.8% and 78.6%, and the 3- and 5-year PFS rates were 86.5% and 75.8%. In the multivariate COX model, NAC duration of more than 3 cycles (HR 0.11 [0.02-0.62], P = 0.013) and poorly differentiated tumor at diagnosis (HR 0.17 [0.03-0.95], P = 0.043) were detected as protective factors for patients OS. Whereas for PFS, NAC duration (HR 0.12 [0.02-0.67], P = 0.015) was the only protective factor confirmed, with tumor differentiation at diagnosis exhibiting marginal significance (HR 0.21 [0.04-1.09], P = 0.063). CONCLUSIONS: Patients with LAGC who achieved a pCR displayed favorable long-term survival outcome, especially those with adequate cycles (≥ 3) of NAC. Besides, poor differentiation at diagnosis might also predict the better OS when pCR achieved.

Mepivacaine Versus Bupivacaine in Adult Surgical Patients: A Meta-analysis, Trial Sequential Analysis of Randomized Controlled Trials.

PURPOSE: Evidence supporting the choice between mepivacaine and bupivacaine is inconclusive. This meta-analysis aims to determine whether mepivacaine can reach a similar effect to bupivacaine after surgeries. DESIGN: A meta-analysis, trial sequential analysis of randomized controlled trials (RCTs). METHODS: RCTs were identified in PubMed, EMBASE (Ovid), Medline (Ovid), and Cochrane Library using a controlled vocabulary (MeSH) and keywords. There were no date and language restrictions. We strictly included RCTs comparing mepivacaine with bupivacaine. The primary outcome was motor function recovery time. Secondary outcomes included postoperative analgesic requirement, transient neurologic symptoms (TNS), pain score at 24 hours, length of stay (LOS), duration of analgesia, complications, and patient satisfaction. A trial sequential analysis (TSA) was performed for motor function recovery time, postoperative analgesic requirement, and TNS. FINDINGS: Seven RCTs with a total of 672 patients were included. Return of motor function was quicker in patients who received mepivacaine than in those who received bupivacaine (weighted mean differences [WMD] = -2.23 minutes; 95% confidence intervals [CI], -3.58 to -0.88; P = .02; I2 = 97.08%; TSA adjusted CI -17.52 to -10.9). Postoperative analgesic requirement was significantly more with mepivacaine (risk ratio [RR] = 3.23; 95% CI, 1.37-7.62; P = .01; I2 = 55.11%; TSA adjusted CI 5.73-63.27). Duration of analgesia (WMD = -8.83 hours; 95% CI, -11.75 to -7.90; P < .001; I2 = 0%) and LOS (WMD = -3.95 hours; 95% CI, -4.83 to -3.07; P < .001; I2 = 0%) in group mepivacaine was significantly shorter compared with bupivacaine. There were no differences for TNS (RR = 3.90; 95% CI, 0.94-16.22; P = .062; I2 = 72.23%), postoperative pain score (standard mean differences [SMD] = 0; 95% CI, -0.10 to 0.10; P = .972; I2 = 0%), complications (RR = 1; 95% CI, 0.70-1.43; P = .998; I2 = 0%), and satisfaction (RR = 0.97; 95% CI, 0.85-1.11; P = .40; I2 = 45%) between bupivacaine and mepivacaine. CONCLUSIONS: Mepivacaine appears to yield a faster return of motor function and shorter LOS compared with bupivacaine. and may be more popular in short-stay and outpatient surgery. However, the results of TSA indicate that more high-quality trials are needed to confirm the true effects.

In vitro compatibility and stability of admixtures containing etoposide, epirubicin hydrochloride and vindesine sulphate in a single infusion bag.

WHAT IS KNOWN AND OBJECTIVES: The etoposide, doxorubicin hydrochloride, vincristine sulphate, cyclophosphamide and prednisone (EPOCH) chemotherapy regimen is effective in patients with relapsed or refractory non-Hodgkin's lymphoma. However, vincristine and doxorubicin hydrochloride are relatively toxic, leading to neurovirulence and cardiotoxicity, respectively. In this study, we replaced these drugs with vindesine and epirubicin hydrochloride to reduce the cardiotoxicity and evaluated admixtures containing these drugs along with etoposide in a single infusion bag in vitro. METHODS: The appearance and pH of the admixtures were evaluated, and the number of particles was detected. High-performance liquid chromatography was used to measure the concentration and degradation rates of etoposide, epirubicin hydrochloride and vindesine sulphate in each admixture. RESULTS AND DISCUSSION: No precipitation occurred when mixing clinically relevant concentrations of etoposide, epirubicin hydrochloride and vindesine sulphate in a 0.9% NaCl injection solution. Furthermore, the delta pH of the admixtures was ≤0.12 throughout the experiment, and the number of particles (≥10 and ≥25 µm) in the solutions over the 24 hours post-preparation period met USP standards. Etoposide, epirubicin hydrochloride and vindesine sulphate were retained at >96% of their initial concentrations in the admixtures at 25°C over the course of the experiment. Etoposide, epirubicin hydrochloride and vindesine sulphate are compatible when mixed in a 0.9% NaCl injection solution, and the admixtures are stable for at least 24 hours when stored in infusion bags. WHAT IS NEW AND CONCLUSION: This in vitro analysis indicates the suitability of our novel admixtures containing less toxic drug equivalents in a single infusion bag for clinical application.

Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5.

Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N(6)-methyladenosine (m(6)A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m(6)A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m(6)A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine.

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase.

Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-acquired infection, which manifests as surgical site infections, bacteremia, and sepsis. Due to drug-resistance, prophylaxis of MRSA infection with antibiotics frequently fails or incites nosocomial diseases such as Clostridium difficile infection. Sortase A is a transpeptidase that anchors surface proteins in the envelope of S. aureus, and sortase mutants are unable to cause bacteremia or sepsis in mice. Here we used virtual screening and optimization of inhibitor structure to identify 3-(4-pyridinyl)-6-(2-sodiumsulfonatephenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole and related compounds, which block sortase activity in vitro and in vivo. Sortase inhibitors do not affect in vitro staphylococcal growth yet protect mice against lethal S. aureus bacteremia. Thus, sortase inhibitors may be useful as antiinfective therapy to prevent hospital-acquired S. aureus infection in high-risk patients without the side effects of antibiotics.

Pristimerin Exerts Pharmacological Effects Through Multiple Signaling Pathways: A Comprehensive Review.

Pristimerin, a natural triterpenoid isolated from the plants of southern snake vine and Maidenwood in the family Weseraceae, is anti-inflammatory, insecticidal, antibacterial, and antiviral substance and has been used for its cardioprotective and antitumor effects and in osteoporosis treatment. These qualities explain Pristimerin's therapeutic effects on different types of tumors and other diseases. More and more studies have shown that pristimerin acts in a wide range of biological activities and has shown great potential in various fields of modern and Chinese medicine. While Pristimerin's wide range of pharmacological effects have been widely studied by others, our comprehensive review suggests that its mechanism of action may be through affecting fundamental cellular events, including blocking the cell cycle, inducing apoptosis and autophagy, and inhibiting cell migration and invasion, or through activating or inhibiting certain key molecules in several cell signaling pathways, including nuclear factor κB (NF-κB), phosphatidylinositol 3-kinase/protein kinase B/mammalian-targeted macromycin (PI3K/Akt/mTOR), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinase 1/2 (ERK1/2), Jun amino-terminal kinase (JNK1/2/3), reactive oxygen species (ROS), wingless/integrin1 (Wnt)/ß-catenin, and other signaling pathways. This paper reviews the research progress of Pristimerin's pharmacological mechanism of action in recent years to provide a theoretical basis for the molecular targeting therapy and further development and utilization of Pristimerin. It also provides insights into improved treatments and therapies for clinical patients and the need to explore pristimerin as a potential facet of treatment.

Hyaluronic acid-poly(glyceryl)10-stearate nanoemulsion for co-delivery of fish oil and resveratrol: Enhancing bioaccessibility and antioxidant potency.

Hyaluronic acid (HA), an endogenous polysaccharide comprising alternating D-glucuronic acid and N-acetylglucosamine units, is renowned for its high hydrophilicity, biocompatibility, and biodegradability. These attributes have rendered HA invaluable across medical and drug delivery fields. HA can be altered through physical, chemical, or enzymatic methods to improve the properties of the modified substances. In this work, we synthesized a derivative via the esterification of HA with poly(glyceryl)10-stearate (PG10-C18), designated as HA-PG10-C18. This novel derivative was employed to fabricate a nano co-delivery system (HA-PG10-C18@Res-NE) for fish oil and resveratrol (Res), aiming to enhance their stability and bioaccessibility. An exhaustive investigation of HA-PG10-C18@Res-NE revealed that the HA-modified system displayed superior physicochemical stability, notably in withstanding oxidation and neutralizing free radicals. Moreover, in vitro simulated digestion underscored the system's enhanced bioaccessibility of Res and more efficient release of free fatty acids. These outcomes underscore the strategic advantage of HA in modifying PG10-C18 for nanoemulsion formulation. Consequently, HA-PG10-C18 stands as a promising emulsifier for encapsulating lipophilic bioactives in functional foods, nutraceuticals, and pharmaceuticals.

Failure of enhanced recovery after surgery in liver surgery: a systematic review and meta analysis.

Purpose: This study aimed to conduct a systematic review of the literature to identify and summarize the existing evidence regarding ERAS failure and related risk factors after hepatic surgery. The objective was to provide physicians with a better understanding of these factors so that they can take appropriate action to minimize ERAS failure and improve patient outcomes. Method: A literature search of the PubMed MEDLINE, OVID, EMBASE, Cochrane Library, and Web of Science was performed. The search strategy involved terms related to ERAS, failure, and hepatectomy. Result: A meta-analysis was conducted on four studies encompassing a total of 1,535 patients, resulting in the identification of 20 risk factors associated with ERAS failure after hepatic surgery. Four of these risk factors were selected for pooling, including major resection, ASA classification of ≥3, advanced age, and male gender. Major resection and ASA ≥ 3 were identified as statistically significant factors of ERAS failure. Conclusion: The comprehensive literature review results indicated that the frequently identified risk factors for ERAS failure after hepatic surgery are linked to operative and anesthesia factors, including substantial resection and an American Society of Anesthesiologists score of 3 or higher. These insights will assist healthcare practitioners in taking prompt remedial measures. Nevertheless, there is a requirement for future high-quality randomized controlled trials with standardized evaluation frameworks for ERAS programs.

Targeting neddylation as a novel approach to lung cancer treatment (Review).

As a protein that resembles ubiquitin, neural precursor cell expressed developmentally downregulated 8 (NEDD8) takes part in neddylation, which modifies substrates in a manner similar to ubiquitination and alters the activity of target proteins. Neddylation may affect the activity of multiple signaling pathways, have a regulatory role in tumor formation, progression and metastasis, and influence the prognosis of cancer treatment. The present review summarizes the regulatory roles of NEDD8 in the MDM2­p53, NF­κB, PI3K/AKT/mTOR, hypoxia­inducible factor, Hippo and receptor tyrosine kinase signaling pathways, as well as in the development and progression of lung cancer.

Development and validation of nomograms to predict early death for elderly lung cancer patients.

Background: Due to the aging of society, the average age of LC (lung cancer) patients has increased in recent years. The purpose of this study was to determine the risk factors and develop nomograms to predict the probability of early death (dead in three months) for elderly (≥ 75 years old) LC patients. Methods: Data of elderly LC patients were obtained from the SEER database by using the SEER stat software. All patients were randomly divided into a training cohort and a validation cohort in a ratio of 7:3. The risk factors of all-cause early and cancer-specific early death were identified by univariate logistic regression and backward stepwise multivariable logistic regression in the training cohort. Then, risk factors were used to construct nomograms. The performance of nomograms was validated by receiver operating curves (ROC), calibration curves, and decision curve analysis (DCA) in the training cohort and validation cohort. Results: A total of 15,057 elderly LC patients in the SEER database were included in this research and randomly divided into a training cohort (n = 10,541) and a validation cohort (n = 4516). The multivariable logistic regression models found that there were 12 independent risk factors for the all-cause early death and 11 independent risk factors for the cancer-specific early death of the elderly LC patients, which were then integrated into the nomograms. The ROC indicated that the nomograms exhibited high discriminative ability in predicting all-cause early (AUC in training cohort = 0.817, AUC in validation cohort = 0.821) and cancer-specific early death (AUC in training cohort = 0.824, AUC in validation cohort = 0.827). The calibration plots of the nomograms were close to the diagonal line revealing that there was good concordance between the predicted and practical early death probability in the training and validation cohort. Moreover, the results of DCA analysis indicated that the nomograms had good clinical utility in predicting early death probability. Conclusion: The nomograms were constructed and validated to predict the early death probability of elderly LC patients based on the SEER database. The nomograms were expected to have high predictive ability and good clinical utility, which may help oncologists develop better treatment strategies.

Synthesis and high-temperature ferromagnetism of Fe-doped SiGe diluted magnetic semiconductor thin films.

Fe-doped SiGe (Si0.25Ge0.75:Fex, x = 0.01, 0.025, and 0.05) thin films were prepared by radio frequency magnetron sputtering and subsequent rapid thermal annealing on a Ge (100) substrate and their structural, magnetic and magneto-transport properties were investigated. Structural characterization using AFM, SEM, XRD, and HRTEM shows that the obtained samples are polycrystalline and their lattice constants increase with the Fe concentration. Analysis of their electronic and spintronic states using XPS and XMCD reveals that Fe dopants mainly exist as substitutional Fe2+ ions in the SiGe lattice, providing both local magnetic moments and hole carriers. Furthermore, magnetization measurements indicate that all the samples exhibit ferromagnetism, and their Curie temperature increases with the Fe concentration up to 294 K; meanwhile, magneto-transport measurements reveal a giant magnetoresistance (GMR) effect of over 800% and an anomalous Hall effect (AHE), as well as semiconducting behaviors, in the samples. Further analysis suggests that the ferromagnetism comes from a hole-mediated process originating from substitutional Fe dopants in the SiGe matrix and this is enhanced by the tensile strain in the films. The synthesis and high-temperature ferromagnetism of Fe-doped SiGe thin films may play a key role in group IV-based spintronic applications.

Investigation of long-term symptoms and influencing factors in patients with mild traumatic brain injury: A cross-sectional study.

BACKGROUND: Traumatic brain injury is the leading cause of death and disability in individuals under the age of 45, which places a heavy disease burden on patients and society. However, the prevalence of long-term symptoms in individuals who suffered from mild traumatic brain injury and how psychosocial factors affect their long-term symptoms remain unclear. OBJECTIVE: To determine howpsychosocial factors influence long-term symptomsin individuals who suffered from mild traumatic brain injury as well as the prevalence of long-term symptoms. METHODS: A demographic characteristics questionnaire, adapted self-report questionnaire of family relationship quality, revised Chinese version of the disease perception questionnaire, Rivermead postconcussion syndrome symptom questionnaire, Glasgow Outcome Scale-Extended, and Brief Symptoms Inventory 18 were used to collect data anonymously. Psychosocial factors associated with long-term symptoms in individuals who suffered from mild traumatic brain injury weremeasuredusingmultiple linear regression. RESULTS: More than half of individuals who suffered from mild traumatic brain injury showed at least 1 long-term symptom after injury. Our results indicated that family relationship quality, disease perception, and demographic characteristics were related to the long-term symptoms of individuals who suffered from mild traumatic brain injury. CONCLUSIONS: Our study shows that theprevalence of long-term symptomsfollowingmild traumatic brain injuryishigh. Psychosocial factors are related to patients' long-term symptoms. The findings indicate that healthcare administrators ought to adopt a robust health promotion strategy that prioritizes familial support and health education of diseases to ameliorate long-term symptoms in individuals who suffered from mild traumatic brain injury.

Associations of Serum Clara Cell Protein 16 with Severity and Prognosis in Adults with Community-Acquired Pneumonia.

Background: Clara cell protein 16 (CC16) has multiple functions, including antioxidant, anti-inflammatory, and immune regulation properties. Nevertheless, the concrete function of CC16 in adult patients with community-acquired pneumonia (CAP) remained blurred. Methods: A total of 541 adult patients with CAP were recruited on admission. Peripheral blood specimens, clinical parameters, and demographic characteristics were collected. The concentration of serum CC16 was evaluated through ELISA. The relationships between serum CC16 and clinical parameters were appraised by Spearman or Pearson correlative analyses. The correlations of serum CC16 with severity and prognosis were assessed using linear or logistic regression models. Results: The level of CC16 was gradually decreased across with the elevated severity scores system of CAP. After treatment, the level of serum CC16 was upregulated. Correlative analyses found that serum CC16 was negatively related to inflammatory cytokines. Additionally, multivariate linear and logistic regression models revealed that serum CC16 was inversely associated with severity scores system. In addition, reduced serum CC16 on admission elevated the risks of vasoactive agent usage, ICU admission, and death during hospitalization. We observed an almost discriminatory ability for severity and death between serum CC16 and severity scores system, and were all obviously elevated compared to routine inflammatory and infectious markers. Conclusion: There are substantially inverse correlations between serum CC16 level on admission with severity scores and poorly prognostic outcomes, indicating that CC16 is involved in the pathophysiological process of CAP. This study is helpful for establishing the potential application of serum CC16 in risk evaluation and targeted treatment.

Arsenic exposure and lung function decline in chronic obstructive pulmonary disease patients: The mediating influence of systematic inflammation and oxidative stress.

Lung tissue is one of the target sites of arsenic (As). The goal of this investigation was to assess the associations of blood As concentration with pulmonary function indicators in patients with chronic obstructive pulmonary disease (COPD), as well as the roles of systemic inflammation and oxidative stress in this relationship. All 791 COPD patients were selected. Blood As concentration, and tumour necrosis factor-α (TNF-α) and 8-iso-prostaglandin-F2α (8-iso-PGF2α) were detected in the serum of COPD cases. Blood As was robustly related to pulmonary function parameters in an inverse dose-dependent manner. Multivariate linear regression analyses verified that a 1-unit increase of blood As was linked to declines of 0.263 L in FVC, 0.288 L in FEV1, 3.454 in FEV1/FVC%, and 0.538 in predicted FEV1%, respectively. The potential for pulmonary function decline gradually increased across the elevated tertiles of blood As. Nonsmokers were susceptible to As-induced pulmonary function reduction. Blood As was positively linked to the levels of TNF-α and 8-iso-PGF2α. Increased TNF-α and 8-iso-PGF2α partially mediated As-induced the reductions in FEV1 and FVC among COPD patients. As exposure is intensely linked to pulmonary function reduction. Systematic inflammation and oxidative stress partially mediate such associations in COPD patients.

Emerging trends and focus of research on the relationship between traumatic brain injury and gut microbiota: a visualized study.

Background: Traumatic brain injury (TBI) is one of the most serious types of trauma and imposes a heavy social and economic burden on healthcare systems worldwide. The development of emerging biotechnologies is uncovering the relationship between TBI and gut flora, and gut flora as a potential intervention target is of increasing interest to researchers. Nevertheless, there is a paucity of research employing bibliometric methodologies to scrutinize the interrelation between these two. Therefore, this study visualized the relationship between TBI and gut flora based on bibliometric methods to reveal research trends and hotspots in the field. The ultimate objective is to catalyze progress in the preclinical and clinical evolution of strategies for treating and managing TBI. Methods: Terms related to TBI and gut microbiota were combined to search the Scopus database for relevant documents from inception to February 2023. Visual analysis was performed using CiteSpace and VOSviewer. Results: From September 1972 to February 2023, 2,957 documents published from 98 countries or regions were analyzed. The number of published studies on the relationship between TBI and gut flora has risen exponentially, with the United States, China, and the United Kingdom being representative of countries publishing in related fields. Research has formed strong collaborations around highly productive authors, but there is a relative lack of international cooperation. Research in this area is mainly published in high-impact journals in the field of neurology. The "intestinal microbiota and its metabolites," "interventions," "mechanism of action" and "other diseases associated with traumatic brain injury" are the most promising and valuable research sites. Targeting the gut flora to elucidate the mechanisms for the development of the course of TBI and to develop precisely targeted interventions and clinical management of TBI comorbidities are of great significant research direction and of interest to researchers. Conclusion: The findings suggest that close attention should be paid to the relationship between gut microbiota and TBI, especially the interaction, potential mechanisms, development of emerging interventions, and treatment of TBI comorbidities. Further investigation is needed to understand the causal relationship between gut flora and TBI and its specific mechanisms, especially the "brain-gut microbial axis."

Case Report: Diffuse Cerebral Microbleeds in Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vascular disease caused by a homozygous mutation in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. Cerebral microbleeds (CMBs) are increasingly being recognized as neuroimaging findings occurring with cerebrovascular disease and have different etiologies. Mild to moderate CMBs are not unusual in CARASIL, and they are observed to affect cortical and subcortical structures; in contrast, diffuse CMBs, especially in the cerebellum, are rare. In this case, we report a novel mutation of HTRA1 in a 43-year-old woman whose imaging indicated multiple CMBs in all lobes, brain stem, and cerebellum. The amount and location of CMBs vary in CARASIL cases, and the potential cause is not fully understood. This study revealed that specific imaging findings of this patient may be related to a new genetic mutation.

Efficacy of intra-arterial chemotherapy with sequential anti-PD-1 antibody in unresectable gastric cancer: A retrospective real-world study.

Background: The prognosis of unresectable gastric cancer is poor, while the efficacy of anti-PD antibodies has not been evaluated. Methods: Patients with unresectable gastric cancer who received intra-arterial chemotherapy (IAC) with sequential anti-PD-1 antibody as induction therapy in Jinling Hospital were retrospectively analyzed. The primary outcome is R0 resection rate. The secondary outcomes include safety, conversion surgery rate, overall survival (OS) and progression free survival (PFS) after postoperative IAC and anti-PD-1 treatments. Meanwhile, Tumor immunity in the microenvironment (TIME) before and after IAC was comprehensively dissected with multiplex immunofluorescence in order to detect possible mechanisms favoring anti-PD-1 treatment response. Results: Between May 2019 and October 2020, 36 patients received at least one cycle of IAC with sequential anti-PD-1 antibody in our institution. The objective response was achieved in 28 patients (77.8%). Thirty patients (83.3%) successfully underwent conversion surgery, among which R0 resection was managed in 25/30 patients, and 23.3% (7/30) was assessed as pathological complete remission. During the median follow-up period of 19.7 months, patients who underwent R0 resection displayed superior OS (HR 0.14 [95% CI 0.04-0.50], P < 0.0001) and PFS (HR 0.11 [0.03-0.44], P < 0.0001) than those who did not. Grade 3 adverse events (AEs) were only encountered in 19.4% patients, no grade 4 AEs observed. In TIME analysis, the number of tertiary lymphoid structures (TLSs) (P = 0.004) were greatly induced by IAC, as well as CD8+ T cells (P = 0.011) and PD-1+ cells (P = 0.025). Meanwhile, Tumor associated macrophages shifted towards anti-tumor M1-like subtypes, with CD68+CD163+ M2-like subpopulation significantly decreased (P = 0.04). Conclusion: Preoperative IAC with sequential anti-PD-1 antibody exhibited promising clinical benefit for unresectable gastric cancer with remarkable conversion rate and R0 resection rate, and also prolonged survival as postoperative regimen. TIME transformation induced by ICA might mediate the additive effect with the immune checkpoint inhibitor.

Near-Infrared Light-Controllable Multifunction Mesoporous Polydopamine Nanocomposites for Promoting Infected Wound Healing.

The successful treatment of infected wounds requires strategies with effective antimicrobial, anti-inflammatory, and healing-promoting properties. Accordingly, the use of Cu2+ and tetracycline (TC), which can promote angiogenesis, re-epithelialization, and collagen deposition, also antibacterial activity, at the wound site, has shown application prospects in promoting infected wound repair. However, realizing controllable release to prolong action time and avoid potential toxicities is critical. Moreover, near-infrared light (NIR)-activated mesoporous polydopamine nanoparticles (MPDA NPs) reportedly exert anti-inflammatory effects by eliminating the reactive oxygen species generated during inflammatory responses. In this study, we assess whether Cu2+ and TC loaded in MPDA NPs can accelerate infected wound healing in mice. In particular, Cu2+ is chelated and immobilized on the surface of MPDA NPs, while a thermosensitive phase-change material (PCM; melting point: 39-40 °C), combined with antibiotics, was loaded into the MPDA NPs as a gatekeeper (PPMD@Cu/TC). Results show that PPMD@Cu/TC exhibits significant great photothermal properties with NIR irradiation, which induces the release of Cu2+, while inducing PCM melting and, subsequent, TC release. In combination with anti-inflammatory therapy, NIR-triggered Cu2+ and TC release enables the nanocomposite to eradicate bacterial wound infections and accelerate healing. Importantly, negligible damage to primary organs and satisfactory biocompatibility were observed in the murine model. Collectively, these findings highlight the therapeutic potential of this MPDA-based platform for controlling bacterial infection and accelerating wound healing.

Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy.

The co-delivery of chemotherapeutic drugs and microRNAs (miR) represents a promising strategy for tumor therapy due to the synergistic effect achieved. In the present study, hydrophobic doxorubicin (DOX) and negatively charged miR-34a were simultaneously delivered via a reducible self-assembling disulfide cross-linked stearyl-peptide-based micellar system (SHRss) using poly(l-arginine)-poly(l-histidine)-stearoyl as the copolymer building unit. The nanoscale SHRss micelles exhibited a low critical micelle concentration (CMC) with positive surface charge. In addition, the present micellar system facilitated the escape of miR-34a from the endosome and release of DOX into the cell nucleus, leading to the downregulation of silent information regulator 1 (SIRT1) expression and inhibition of DU145 and PC3 androgen-independent prostate cancer cell proliferation. In addition, DOX and miR-34a, delivered by SHRss micelles, passively targeted tumor tissue. Furthermore, a synergistic anti-proliferative effect was observed compared with DOX or miR-34a treatment alone in vivo. Our results demonstrate that the SHRss micelles developed in the present study represent a promising approach for combined delivery of gene agents and hydrophobic chemotherapeutic drugs in cancer therapy.