Mechanisms of cancer cell killing by metformin: a review on different cell death pathways.

Cancer resistance to anti-tumour agents has been one of the serious challenges in different types of cancer treatment. Usually, an increase in the cell death markers can predict a higher rate of survival among patients diagnosed with cancer. By increasing the regulation of survival genes, cancer cells can display a higher resistance to therapy through the suppression of anti-tumour immunity and inhibition of cell death signalling pathways. Administration of certain adjuvants may be useful in order to increase the therapeutic efficiency of anti-cancer therapy through the stimulation of different cell death pathways. Several studies have demonstrated that metformin, an antidiabetic drug with anti-cancer properties, amplifies cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells. Stimulation of the immune system by metformin has been shown to play a key role in the induction of cell death. It seems that the induction or suppression of different cell death mechanisms has a pivotal role in either sensitization or resistance of cancer cells to therapy. This review explains the cellular and molecular mechanisms of cell death following anticancer therapy. Then, we discuss the modulatory roles of metformin on different cancer cell death pathways including apoptosis, mitotic catastrophe, senescence, autophagy, ferroptosis and pyroptosis.

Discharge Against Medical Advice After Hospitalization for Sepsis: Predictors, 30-Day Readmissions, and Outcomes.

BACKGROUND: Sepsis is a leading cause of death worldwide. However, little has been known concerning the status of discharge against medical advice (DAMA) in sepsis patients. OBJECTIVE: To identify factors associated with DAMA, evaluate the association of DAMA with 30-day unplanned readmission and readmitted outcomes after sepsis hospitalization. METHODS: Using the National Readmission Database, we identified sepsis patients who discharged routinely or DAMA in 2017. Multivariable models were used to identify factors related to DAMA, evaluate the association between DAMA and readmission, and elucidate the relationship between DAMA and outcomes in patients readmitted within 30 days. RESULTS: Among 1,012,650 sepsis cases, patients with DAMA accounted for 3.88% (n = 39,308). The unplanned 30-day readmission rates in patients who discharged home and DAMA were 13.08% and 27.21%, respectively. Predictors of DAMA in sepsis included Medicaid, diabetes, smoking, drug abuse, alcohol abuse, and psychoses. DAMA was statistically significantly associated with 30-day (odds ratio [OR] 2.18, 95% confidence interval [CI] 2.09-2.28), 60-day (OR 1.98, 95% CI 1.90-2.06), and 90-day (OR 1.88, 95% CI 1.81-1.96) readmission. DAMA is also associated with higher mortality in patients readmitted within 30 days (OR 1.38, 95% CI 1.17-1.63), whereas there were no statistically significant differences in length of stay and costs between patients who discharged home or DAMA. CONCLUSIONS: DAMA occurs in nearly 3.88% of sepsis patients and is linked to higher readmission and mortality. Those at high risk of DAMA should be early identified to motivate intervention to avoid premature discharges and associated adverse outcomes.

Short-term changes in algal blooms and phytoplankton community after the passage of Super Typhoon Lekima in a temperate and inner sea (Bohai Sea) in China.

Extensive multi-species harmful algal blooms (HABs) were triggered by Super Typhoon Lekima in Laizhou Bay (Bohai Sea) in August 2019. After conducting two field cruises before and after the typhoon passage, we employed both high-performance liquid chromatography (HPLC)-pigment and microscopic methods to study the changes in the phytoplankton community and biomass. Following the passage of Lekima, the average surface salinity decreased, while dissolved inorganic nitrogen and dissolved silicate concentrations increased in the study area. The phytoplankton abundance and Chl a significantly increased after the typhoon event. Post-typhoon, the highest abundance values of Pseudo-nitzschia spp., Noctiluca scintillans, and Coscinodiscus spp. reached 106 cells/L and those of Bacillaria paxillifera, Ceratium spp., and Gymnodinium catenatum were in the order of 105 cells/L. HPLC-pigment CHEMTAX analysis showed that the biomass (Chl a) of dinoflagellates, diatoms, cryptophytes, chlorophytes, and haptophytes increased significantly after the typhoon. The increase in Chl a concentration was mainly attributable to large-sized phytoplankton, which are mostly diatoms and dinoflagellates. This study highlights that typhoons may cause HABs by introducing large amounts of freshwater and nutrients and change the phytoplankton community in a temperate and inner bay.

Helicobacter pylori infection is associated with the co-occurrence of bacteria in the oral cavity and the gastric mucosa.

BACKGROUND: Pathogens capable of impacting gastrointestinal tract tumor development are located in the oral cavity, but whether these oral bacteria are able to colonize the gastric mucosa in gastric cancer (GC) patients and whether Helicobacter pylori infection can influence this process remains to be established. METHODS: Microbial 16S rDNA deep sequencing was conducted to characterize bacteria present in paired gastric mucosa and tongue coating samples in 27 patients with superficial gastritis (SG) and 11 GC patients. RESULTS: While the overall composition of the gastric mucosa and tongue coating microbiomes differed substantially, certain bacteria were present in both of these communities. The co-occurrence of bacteria between the tongue coating and gastric mucosa differed significantly between SG and GC patients. Of the 15 most abundant shared oral bacteria genera (the core shared oral bacteria), which were associated with differences in microbiota composition between these tongue coating and gastric mucosa, three were enriched in the gastric mucosa of GC patients relative to SG patients, whereas, 12 were depleted in GC patient samples. Furthermore, the prevalence and relative abundance of these core shared oral bacteria in the gastric mucosa were also linked to H. pylori infection status, and the core shared oral bacteria were also associated with the overall composition of the gastric mucosal microbiome. CONCLUSIONS: Helicobacter pylori infections are linked to the co-occurrence of bacteria in the oral microbiome and the gastric mucosal microbiome. Ectopic colonization of oral microbes may be a primary driver of H. pylori-induced gastric microbial dysbiosis in patients with GC.

A Comparison of Tumor-Associated and Non-Tumor-Associated Gastric Microbiota in Gastric Cancer Patients.

BACKGROUND: How gastric cancer (GC) incidence is associated with changes in the gastric microbiome has not been firmly established. The present study therefore aims to investigate the microbial communities present within the gastric mucosa of patients with superficial gastritis (SG) or GC. METHODS: Paired tumor and paracancerous samples of the gastric mucosa were collected from 18 patients being surgically treated for GC and from 32 patients with SG being treated via gastroscopy. The gastric microbiome in these samples was then profiled via 16S rRNA sequencing, with a linear discriminant analysis effect size (LEfSe) approach used to identify and compare different bacteria, and with PICRUSt used for predictive functional analyses. RESULTS: GC patients exhibited a distinct gastric microbiota profile from that observed in SG patients. These changes were evident in both tumor and paracancerous tissues from GC patients. Specifically, we found that 6 bacterial genera were specifically enriched in GC tissue samples relative to SG samples, while 18 genera were depleted in these same samples. Based on the differential abundance of these bacteria, we were able to calculate microbial dysbiosis index (MDI) values, which were significantly higher in GC patients than in SG patients. In addition, MDI values were negatively correlated with gastric Shannon index and were positively correlated with relative Helicobacter spp. abundance. Importantly, these MDI values were readily able to discriminate between GC and SG patient samples. Functional analysis suggested that GC patients were more likely to harbor a nitrosating microbial community. CONCLUSIONS: GC patients exhibited a gastric microbiome profile distinct from that observed in SG patients, with these differences being evident in both tumor and paracancerous tissues. Differences in the relative abundance of Helicobacter spp. may be the primary driver of gastric dysbiosis in GC patients.

A Continuous Identity Authentication Scheme Based on Physiological and Behavioral Characteristics.

Wearable devices have flourished over the past ten years providing great advantages to people and, recently, they have also been used for identity authentication. Most of the authentication methods adopt a one-time authentication manner which cannot provide continuous certification. To address this issue, we present a two-step authentication method based on an own-built fingertip sensor device which can capture motion data (e.g., acceleration and angular velocity) and physiological data (e.g., a photoplethysmography (PPG) signal) simultaneously. When the device is worn on the user's fingertip, it will automatically recognize whether the wearer is a legitimate user or not. More specifically, multisensor data is collected and analyzed to extract representative and intensive features. Then, human activity recognition is applied as the first step to enhance the practicability of the authentication system. After correctly discriminating the motion state, a one-class machine learning algorithm is applied for identity authentication as the second step. When a user wears the device, the authentication process is carried on automatically at set intervals. Analyses were conducted using data from 40 individuals across various operational scenarios. Extensive experiments were executed to examine the effectiveness of the proposed approach, which achieved an average accuracy rate of 98.5% and an F1-score of 86.67%. Our results suggest that the proposed scheme provides a feasible and practical solution for authentication.

Preload Monitoring of Bolted L-Shaped Lap Joints Using Virtual Time Reversal Method.

L-shaped bolt lap joints are commonly used in aerospace and civil structures. However, bolt joints are frequently subjected to loosening, and this has a significant effect on the safety and reliability of these structures. Therefore, bolt preload monitoring is very important, especially at the early stage of loosening. In this paper, a virtual time reversal guided wave method is presented to monitor preload of bolted L-shaped lap joints accurately and simply. In this method, a referenced reemitting signal (RRS) is extracted from the bolted structure in fully tightened condition. Then the RRS is utilized as the excitation signal for the bolted structure in loosening states, and the normalized peak amplitude of refocused wave packet is used as the tightness index (TIA). The proposed method is experimentally validated by L-shaped bolt joints with single and multiple bolts. Moreover, the selections of guided wave frequency and tightness index are also discussed. The results demonstrate that the relationship between TIA and bolt preload is linear. The detection sensitivity is improved significantly compared with time reversal (TR) method, particularly when bolt loosening is at its embryo stage. The results also show that TR method is an effective method for detection of the number of loosening bolts.

Post-transcriptional regulation of long noncoding RNAs in cancer.

It is a great surprise that the genomes of mammals and other eukaryotes harbor many thousands of long noncoding RNAs (lncRNAs). Although these long noncoding transcripts were once considered to be simply transcriptional noise or cloning artifacts, multiple studies have suggested that lncRNAs are emerging as new players in diverse human diseases, especially in cancer, and that the molecular mechanisms of lncRNAs need to be elucidated. More recently, evidence has begun to accumulate describing the complex post-transcriptional regulation in which lncRNAs are involved. It was reported that lncRNAs can be implicated in degradation, translation, pre-messenger RNA (mRNA) splicing, and protein activities and even as microRNAs (miRNAs) sponges in both a sequence-dependent and sequence-independent manner. In this review, we present an updated vision of lncRNAs and summarize the mechanism of post-transcriptional regulation by lncRNAs, providing new insight into the functional cellular roles that they may play in human diseases, with a particular focus on cancers.

Promoting antitumor activities of hydroxycamptothecin by encapsulation into acid-labile nanoparticles using electrospraying.

PURPOSE: Acid-labile nanoparticles are proposed to enhance the tumor targeting and anti-tumor therapy of hydroxycamptothecin (HCPT) in response to the acidic microenvironment within cells and tumor tissues. METHODS: HCPT was entrapped into matrix polymers containing acid-labile segments and galactose moieties (PGBELA) through an electrospraying technique. The antitumor activities of HCPT-loaded nanoparticles were evaluated both on HepG2 cells and after intravenous injection into H22 tumor-bearing mice. RESULTS: The electrosprayed nanoparticles were obtained with enhanced loading efficiency and extended release of HCPT compared with other nanoparticle preparation methods. The acid-lability and targeting capability of PGBELA nanoparticles resulted in a 5 times higher inhibitory activity after incubation in pH 6.8 media compared to that of pH 7.4. Animal studies indicated that both the blood circulation time and tumor distribution of PGBELA nanoparticles were significantly increased. HCPT/PGBELA nanoparticles indicated a superior in vivo antitumor activity and fewer side effects than other treatments on the basis of tumor growth, animal survival rate, tissue necrosis and cell apoptosis evaluation. CONCLUSION: Biodegradable PGBELA nanoparticles are capable of achieving site-specific drug delivery by active targeting and triggered release by acidic pH both in tumor tissues and after internalization within tumor cells, thereby providing a novel strategy for cancer treatment.

Is high-frequency oscillatory ventilation more effective and safer than conventional protective ventilation in adult acute respiratory distress syndrome patients? A meta-analysis of randomized controlled trials.

INTRODUCTION: Comprehensively evaluating the efficacy and safety of high-frequency oscillatory ventilation (HFOV) is important to allow clinicians who are using or considering this intervention to make appropriate decisions. METHODS: To find randomized controlled trials (RCTs) comparing HFOV with conventional mechanical ventilation (CMV) as an initial treatment for adult ARDS patients, we searched electronic databases (including PubMed, MedLine, Springer Link, Elsevier Science Direct, ISI web of knowledge, and EMBASE) with the following terms: "acute respiratory distress syndrome", "acute lung injury", and "high frequency oscillation ventilation". Additional sources included reference lists from the identified primary studies and relevant meta-analyses. Two investigators independently screened articles and extracted data. Meta-analysis was conducted using random-effects models. RESULTS: We included 6 RCTs with a total of 1,608 patients in this meta-analysis. Compared with CMV, HFOV did not significantly reduce the mortality at 30 or 28 days. The pooled relative risk (RR) was 1.051 (95% confidence interval (CI) 0.813 to 1.358). ICU mortality was also not significantly reduced in HFOV group, with a pooled RR of 1.218 (95% CI 0.925 to 1.604). The pooled effect sizes of HFOV for oxygenation failure, ventilation failure and duration of mechanical ventilation were 0.557 (95% CI 0.351 to 0.884), 0.892 (95% CI 0.435 to 1.829) and 0.079 (95% CI -0.045 to 0.203), respectively. The risk of barotrauma and hypotension were similar between the CMV group and HFOV group, with a RR of 1.205 (95% CI 0.834 to 1.742) and a RR of 1.326 (95% CI 0.271 to 6.476), respectively. CONCLUSIONS: Although HFOV seems not to increase the risk of barotrauma or hypotension, and reduces the risk of oxygenation failure, it does not improve survival in adult acute respiratory distress syndrome patients.

Study on the Correlation Between the Expression of NF-Ƙb in the Alveolar Lavage Fluid of Children with Severe Mycoplasma Pneumoniae Pneumonia, Its Clinical Characteristics, and Cellular Immunity.

Objective: This study explored the level of nuclear factor-ƙB (NF-ƙB) in the bronchoalveolar lavage fluid (BALF) of children with severe Mycoplasma Pneumoniae pneumonia (SMPP) and the correlation between NF-ƙB, cellular immunity, and clinical characteristics. Methods: A total of 41 hospitalized children diagnosed with SMPP were selected and included in the SMPP group, and 13 bronchial foreign bodies (FB) without infection during the same period were included in the FB group. The NF-ƙB in the BALF of participants was detected by enzyme-linked immunosorbent assay. The correlation between NF-ƙB and laboratory findings, cellular immunity, and the clinical features in children with SMPP was analyzed. The differences in chest imaging and bronchoscopy in children with SMPP were observed. Results: The levels of NF-ƙB were significantly increased in the SMPP group compared with the FB group (P < 0.001). There were correlations between different NF-ƙB pairs in the SMPP group (P < 0.01). Nuclear factor-ƙB (NF-ƙB) correlated with IL-6, the mycoplasma load in BALF, fever peak, length of hospital stay, and sputum suppository (P < 0.05). The higher the intracellular NF-ƙB level in BALF, the lower the CD3+ CD4+ value in peripheral blood (P < 0.05). Intracellular NF-ƙB and total NF-ƙB correlated with pleural effusion, pericardial effusion, and extrapulmonary complications (P < 0.05). Conclusion: NF-ƙB is involved in airway inflammation changes in children with SMPP. The higher the level of NF-ƙB in the airway, the more severe the clinical manifestations, and the longer the length of hospital stay is likely to be.

A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer.

Despite the groundbreaking impact of immune checkpoint blockade (ICB), response rates in non-small cell lung cancer remain modest, particularly in immune-excluded or immune-desert microenvironments. Toll-like receptor 7 (TLR7) emerges as a latent target bridging innate and adaptive immunity, offering a promising avenue for combination therapies to augment ICB efficacy. Here, we explored the anti-tumor activity of the novel oral TLR7 agonist TQ-A3334 and its potential to enhance anti-programmed death ligand 1 (PD-L1) therapy through a combination strategy in a syngeneic murine lung cancer model. Oral administration of TQ-A3334 significantly alleviated tumor burden in C57BL/6J mice, modulated by type I interferon (IFN), and exhibited low toxicity. This therapy elicited activation of both innate and adaptive immune cells in tumor tissue, particularly increasing the abundance of CD8+ TILs through type I IFN pathway and subsequent CXCL10 expression. In vitro examinations validated that IFN-α-stimulated tumor cells exhibited increased secretion of CXCL10, conducive to the promoted trafficking of CD8+ T cells. Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8+ TIL frequency compared to monotherapy. These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer.

Effects of prolonged face mask use among patients with hypertension or diabetes during the COVID-19 pandemic.

OBJECTIVE: We aimed to investigate the impacts of prolonged mask use on patients with hypertension or diabetes during the COVID-19 pandemic. METHODS: This study included patients with hypertension or diabetes who visited the outpatient department of Nanjing Yimin Hospital between 1 February 2022 and 31 January 2023. We compared the change in blood pressure (BP) and fasting plasma glucose in patients with hypertension or diabetes and adjustments to treatment between the group with prolonged mask-wearing group (≥20 hours/week) and the control group (<20 hours/week). RESULTS: Compared with the control group of hypertensive patients, the prolonged mask-wearing group had significantly higher diastolic blood pressure (DBP) and mean arterial pressure (MAP). These two groups had had similar DBP and MAP 1 year earlier. Likewise, the prolonged mask-wearing group of patients with diabetes had a greater need than the control group for upgraded treatment to reach their therapeutic goals. CONCLUSIONS: This study suggests that prolonged mask use by patients with hypertension or diabetes has negative effects on hypertension and plasma glucose control. BP and plasma glucose monitoring should be improved in these patient populations and their treatment should be adjusted in a timely manner.

[Percutaneous foraminal endoscopy for the treatment of lumbar lateral recess stenosis in elderly].

OBJECTIVE: To investigate the clinical efficacy and safety of percutaneous foraminal endoscopy in the treatment of lumbar lateral recess stenosis in elderly. METHODS: The clinical data of 31 elderly patients with lumbar lateral recess stenosis treated by percutaneous foraminal endoscopic decompression from March 2018 to August 2019 were retrospectively analyzed. Including 16 males and 15 females, aged from 65 to 81 years with an average of (71.13±5.20) years, the course of disease ranged from 3 months to 7 years with an average of (14.36±6.52) months. Visual analogue scale (VAS) and Oswestry disability index (ODI) were used to assess clinical symptom and functional status before operation and 1, 6, 12 months after operation. At the final follow-up, the modified Macnab standard was used to evaluate clinical efficacy. RESULTS: All patients were completed the operation successfully. The operation time was from 75 to 120 min with an average of (97.84±11.22 ) min. All 31 patients were followed up from 12 to 28 months with an average of (17.29±5.56) months. Postoperative lumbago-leg pain VAS and ODI were significantly improved at 1, 6, and 12 months(P<0.01). At the final follow-up, according to the modified Macnab standard to evaluate the effect, 23 got excellent results, 5 good, 3 fair. One patient had severe adhesions between peripheral tissues and nerve root, and postoperative sensory abnormalities in the lower extremities were treated conservatively with traditional Chinese medicine and neurotrophic drugs, which recovered at 2 weeks after surgery. No complications such as nerve root injury and infection occurred. CONCLUSION: The intervertebral foraminal endoscopy technique, which is performed under local anesthesia for a short period of operation, ensures adequate decompression while minimizing complications, and is a safe and effective surgical procedure for elderly patients with lumbar lateral recess stenosis.

[Effect of Different Antitumor Regimens on Incidence and Severity of Corona Virus 
Disease 2019 Pneumonia in Lung Cancer Patients: 
A Single-center Retrospective Study].

BACKGROUND: Studies have shown that the incidence and severity of corona virus disease 2019 (COVID-19) in patients with lung cancer are higher than those in healthy people. At present, the main anti-tumor treatments for lung cancer include surgery, immunotherapy, chemotherapy, radiotherapy, targeted therapy and anti-angiogenesis therapy. While the effects of different anti-tumor treatments on the occurrence and severity of COVID-19 pneumonia are not uniform. Therefore, we aimed to describe clinical characteristics and antitumor therapy of patients with lung cancer and COVID-19 pneumonia, and examined risk factors for severity in this population. METHODS: From December 1, 2022 to February 15, 2023, a retrospective study was conducted in 217 patients diagnosed with COVID-19 and pathologically confirmed lung cancer in the Jinling Hospital. We collected data about patients' clinical features, antitumor treatment regimen within 6 months, and the diagnosis and treatment of COVID-19. Risk factors for occurrence and severity of COVID-19 pneumonia were identified by univariable and multivariable Logistic regression models. RESULTS: (1) Among the 217 patients included, 51 (23.5%) developed COVID-19 pneumonia, of which 42 (82.4%) were classified as medium and 9 (17.6%) were classified as severe; (2) Univariate and multivariate analysis revealed overweight (OR=2.405, 95%CI: 1.095-5.286) and intrapulmonary focal radiotherapy (OR=2.977, 95%CI: 1.071-8.274) are risk factors for increasing occurrence of COVID-19 pneumonia, while other therapies are not; (3) Chronic obstructive pulmonary disease (COPD) history (OR=7.600, 95%CI: 1.430-40.387) was more likely to develop severe pneumonia and anti-tumor therapies such as intrapulmonary focal radiotherapy, chemotherapy, targeted therapy and immunotherapy did not increase severity. CONCLUSIONS: Intrapulmonary focal radiation therapy within 6 months increased the incidence of COVID-19 pneumonia, but did not increase the severity. However, there was no safety concern for chemotherapy, targeted therapy, surgery and immunotherapy.

Exploration on the first-line treatment of ERBB2-altered advanced non-small cell lung cancer: A multicenter retrospective study.

BACKGROUND: Although the treatment of ERBB2-altered non-small cell lung cancer (NSCLC) has been studied for many years, there are no comprehensive studies to evaluate the benefits of various therapies as first-line treatment. Through the development of immunotherapy, more and more different combination treatments were applicated in clinical practice, therefore, we conducted a multicenter retrospective study to evaluate the efficacy of different treatments. METHODS: We enrolled patients with ERBB2-altered NSCLC who had undergone at least one-line systemic anticancer treatment to evaluate the efficacy of first-line chemotherapy alone (Chemo), anti-ERBB2 tyrosine kinase inhibitor (TKI), chemotherapy plus immunotherapy (Chemo + Immuno), chemotherapy plus anti-angiogenesis therapy (Chemo + Antiangio) and chemotherapy combined with immunotherapy and anti-angiogenesis therapy (Chemo + Immuno + Antiangio). The clinical outcomes included objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), one-year and three-year survival rate. RESULTS: We enroll 36 patients harboring ERBB2 mutation and 29 with ERBB2 amplification. The overall ORR was 30.8%, DCR was 69.2% and mPFS was 5.7 months. Chemo + Immuno and Chemo + Antiangio both achieved longer mPFS than TKI (7.8 vs 3.6 months, HR: 0.24, 95 %CI: 0.09-0.64, P = 0.002; 5.9 vs 3.6 months, HR: 0.36, 95 %CI: 0.15-0.88, P = 0.019; respectively), while there was no significant difference in mPFS between Chemo + Immuno or Chemo + Antiangio and Chemo (both P > 0.05), the mPFS of the first two was longer. For ERBB2-mutant patients, the mPFS was 5.9 months, and Chemo + Immuno and Chemo + Antiangio both achieved longer mPFS than TKI (12.9 vs 2.9 months, HR: 0.15, 95 %CI: 0.03-0.68, P = 0.005; 7.1 vs 2.9 months, HR: 0.50, 95 %CI: 0.29-0.88, P = 0.009, respectively). In the same therapies, patients with ERBB2 mutation or ERBB2 amplification showed no statistical significance in PFS (both P > 0.05). CONCLUSIONS: In the first-line treatment of ERBB2-altered NSCLC, chemotherapy combined with immunotherapy or anti-angiogenesis therapy may have greater survival benefits than ERBB2-target therapy, but the efficacy may not be better than that of chemotherapy.

Galactose decorated acid-labile nanoparticles encapsulating quantum dots for enhanced cellular uptake and subcellular localization.

PURPOSE: Biodegradable polymers containing acid-labile segments and galactose grafts were formulated into nanoparticles in current study, and enhanced cellular uptake and subcellular distribution were clarified. METHODS: Quantum dots (QDs) was utilized as an imaging agent and a model of bioactive substances, and entrapped into nanoparticles of around 200 nm through a nanoprecipitation process. RESULTS: The acid-labile characteristics of QDs-loaded nanoparticles were approved by the hemolysis capability, the degradation behaviors of matrix polymers, and the fluorescence decay of entrapped QDs after incubation into buffer solutions of different pH values. The galactose grafts increased the acid-lability, due to the hydrophilic moieties on the acid-labile segments, and enhanced uptake efficiency of over 50 % was found after 4 h incubation with HepG2 cells, due to the galactose-receptor mediated endocytosis. The acid-lability led to an efficient endosomal escape of QDs-loaded nanoparticles into cytoplasm. CONCLUSIONS: The integration of acid-lability, targeting effect, and full biodegradable backbone into nanoparticle matrices constitutes a promising platform for intracellular delivery of bioactive substances for disease diagnosis, imaging and treatment.

Promoted transfection efficiency of pDNA polyplexes-loaded biodegradable microparticles containing acid-labile segments and galactose grafts.

PURPOSE: Targeting to antigen-presenting cells and efficient intracellular delivery of pDNA are essential for development of microsphere formulations of DNA vaccine. METHODS: Biodegradable polymers containing acid-labile segments and galactose grafts were developed to entrap pDNA polyplexes into microspheres, which were proposed to promote transfection efficiency of pDNA. RESULTS: Acid-labile characteristics were approved by the hemolysis capabilities of red blood cells and degradation behaviors of matrix polymers; release of pDNA polyplexes from microspheres was significantly accelerated after incubation in acid buffers. Presence of galactose moieties enhanced cellular uptake of microspheres and increased acid-lability due to hydrophilic grafts on acid-labile segments. There was no apparent cytotoxicity of blank microspheres; cytotoxicity of pDNA polyplexes was significantly decreased after encapsulation into and sustained release from microspheres. High transfection efficiency and a dose-dependent transfection were indicated for pDNA polyplex-loaded acid-labile microspheres when balancing with cytotoxicity. CONCLUSIONS: Integration of acid-lability, targeting effect into full biodegradable backbone represents an exciting approach to promote transfection efficiency through modulating release of pDNA polyplexes, targeting to antigen-presenting cells and intracellular delivery of pDNA.

An unusual case of piperacillin-tazobactam-induced fever, eosinophilia, thrombocytopenia and liver damage.

Piperacillin-tazobactam is a broad-spectrum antimicrobial agent that is commonly used in clinical practice. The development of delayed drug hypersensitivity reaction (DHR) has been reported in several cases previously. Here we describe an unusual case of non-immediate DHR due to a prolonged course of piperacillin-tazobactam. We report a 22-year-old man who developed fever, eosinophilia, thrombocytopenia and elevated hepatic enzymes following 17 days of piperacillin-tazobactam for methicillin-sensitive Staphylococcus aureus (MSSA) pneumonia. These adverse reactions were reversed immediately after antibiotic cessation. Our case highlights that clinicians should be aware of delayed adverse effects in patients receiving long-term piperacillin-tazobactam treatment.

Neutrophil-derived long noncoding RNA IL-7R predicts development of multiple organ dysfunction syndrome in patients with trauma.

PURPOSE: Overactive neutrophils are thought to be key drivers in the development of post-traumatic multiple organ dysfunction syndrome (MODS). Little is known about the role of inflammation-related lnc-IL7R in trauma. Thus, we aimed to explore the association between neutrophil-derived lnc-IL7R and post-traumatic MODS. METHODS: Total RNA was extracted from the isolated circulating neutrophils in 60 patients with trauma and 33 healthy volunteers for lnc-IL7R expression determination by real-time PCR. The correlation of lnc-IL7R expression with disease severity and the development of post-traumatic MODS was analyzed. RESULTS: The lnc-IL7R levels were significantly lower in trauma patients, especially in those with severe trauma [Injury Severity Score (ISS) ≥ 16], and correlated negatively with the ISS, Acute Physiology and Chronic Health Evaluation II score, and length of ICU stay. The lnc-IL7R levels were also significantly decreased in patients who developed MODS than in those who did not. Lnc-IL7R was an independent predictor of MODS [odds ratio (OR) 0.654, (0.435-0.982), p = 0.041]. The area under the curve for predicting post-traumatic MODS was 0.799 (sensitivity 76.9%, specificity 71.4%), with a cutoff value of 0.024. CONCLUSIONS: Neutrophil-derived lnc-IL7R is an independent predictor of post-traumatic MODS; therefore, it could be a useful predictive marker for MODS.