Photoelectrochemical Solution Gated Graphene Field-Effect Transistor Functionalized by Enzymatic Cascade Reaction for Organophosphate Detection.

Solution Gated Graphene Field-Effect Transistors (SGGT) are eagerly anticipated as an amplification platform for fabricating advanced ultra-sensitive sensors, allowing significant modulation of the drain current with minimal gate voltage. However, few studies have focused on light-matter interplay gating control for SGGT. Herein, this challenge is addressed by creating an innovative photoelectrochemical solution-gated graphene field-effect transistor (PEC-SGGT) functionalized with enzyme cascade reactions (ECR) for Organophosphorus (OPs) detection. The ECR system, consisting of acetylcholinesterase (AChE) and CuBTC nanomimetic enzymes, selectively recognizes OPs and forms o-phenylenediamine (oPD) oligomers sediment on the PEC electrode, with layer thickness related to the OPs concentration, demonstrating time-integrated amplification. Under light stimulation, the additional photovoltage generated on the PEC gate electrode is influenced by the oPD oligomers sediment layer, creating a differentiated voltage distribution along the gate path. PEC-SGGT, inherently equipped with built-in amplification circuits, sensitively captures gate voltage changes and delivers output with an impressive thousandfold current gain. The seamless integration of these three amplification modes in this advanced sensor allows a good linear range and highly sensitive detection of OPs, with a detection limit as low as 0.05 pm. This work provides a proof-of-concept for the feasibility of light-assisted functionalized gate-controlled PEC-SGGT for small molecule detection.

Mno-miR164a and MnNAC100 regulate the resistance of mulberry to Botrytis cinerea.

Although microRNAs (miRNAs) regulate the defense response of a variety of plant species against a variety of pathogenic fungi, the involvement of miRNAs in mulberry's defense against Botrytis cinerea has not yet been documented. In this study, we identified responsive B. cinerea miRNA mno-miR164a in mulberry trees. After infection with B. cinerea, the expression of mno-miR164a was reduced, which was fully correlated with the upregulation of its target gene, MnNAC100, responsible for encoding a transcription factor. By using transient infiltration/VIGS mulberry that overexpressed mno-miR164a or knocked-down MnNAC100, our study revealed a substantial enhancement in mulberry's resistance to B. cinerea when mno-miR164a was overexpressed or MnNAC100 expression was suppressed. This enhancement was accompanied by increased catalase (CAT) activity and reduced malondialdehyde (MDA) content. In addition, mno-miR164a-mediated inhibition of MnNAC100 enhanced the expression of a cluster of defense-related genes in transgenic plants upon exposure to B. cinerea. Meanwhile, MnNAC100 acts as a transcriptional repressor, directly suppressing the expression of MnPDF1.2. Our study indicated that the mno-miR164a-MnNAC100 regulatory module manipulates the defense response of mulberry to B. cinerea infection. This discovery has great potential in breeding of resistant varieties and disease control.

Unraveling the Contribution of MulSOS2 in Conferring Salinity Tolerance in Mulberry (Morus atropurpurea Roxb).

Salinity is one of the most serious threats to sustainable agriculture. The Salt Overly Sensitive (SOS) signaling pathway plays an important role in salinity tolerance in plants, and the SOS2 gene plays a critical role in this pathway. Mulberry not only has important economic value but also is an important ecological tree species; however, the roles of the SOS2 gene associated with salt stress have not been reported in mulberry. To gain insight into the response of mulberry to salt stress, SOS2 (designated MulSOS2) was cloned from mulberry (Morus atropurpurea Roxb), and sequence analysis of the amino acids of MulSOS2 showed that it shares some conserved domains with its homologs from other plant species. Our data showed that the MulSOS2 gene was expressed at different levels in different tissues of mulberry, and its expression was induced substantially not only by NaCl but also by ABA. In addition, MulSOS2 was exogenously expressed in Arabidopsis, and the results showed that under salt stress, transgenic MulSOS2 plants accumulated more proline and less malondialdehyde than the wild-type plants and exhibited increased tolerance to salt stress. Moreover, the MulSOS2 gene was transiently overexpressed in mulberry leaves and stably overexpressed in the hairy roots, and similar results were obtained for resistance to salt stress in transgenic mulberry plants. Taken together, the results of this study are helpful to further explore the function of the MulSOS2 gene, which provides a valuable gene for the genetic breeding of salt tolerance in mulberry.

The Type VI Secretion System Contributes to the Invasiveness of Liver Abscess Caused by Klebsiella pneumoniae.

BACKGROUND: Klebsiella pneumoniae liver abscess (KPLA) with extrahepatic migratory infections is defined as invasive KPLA (IKPLA). The type VI secretion system (T6SS) is involved in the pathogenesis of KPLA. We hypothesized that T6SS plays a role in IKPLA. METHODS: 16S ribosomal RNA gene sequencing was performed on abscess samples. Polymerase chain reaction (PCR) and reverse-transcription PCR (RT-PCR) was used to validate the expression difference of T6SS hallmark genes. In vitro and in vivo experiments were performed to identify the pathogenic feature of T6SS. RESULTS: PICRUSt2 predicted that the T6SS-related genes were notably enriched in the IKPLA group. PCR detection of T6SS hallmark genes (hcp, vgrG, and icmF) showed that 197 (81.1%) were T6SS-positive strains. The T6SS-positive strain detection rate in the IKPLA group was higher than in the KPLA group (97.1% vs 78.4%; P < .05). RT-PCR showed that the hcp expression level was markedly increased in IKPLA isolates (P < .05). The T6SS-positive isolates showed higher survival against serum and neutrophil killing (all P < .05). The T6SS-positive K pneumoniae-infected mice had a shorter survival time, higher mortality, and an increased interleukin 6 expression in the liver and lungs (all P < .05). CONCLUSIONS: T6SS is an essential virulence factor for K pneumoniae and contributes to IKPLA.

Mechanistic Study on the Corrosion of (La,Sr)(Co,Fe)O3-δ Cathodes Induced by CO2.

Solid Oxide Fuel Cell (SOFC) cathodes operating in ambient atmospheric conditions inevitably encounter CO2 contamination, leading to sustained performance deterioration. In this investigation, we examined the impact of CO2 on three variants of (La,Sr)(Co,Fe)O3-δ cathodes and employed the distribution of relaxation times method to distinguish distinct electrochemical processes based on impedance spectra analysis. We meticulously analyzed and discussed the corrosion resistance of these (La,Sr)(Co,Fe)O3-δ cathodes under high CO2 concentrations, relying on the experimental data. Electrochemical impedance spectroscopy results revealed that La0.6Sr0.4Co0.2Fe0.8O3-δ (LSCF-6428), La0.4Sr0.6Co0.2Fe0.8O3-δ (LSCF-4628), and La0.4Sr0.6Co0.2Fe0.7Nb0.1O3-δ (LSCFN-46271) cathodes exhibited persistent degradation when exposed to CO2 at temperatures of 650 °C or 800 °C during the durability-testing period. An increase in electrode polarization resistance was observed upon CO2 introduction to the electrode, but electrode performance recovered upon returning to a pure air environment. Furthermore, X-ray diffraction and scanning electron microscopy analyses confirmed that CO2 did not cause permanent damage to the (La,Sr)(Co,Fe)O3-δ cathodes. These findings indicate that the (La,Sr)(Co,Fe)O3-δ cathodes exhibit excellent resistance to CO2-induced corrosion.

Distance Matters: A Distance-Aware Medical Image Segmentation Algorithm.

The transformer-based U-Net network structure has gained popularity in the field of medical image segmentation. However, most networks overlook the impact of the distance between each patch on the encoding process. This paper proposes a novel GC-TransUnet for medical image segmentation. The key innovation is that it takes into account the relationships between patch blocks based on their distances, optimizing the encoding process in traditional transformer networks. This optimization results in improved encoding efficiency and reduced computational costs. Moreover, the proposed GC-TransUnet is combined with U-Net to accomplish the segmentation task. In the encoder part, the traditional vision transformer is replaced by the global context vision transformer (GC-VIT), eliminating the need for the CNN network while retaining skip connections for subsequent decoders. Experimental results demonstrate that the proposed algorithm achieves superior segmentation results compared to other algorithms when applied to medical images.

Nanovaccines Mediated Subcutis-to-Intestine Cascade for Improved Protection against Intestinal Infections.

Parenteral vaccines typically can prime systemic humoral immune response, but with limited effects on cellular and mucosal immunity. Here, a subcutis-to-intestine cascade for navigating nanovaccines to address this limitation is proposed. This five-step cascade includes lymph nodes targeting, uptaken by dendritic cells (DCs), cross-presentation of antigens, increasing CCR9 expression on DCs, and driving CD103+ DCs to mesenteric lymph nodes, in short, the LUCID cascade. Specifically, mesoporous silica nanoparticles are encapsulated with antigen and adjuvant toll-like receptor 9 agonist cytosine-phosphate-guanine oligodeoxynucleotides, and further coated by a lipid bilayer containing all-trans retinoic acid. The fabricated nanovaccines efficiently process the LUCID cascade to dramatically augment cellular and mucosal immune responses. Importantly, after being vaccinated with Salmonella enterica serovar Typhimurium antigen-loaded nanovaccine, the mice generate protective immunity against challenge of S. Typhimurium. These findings reveal the efficacy of nanovaccines mediated subcutis-to-intestine cascade in simultaneously activating cellular and mucosal immune responses against mucosal infections.

Development and validation of a prediction model based on clinical and CT features for invasiveness of K. pneumoniae liver abscess.

OBJECTIVES: Klebsiella pneumoniae liver abscess (KPLA) complicated with extrahepatic migratory infection (EMI) is defined as invasive KPLA. The current study aimed to develop and validate a risk prediction model for the invasiveness of KPLA. METHODS: From 2010 to 2020, KPLA patients from four institutes were selected retrospectively. In the development cohort, risk factors from a logistic regression analysis were utilized to develop the prediction model. External validation was performed using an independent cohort. RESULTS: A total of 382 KPLA patients comprised two separate cohorts: development cohort (institute 1, n = 286) and validation cohort (institute 2-4, n = 86). The overall incidence of EMI was 19.1% (development cohort, n = 55; validation cohort, n = 18, p > 0.05). In the development cohort, four risk factors (age ≤ 40 years, fasting blood glucose (FBG) > 7 mmol/L, no rim enhancement, and thrombophlebitis on CT), significantly associated with EMI, were incorporated into the scoring system. The area under curve (AUC) of the receiver operating characteristic curve (ROC) in the development and validation cohorts was 0.931 (95% confidence interval [CI]: 0.93-0.95) and 0.831 (95% CI: 0.86-0.91), respectively. The calibration curves fitted well. The incidence of EMI was 3.3% and 56.5% for the low- (total scores ≤ 4) and high-risk (total scores > 4) groups in the development cohort, and 3.2% and 66.7% in the validation cohort (all p < 0.001), respectively. CONCLUSIONS: Age ≤ 40 years, FBG > 7 mmol/L, no rim enhancement, and thrombophlebitis were independent risk factors for EMI. This validated prediction model may aid clinicians in identifying KPLA patients at increased risk for invasiveness. KEY POINTS: • Four risk factors are significantly associated with extrahepatic migratory infections (EMI): age ≤ 40 years, fasting blood glucose (FBG) > 7 mmol/L, no rim enhancement, and thrombophlebitis on CT. • Based on these risk factors, the current study developed and validated a prediction model for the invasiveness of Klebsiella pneumoniae liver abscess (KPLA). • This validated prediction model may in the help early identification of KPLA patients at increased risk for invasiveness.

D2D Social Selection Relay Algorithm Combined with Auction Principle.

In a D2D (device-to-device) communication system, this paper proposes a relay selection strategy based on social perception. Firstly, the social threshold is introduced into the D2D relay network to screen and filter the potential relay users, thus effectively reducing the detection cost. Then, an auction algorithm is used to motivate the relay users to increase their transmission power. The simulation results show that the algorithm not only improves the throughput but also reduces the probability of a system outage.

Nanoemulsions Target to Ectopic Lymphoids in Inflamed Joints to Restore Immune Tolerance in Rheumatoid Arthritis.

Inducing immune tolerance through repeated administration of self-antigens is a promising strategy for treating rheumatoid arthritis (RA), and current research indicates that coadministration of immunomodulators can further orchestrate the tolerogenic response. However, most of the clinical trials based on tolerance induction have negligible therapeutic effects. Peripheral lymphoid organs play critical roles in immunotherapy. Here, we design an engineered nanoemulsion for targeted codelivery of self-antigens and an immunomodulator to ectopic lymphoid structures (ELSs) in inflamed joints of RA. Namely, a citrullinated multiepitope self-antigen (CitP) and rapamycin are incorporated into the nanoemulsions (NEs@CitP/Rapa), which are fabricated by a facial method using commercialized pharmaceutical excipients. After intravenous administration, the nanoemulsion shows satisfactory accumulation in the inflamed paws and provides enhanced anti-inflammatory effect in various experimental murine models of RA. Our study provides a promising targeting strategy to induce immune tolerance for the treatment of RA.

FTH promotes the proliferation and renders the HCC cells specifically resist to ferroptosis by maintaining iron homeostasis.

BACKGROUND: Ferroptosis is a newly identified type of programmed cell death, which preferentially targets iron-rich cancer cells such as hepatocellular carcinoma (HCC). Ferritin heavy chain (FTH) is a major iron storing nanocage to store redox-inactive iron, and harbors ferroxidase activity to prevent the iron-mediated production of ROS. Our previous studies have demonstrated that FTH acts as a protective role to increase the cellular resistance to ferroptosis. However, the specific role of FTH in the development of HCC and ferroptosis resistance remains unclear. METHODS: The indicated databases were used for bioinformatics analysis. The abilities of cell proliferation, migration were measured by cell proliferation assay, transwell assay and wound healing assay. The levels of reactive oxygen species (ROS), lipid peroxide, free iron, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were determined by DCF-DA, C11-BODIPY, mitoSOX, mitoTracker, JC-10 and TMRM staining, respectively. The mitochondrial oxygen consumption rate was monitored by the Seahorse XF24 Analyzer. RESULTS: The pan-cancer analysis was performed and showed that FTH expression is upregulated in multiple cancers, such as LIHC, CHOL, HNSC, compared to corresponding normal tissues. In addition, the level of serum ferritin is positively associated with the progression of hepatitis, cirrhosis liver and hepatocellular carcinoma. Further investigation shed light on the strong correlation between FTH expression and tumor grades, cancer stages and prognosis of HCC. Importantly, the proteins interaction network elucidated that FTH is involved in iron homeostasis maintenance and lysosomal-dependent degradation. Enforced expression of FTH accelerates proliferation, migration and endows HCC cells specifically resistant to ferroptosis, but does not protect against cell death caused by cytotoxic compounds like oxaliplatin, irinotecan, and adriamycin. Mechanically, FTH reconstituted cells exhibit diminished peroxides accumulation, reduce mitochondrial ROS level, attenuate the impaired mitochondrial respiratory and rescue the mitochondrial homeostasis. Notably, FTH expression boosts tumorigenic potential in vivo with increased PCNA staining and lesser lipid peroxides generation. CONCLUSION: These results provide new insights that FTH acts as an oncogene in the carcinogenesis and progression of HCC, and is hopeful to be a potential target for therapeutic intervention through ferroptosis.

Anti-PD-L1 mediating tumor-targeted codelivery of liposomal irinotecan/JQ1 for chemo-immunotherapy.

Immune checkpoint blockade therapy has become a first-line treatment in various cancers. But there are only a small percent of colorectal patients responding to PD-1/PD-L1 blockage immunotherapy. How to increase their treatment efficacy is an urgent and clinically unmet need. It is acknowledged that immunogenic cell death (ICD) induced by some specific chemotherapy can enhance antitumor immunity. Chemo-based combination therapy can yield improved outcomes by activating the immune system to eliminate the tumor, compared with monotherapy. Here, we develop a PD-L1-targeting immune liposome (P-Lipo) for co-delivering irinotecan (IRI) and JQ1, and this system can successfully elicit antitumor immunity in colorectal cancer through inducing ICD by IRI and interfering in the immunosuppressive PD-1/PD-L1 pathway by JQ1. P-Lipo increases intratumoral drug accumulation and promotes DC maturation, and thereby facilitates adaptive immune responses against tumor growth. The remodeling tumor immune microenvironment was reflected by the increased amount of CD8+ T cells and the release of IFN-γ, and the reduced CD4+Foxp3+ regulatory T cells (Tregs). Collectively, the P-Lipo codelivery system provides a chemo-immunotherapy strategy that can effectively remodel the tumor immune microenvironment and activate the host immune system and arrest tumor growth.

Consuming Different Structural Parts of Bamboo Induce Gut Microbiome Changes in Captive Giant Pandas.

Giant pandas consume different structural parts of bamboo (shoots, leaves and culms) during different seasons. Previous research showed different bamboo parts have varying nutritional content and that a long-term diet consisting of a single part of bamboo resulted in remarkable metabolic changes within captive giant pandas. However, the effects on the gut microbiome of giant pandas, as a result of a single bamboo part diet, have not been investigated. Here, we evaluated the changes in gut microbial communities based on single bamboo part diets and their potential implications by using 16S rRNA gene-based amplicon sequencing and metagenome shotgun sequencing. We found that the composition and function of the gut microbiome from captive giant pandas fed exclusively culms were significantly different from that of individuals fed shoots or leaves. During the culm feeding period, the gut microbiome showed strongest digestive capabilities for cellulose, hemicellulose and starch, and had the highest potential abilities for the biosynthesis of bile acids, fatty acids and amino acids. This suggests the microbiome aids in breaking down culm, which is more difficult for giant pandas to digest, as a means to compensate for the nutrient poor content of the culm. Genes related to fatty acid metabolism and tricarboxylic acid cycle enzymes were more abundant during the leaf stage diet than that in the shoot and culm stages. Thus, the microbiome may help giant pandas, which typically have low lipase levels, with fat digestion. These results illustrate that adaptive changes in the gut microbiome community and function may be an important mechanism to aid giant panda digestion when consuming different structural parts of bamboo.

Study on the COVID-19 infection status, prevention and control strategies among people entering Shenzhen.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) confirmed cases overseas have continued to rise in the last months, and many people overseas have chosen to return to China. This increases the risk of a large number of imported cases which may cause a relapse of the COVID-19 outbreak. In order to prevent imported infection, the Shenzhen government has implemented a closed-loop management strategy using nucleic acid testing (NAT) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and requiring 14 days of medical observation for individuals with an overseas tour history (Hong Kong, Macao, Taiwan province and other countries). Our study aims to describe the status of COVID-19 infection among people entering Shenzhen, and to evaluate the effect of the closed-loop management strategy. METHODS: We undertook a descriptive study and risk analysis by the entry time, time of reporting, and local confirmed cases in countries of origin. The NAT were completed in Shenzhen Center for Disease Control and Prevention (CDC), ten district-level CDCs, and fever clinics. RESULTS: A total of 86,844 people from overseas entered Shenzhen from January 1 to April 18, 2020; there were 39 imported COVID cases and 293 close contacts. The infection rate of people entering was 4.49‰ [95% Confidence interval (CI): 3.26‰-6.05‰]. Fourteen imported cases (35.9%) came from the UK, and nine (23.08%) came from the USA. People entering from the USA since March 9 or from the UK since March 13 are the high-risk population. As of July 17, there have been no new confirmed cases in Shenzhen for 153 days, and the numbers of confirmed case, close contacts, and asymptomatic cases are 0. CONCLUSIONS: The closed-loop management has been effective in preventing imported infection and controlling domestic relapse. The distribution of entry time and report time for imported cases overseas was similar. This shows that it is important to implement closed-loop management at the port of entry.

Gut microbiota composition and metabolomic profiles of wild and captive Chinese monals (Lophophorus lhuysii).

BACKGROUND: The Chinese monal (Lophophorus lhuysii) is an endangered bird species, with a wild population restricted to the mountains in southwest China, and only one known captive population in the world. We investigated the fecal microbiota and metabolome of wild and captive Chinese monals to explore differences and similarities in nutritional status and digestive characteristics. An integrated approach combining 16S ribosomal RNA (16S rRNA) gene sequencing and ultra-high performance liquid chromatography (UHPLC) based metabolomics were used to examine the fecal microbiota composition and the metabolomic profile of Chinese monals. RESULTS: The results showed that the alpha diversity of gut microbes in the wild group were significantly higher than that in the captive group and the core bacterial taxa in the two groups showed remarkable differences at phylum, class, order, and family levels. Metabolomic profiling also revealed differences, mainly related to galactose, starch and sucrose metabolism, fatty acid, bile acid biosynthesis and bile secretion. Furthermore, strong correlations between metabolite types and bacterial genus were detected. CONCLUSIONS: There were remarkable differences in the gut microbiota composition and metabolomic profile between wild and captive Chinese monals. This study has established a baseline for a normal gut microbiota and metabolomic profile for wild Chinese monals, thus allowing us to evaluate if differences seen in captive organisms have an impact on their overall health and reproduction.

The increased recurrence rate of liver abscess caused by extended-spectrum ß-lactamase-producing Klebsiella pneumoniae.

The pathogenic bacterium Klebsiella pneumoniae (KP) is the major causative agent of pyogenic liver abscess (PLA). But reports about the prognosis of KP-caused PLA (KPLA) are rare. This study aimed to ascertain the recurrence rate of KPLA after initial treatment and its contributing factors. A total of 110 patients who had first-time episodes of KPLA were included into the study. The average follow-up time was 3.65 ± 2.18 years. Twenty (18.18%) KPLA patients experienced recurrence. Those in the recurrence group had a significantly greater incidence of extended-spectrum ß-lactamase (ESBL) production compared with the non-recurrence group (30.0% vs 8.89%, P = 0.018). Diabetes, biliary tract disease, and history of malignancy were not associated with recurrence (all P > 0.05). No difference in the CT characteristics of KPLA (including abscess size, location, whether multilocular, gas production of KPLA, and thrombophlebitis) was found between the two groups. Multivariate regression analysis showed that ESBL production (OR, 6.3; 95% CI, 1.02-38.59; P = 0.04) was an independent risk factor for the recurrence of KPLA. Our findings emphasize that KPLA has a high recurrence rate and ESBL production is an independent risk factor for recurrent KPLA.

Composition and consistence of the bacterial microbiome in upper, middle and lower esophagus before and after Lugol's iodine staining in the esophagus cancer screening.

BACKGROUND: Esophageal bacteria, as the integral composition of human ecosystem, have been reported to be associated with esophageal lesions. However, few studies focus on microbial compositions in different esophageal segments, especially after Lugol's iodine staining (LIS) in the endoscopic examination for the screening of esophageal cancer. We aim to investigate the composition of the bacterial microbiome in upper, middle and lower esophagus and if LIS would affect the detection of bacteria. METHODS: A total of 141 fasting samples including the upper, middle and lower esophagus from 27 participants were collected by brushing the mucosal surface of the esophagus before (Eso) and after (Lug) LIS. Bacterial V3-V4 region of 16S rRNA gene was amplified and sequenced by Illumina's sequencing platform. RESULTS: The top six abundant bacterial phyla taxa among three locations from both Eso and Lug groups were Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria and TM7. In terms of genera, the bacterium in three locations from two groups was all characterized by a highest relative abundance of Streptococcus. Bacteria diversity and the relative abundance between Eso and Lug were comparable (p > .05). Bacteria diversity was consistent in different esophageal locations within the individual. CONCLUSION: The bacterial microbiome in healthy esophagus are highly diverse and consistent even among three physiological sites at all clades. Lugol's iodine staining would not change local microenvironment in term of microbial composition. These findings provide an essential baseline for future studies investigating local and systemic bacterial microbiome and esophageal diseases.

Clinical and computed tomography features of extended-spectrum ß-lactamase-producing Klebsiella pneumoniae liver abscess.

BACKGROUND: Klebsiella pneumoniae (KP) is the primary pathogen associated with pyogenic liver abscesses (PLAs). Moreover, there has been an increase in the proportion of extended-spectrum beta-lactamase (ESBL)-producing KP. However, the clinical and computed tomography (CT) features of liver abscesses caused by ESBL-producing KP have not been separately described. We aimed to compare the clinical and CT features present in patients with ESBL-producing and non-ESBL-producing KP as well as to determine the risk factors for ESBL-producing KP liver abscesses (KPLAs). METHODS: We performed a retrospective analysis of data obtained from the medical records of patients with a first episode of KPLA admitted to Shengjing Hospital of China Medical University between May 2015 and May 2019. We compared the clinical and CT features between patients with ESBL-producing and non-ESBL-producing KPLA. RESULTS: We enrolled 100 patients with KPLA (14 and 86 in the ESBL-producing and non-ESBL-producing groups, respectively). There was no significant between-group difference in the proportion of patients with comorbid diabetes (71.43% vs. 66.2%, p = 0.086). The ESBL-producing KPLA group had a greater proportion of patients with a history of biliary disease (78.57% vs. 26.74%, p < 0.001) and gastrointestinal malignancy (50% vs. 6.98%, p < 0.001). Multivariate regression analysis showed that a history of biliary disease was an independent risk factor for ESBL-producing KPLA. Compared with the non-ESBL-producing KPLA group, the ESBL-producing KPLA group had a significantly higher intensive care unit (ICU) admission rate (28.57% vs. 2.33%, p < 0.001). All ESBL-producing KP isolates were susceptible to carbapenems and amikacin. Only the presence of multiloculation on CT was found to be significantly different between the groups (50% vs. 82.56%, p = 0.012). CONCLUSIONS: The presence of biliary disease was an independent risk factor for ESBL-producing KPLA. Patients with ESBL-producing KPLA had a higher ICU admission rate, with only half of patients having evidence of multiloculation on CT.

Reprogramming Tumor Immune Microenvironment (TIME) and Metabolism via Biomimetic Targeting Codelivery of Shikonin/JQ1.

Remodeling tumor immune microenvironment (TIME) is an important strategy to lift the immunosuppression and achieve immune normalization. In this work, a mannosylated lactoferrin nanoparticulate system (Man-LF NPs) is developed for dual-targeting biomimetic codelivery of shikonin and JQ1 via the mannose receptor and LRP-1 that are overexpressed in both cancer cells and tumor-associated macrophages. The Man-LF NPs can serve as multitarget therapy for inducing immune cell death in the cancer cells, repressing glucose metabolism and repolarizing tumor-associated macrophages, and consequently, lead to remodeling the TIME (e.g., promotion of dendritic cell maturation and CD8+ T cell infiltration, as well as suppression of Treg). Moreover, JQ1 is a suppressor of PD-L1, and the Man-LF NPs can also work on PD-L1 checkpoint blockage. The results reveal the synergistic combination of shikonin and JQ1 and the treatment potency of the Man-LF NPs. Importantly, it is demonstrated that the interaction between the tumor metabolism and immunity plays an essential role in immunotherapy, and the developed drug combination and nanoformulation can target the multiple components in the complicated network of TIME, providing a potential therapeutic strategy.

Influence of presence/absence of thyroid gland on the cutoff value for thyroglobulin in lymph-node aspiration to detect metastatic papillary thyroid carcinoma.

BACKGROUND: Thyroglobulin measurement with fine-needle aspiration (Tg-FNA) is a sensitive method for detecting metastatic papillary thyroid carcinoma (PTC). However, the diagnostic threshold is not well established and the influence of the thyroid gland on the cutoff value is also controversial. In this study, patients were classified into two groups according to the presence or absence of thyroid tissue, to determine an appropriate cutoff value for clinical practice. METHODS: Patients with a history of thyroid nodules or surgery for PTC and with enlarged cervical lymph nodes on an FNA examination were enrolled for Tg-FNA detection. RESULTS: One hundred ninety-six lymph nodes (189 patients) were included: 100 from preoperative patients, 49 from patients treated with partial thyroid ablation, and 47 from patients with total thyroid ablation. In 149 lymph nodes from patient with thyroids, the cutoff value for Tg-FNA was 55.99 ng/mL (sensitivity, 95.1%; specificity, 100%), whereas in 47 lymph nodes from patients without a thyroid, it was 9.71 ng/mL (sensitivity, 96.7%; specificity, 100%). Thus, the cutoff value for Tg-FNA was higher in patients with thyroids than in patients without thyroids. CONCLUSIONS: The cutoff value for Tg-FNA is influenced by residual thyroid tissue, and a higher cutoff value is recommended for patients with thyroids than for patients without thyroids.