Renal NF-κB activation impairs uric acid homeostasis to promote tumor-associated mortality independent of wasting.

Tumor-induced host wasting and mortality are general phenomena across species. Many groups have previously demonstrated endocrinal impacts of malignant tumors on host wasting in rodents and Drosophila. Whether and how environmental factors and host immune response contribute to tumor-associated host wasting and survival, however, are largely unknown. Here, we report that flies bearing malignant yki3SA-gut tumors exhibited the exponential increase of commensal bacteria, which were mostly acquired from the environment, and systemic IMD-NF-κB activation due to suppression of a gut antibacterial amidase PGRP-SC2. Either gut microbial elimination or specific IMD-NF-κB blockade in the renal-like Malpighian tubules potently improved mortality of yki3SA-tumor-bearing flies in a manner independent of host wasting. We further indicate that renal IMD-NF-κB activation caused uric acid (UA) overload to reduce survival of tumor-bearing flies. Therefore, our results uncover a fundamental mechanism whereby gut commensal dysbiosis, renal immune activation, and UA imbalance potentiate tumor-associated host death.

A novel antidiuretic hormone governs tumour-induced renal dysfunction.

Maintenance of renal function and fluid transport are essential for vertebrates and invertebrates to adapt to physiological and pathological challenges. Human patients with malignant tumours frequently develop detrimental renal dysfunction and oliguria, and previous studies suggest the involvement of chemotherapeutic toxicity and tumour-associated inflammation1,2. However, how tumours might directly modulate renal functions remains largely unclear. Here, using conserved tumour models in Drosophila melanogaster3, we characterized isoform F of ion transport peptide (ITPF) as a fly antidiuretic hormone that is secreted by a subset of yki3SA gut tumour cells, impairs renal function and causes severe abdomen bloating and fluid accumulation. Mechanistically, tumour-derived ITPF targets the G-protein-coupled receptor TkR99D in stellate cells of Malpighian tubules-an excretory organ that is equivalent to renal tubules4-to activate nitric oxide synthase-cGMP signalling and inhibit fluid excretion. We further uncovered antidiuretic functions of mammalian neurokinin 3 receptor (NK3R), the homologue of fly TkR99D, as pharmaceutical blockade of NK3R efficiently alleviates renal tubular dysfunction in mice bearing different malignant tumours. Together, our results demonstrate a novel antidiuretic pathway mediating tumour-renal crosstalk across species and offer therapeutic opportunities for the treatment of cancer-associated renal dysfunction.

Structural basis for self-cleavage prevention by tag:anti-tag pairing complementarity in type VI Cas13 CRISPR systems.

Bacteria and archaea apply CRISPR-Cas surveillance complexes to defend against foreign invaders. These invading genetic elements are captured and integrated into the CRISPR array as spacer elements, guiding sequence-specific DNA/RNA targeting and cleavage. Recently, in vivo studies have shown that target RNAs with extended complementarity with repeat sequences flanking the target element (tag:anti-tag pairing) can dramatically reduce RNA cleavage by the type VI-A Cas13a system. Here, we report the cryo-EM structure of Leptotrichia shahii LshCas13acrRNA in complex with target RNA harboring tag:anti-tag pairing complementarity, with the observed conformational changes providing a molecular explanation for inactivation of the composite HEPN domain cleavage activity. These structural insights, together with in vitro biochemical and in vivo cell-based assays on key mutants, define the molecular principles underlying Cas13a's capacity to target and discriminate between self and non-self RNA targets. Our studies illuminate approaches to regulate Cas13a's cleavage activity, thereby influencing Cas13a-mediated biotechnological applications.

Copper homeostasis and cuproptosis in cancer immunity and therapy.

Copper is an essential nutrient for maintaining enzyme activity and transcription factor function. Excess copper results in the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), which correlates to the mitochondrial tricarboxylic acid (TCA) cycle, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cuproptosis exerts an indispensable role in cancer progression, which is considered a promising strategy for cancer therapy. Cancer immunotherapy has gained extensive attention owing to breakthroughs in immune checkpoint blockade; furthermore, cuproptosis is strongly connected to the modulation of antitumor immunity. Thus, a thorough recognition concerning the mechanisms involved in the modulation of copper metabolism and cuproptosis may facilitate improvement in cancer management. This review outlines the cellular and molecular mechanisms and characteristics of cuproptosis and the links of the novel regulated cell death modality with human cancers. We also review the current knowledge on the complex effects of cuproptosis on antitumor immunity and immune response. Furthermore, potential agents that elicit cuproptosis pathways are summarized. Lastly, we discuss the influence of cuproptosis induction on the tumor microenvironment as well as the challenges of adding cuproptosis regulators to therapeutic strategies beyond traditional therapy.

Stimuli-responsive nanodelivery systems for amplifying immunogenic cell death in cancer immunotherapy.

Immunogenic cell death (ICD) is a special pattern of tumor cell death, enabling to elicit tumor-specific immune response via the release of damage-associated molecular patterns and tumor-associated antigens in the tumor microenvironment. ICD-induced immunotherapy holds the promise for completely eliminating tumors and long-term protective antitumor immune response. Increasing ICD inducers have been discovered for boosting antitumor immunity via evoking ICD. Nonetheless, the utilization of ICD inducers remains insufficient owing to serious toxic reactions, low localization efficiency within the tumor microenvironmental niche, etc. For overcoming such limitations, stimuli-responsive multifunctional nanoparticles or nanocomposites with ICD inducers have been developed for improving immunotherapeutic efficiency via lowering toxicity, which represent a prospective scheme for fostering the utilization of ICD inducers in immunotherapy. This review outlines the advances in near-infrared (NIR)-, pH-, redox-, pH- and redox-, or NIR- and tumor microenvironment-responsive nanodelivery systems for ICD induction. Furthermore, we discuss their clinical translational potential. The progress of stimuli-responsive nanoparticles in clinical settings depends upon the development of biologically safer drugs tailored to patient needs. Moreover, an in-depth comprehending of ICD biomarkers, immunosuppressive microenvironment, and ICD inducers may accelerate the advance in smarter multifunctional nanodelivery systems to further amplify ICD.

Dual Nickel- and Photoredox-Catalyzed Asymmetric Reductive Cross-Couplings: Just a Change of the Reduction System?

ConspectusIn recent years, nickel-catalyzed asymmetric coupling reactions have emerged as efficient methods for constructing chiral C(sp3) carbon centers. Numerous novel approaches have been reported to rapidly construct chiral carbon-carbon bonds through nickel-catalyzed asymmetric couplings between electrophiles and nucleophiles or asymmetric reductive cross-couplings of two different electrophiles. Building upon these advances, our group has been devoted to interrogating dual nickel- and photoredox-catalyzed asymmetric reductive cross-coupling reactions.In our endeavors over the past few years, we have successfully developed several dual Ni-/photoredox-catalyzed asymmetric reductive cross-coupling reactions involving organohalides. While some probably think that this system is just a change of the reduction system from traditional metal reductants to a photocatalysis system, a question that we also pondered at the beginning of our studies, both the achievable reaction types and mechanisms suggest a different conclusion: that this dual catalysis system has its own advantages in the chiral carbon-carbon bond formation. Even in certain asymmetric reactions where the photocatalysis regime functions only as a reducing system, the robust reducing capability of photocatalysts can effectively accelerate the regeneration of low-valent nickel species, thus expanding the selectable scope of chiral ligands. More importantly, in many transformations, besides reducing nickel catalysts, the photocatalysis system can also undertake the responsibility of alkyl radical formation, thereby establishing two coordinated, yet independent catalytic cycles. This catalytic mode has been proven to play a crucial role in achieving diverse asymmetric coupling reactions with great challenges.In this Account, we elucidate our understanding of this system based on our experience and findings. In the Introduction, we provide an overview of the main distinctions between this system and traditional Ni-catalyzed asymmetric reductive cross-couplings with metal reductants and the potential opportunities arising from these differences. Subsequently, we outline various chiral carbon-carbon bond-forming types obtained by this dual Ni/photoredox catalysis system and their mechanisms. In terms of chiral C(sp3)-C(sp2) bond formation, extensive discussion focuses on the asymmetric arylations of α-chloroboronates, α-trifluoromethyl alkyl bromides, α-bromophosphonates, and so on. In the realm of chiral C(sp3)-C(sp) bond formation, asymmetric alkynylations of α-bromophosphonates and α-trifluoromethyl alkyl bromides have been presented herein. Regarding C(sp3)-C(sp3) bond formation, we take the asymmetric alkylation of α-chloroboronates as a compelling example to illustrate the great efficiency of this dual catalysis system. This summary would enable a better grasp of the advantages of this dual catalysis system and clarify how the photocatalysis regime facilitates enantioselective transformations. We anticipate that this Account will offer valuable insights and contribute to the development of new methodologies in this field.

Tunable optical spatial differential operation via photonic spin Hall effect in a Weyl semimetal.

Optical differential operation is the basic principle of optical image edge detection, which has the advantages of high efficiency, simple structure and markerless compared with the traditional digital image processing methods. In this paper, we propose an optical differential operation with high contrast based on the photonic spin Hall effect in a Weyl semimetal, which enables to switch between one- and two-dimensional edge detection. Due to the unique optical and electrical properties of the Weyl semimetal, a transport model for the differential operation is established, which is closely related to the beam shifts. By tuning the incidence conditions, we effectively manipulate the in-plane and transverse shifts to switch differential operations between one and two dimensions. The contrast of the differential operation is further regulated by changing the physical parameters of the Weyl semimetal, and can be improved by two orders of magnitude compared to the conventional differentiator. This study provides new possibilities in edge detection and image processing owing to the advantages of switchable dimension and high contrast.

Peripheral 5-HT Mediates Gonadotropin-Inhibitory Hormone-Induced Feeding Behavior and Energy Metabolism Disorder in Chickens via the 5-HT2C Receptor.

INTRODUCTION: Since the discovery of gonadotropin-inhibitory hormone (GnIH), it has been found to play a critical role in reproduction in vertebrates. Recently, a regulatory role of GnIH in appetite and energy metabolism has emerged, although its precise physiological mechanisms remain unknown. METHODS: Thus, the present study evaluated the effects of a single or long-term intraperitoneal GnIH treatment on the food intake, weight, and glucolipid metabolism of chickens, as well as investigating the possible neuroendocrinology factors and mechanisms involved in GnIH-induced obesity and glucolipid metabolism disorder. RESULTS: Our results show that the intraperitoneal administration of GnIH to chickens resulted in a marked body mass increase, hyperlipidemia, hyperglycemia, and glucose intolerance. Subsequently, the results of metabolomics studies and the pharmacological inhibition of the 5-HT2C receptor revealed that blocking the 5-HT2C receptor reinforced the effects of GnIH on food intake, body weight, and blood glucose and lipid levels, resulting in even worse cases of GnIH-induced hyperglycemia, hyperlipidemia, and hepatic lipid deposition. This suggests that, via the 5-HT2C receptor, peripheral 5-HT may act as a negative feedback regulator to interplay with GnIH and jointly control energy balance homeostasis in chickens. DISCUSSION: Our present study provides evidence of cross-talk between GnIH and 5-HT in food intake and energy metabolism at the in vivo pharmacological level, and it proposes a molecular basis for these interactions, suggesting that functional interactions between GnIH and 5-HT may open new avenues for understanding the mechanism of the neuroendocrine network involved in appetite and energy metabolism, as well as providing a new therapeutic strategy to prevent obesity, diabetes, and metabolic disorders.

Enhancing the Solubility, Stability, and Bioavailability of Retinol Acetate through Mechanochemistry.

This study utilizes mechanochemistry to prepare retinol acetate (RA) solid dispersion (RA-sodium starch octenyl succinate (SSOS)), resulting in improved solubility, stability, and bioavailability compared with raw RA and commercial RA microcapsules. RA, poloxamer 188, SSOS, and milling beads (8 mm) were mixed in a ratio of 2:1:8:220 (w/w) and ball-milled at 100 rpm for 3 h. RA-SSOS exhibited a solubility of 1020.35 µL/mL and a 98.09% retention rate after aging at 30 °C. Rats fed with RA-SSOS showed an ∼30% increase in organ RA content. Characterization analysis attributed the solubility and stabilization of RA-SSOS to hydrogen bonding between RA and SSOS, along with an amorphous state. RA-SSOS offers significant advantages for the pharmaceutical and food industries, leveraging mechanochemistry to enhance solid dispersions for hydrophobic compounds and optimize drug delivery.

Single-cell RNA-seq analysis decodes the kidney microenvironment induced by polystyrene microplastics in mice receiving a high-fat diet.

In recent years, the environmental health issue of microplastics has aroused an increasingly significant concern. Some studies suggested that exposure to polystyrene microplastics (PS-MPs) may lead to renal inflammation and oxidative stress in animals. However, little is known about the essential effects of PS-MPs with high-fat diet (HFD) on renal development and microenvironment. In this study, we provided the single-cell transcriptomic landscape of the kidney microenvironment induced by PS-MPs and HFD in mouse models by unbiased single-cell RNA sequencing (scRNA-seq). The kidney injury cell atlases in mice were evaluated after continued PS-MPs exposure, or HFD treated for 35 days. Results showed that PS-MPs plus HFD treatment aggravated the kidney injury and profibrotic microenvironment, reshaping mouse kidney cellular components. First, we found that PS-MPs plus HFD treatment acted on extracellular matrix organization of renal epithelial cells, specifically the proximal and distal convoluted tubule cells, to inhibit renal development and induce ROS-driven carcinogenesis. Second, PS-MPs plus HFD treatment induced activated PI3K-Akt, MAPK, and IL-17 signaling pathways in endothelial cells. Besides, PS-MPs plus HFD treatment markedly increased the proportions of CD8+ effector T cells and proliferating T cells. Notably, mononuclear phagocytes exhibited substantial remodeling and enriched in oxidative phosphorylation and chemical carcinogenesis pathways after PS-MPs plus HFD treatment, typified by alterations tissue-resident M2-like PF4+ macrophages. Multispectral immunofluorescence and immunohistochemistry identified PF4+ macrophages in clear cell renal cell carcinoma (ccRCC) and adjacent normal tissues, indicating that activate PF4+ macrophages might regulate the profibrotic and pro-tumorigenic microenvironment after renal injury. In conclusion, this study first systematically revealed molecular variation of renal cells and immune cells in mice kidney microenvironment induced by PS-MPs and HFD with the scRNA-seq approach, which provided a molecular basis for decoding the effects of PS-MPs on genitourinary injury and understanding their potential profibrotic and carcinogenesis in mammals.

Association between elevated preoperative red cell distribution width and mortality after brain tumor craniotomy.

BACKGROUND: Red cell distribution width (RDW) has been recognized as a potential inflammatory biomarker, with elevated levels associated with adverse outcomes in various diseases. However, its role in predicting outcomes after brain tumor craniotomy remains unclear. We aimed to assess whether preoperative RDW influences mortality and postoperative complications in patients undergoing brain tumor craniotomy. METHODS: This retrospective cohort study analyzed serum RDW levels in patients undergoing brain tumor craniotomy at West China Hospital. RDW was evaluated in two forms: RDW-CV and RDW-SD, and was categorized into four quartiles for analysis by using logistic regression and multivariate analysis to adjust for confounding. RESULTS: The study encompassed 10,978 patients undergoing brain tumor craniotomy. our analysis revealed no significant difference in 30-day mortality across various RDW-CV levels. However, we observed a dose-response relationship with preoperative RDW-CV levels in assessing long-term mortality risks. Specifically, patients with RDW-CV levels of 12.6-13.2% (HR 1.04, 95% CI 1.01-1.18), 13.2-13.9% (HR 1.12, 95% CI 1.04-1.26), and > 13.9% (HR 1.34, 95% CI 1.18-1.51) exhibited a significantly higher hazard of long-term mortality compared to those with RDW-CV < 12.6%. When preoperative RDW-CV was analyzed as a continuous variable, for each 10% increase in RDW-CV, the adjusted OR of long-term mortality was 1.09 (95% CI 1.05-1.13). we also observed significant associations between preoperative higher RDW-CV levels and certain postoperative complications including acute kidney injury (OR 1.46, 95% CI: 1.10-1.94), pneumonia infection (OR 1.19 95% CI: 1.05-1.36), myocardial infarction (OR 1.32, 95% CI: 1.05-1.66), readmission (OR 1.15, 95% CI: 1.01-1.30), and a prolonged length of hospital stay (OR 1.11, 95% CI: 1.02-1.21). For RDW-SD levels, there was no significant correlation for short-term mortality, long-term mortality, and postoperative complications. CONCLUSIONS: Our study showed elevated preoperative RDW-CV is significantly associated with increased long-term mortality and multiple postoperative complications, but no such association is observed with RDW-SD. These findings show the prognostic importance of RDW-CV, reinforcing its potential as a valuable tool for risk stratification in the preoperative evaluation of brain tumor craniotomy patients.

Deoxygenative Transformation of Alcohols via Phosphoranyl Radical from Exogenous Radical Addition.

A general approach to the direct deoxygenative transformation of primary, secondary, and tertiary alcohols has been developed. It undergoes through phosphoranyl radical intermediates generated by the addition of exogenous iodine radical to trivalent alkoxylphosphanes. Since these alkoxylphosphanes are readily in situ obtained from alcohols and commercially available, inexpensive chlorodiphenylphosphine, a diverse range of alcohols with various functional groups can be utilized to proceed deoxygenative cross-couplings with alkenes or aryl iodides. The selective transformation of polyhydroxy substrates and the rapid synthesis of complex organic molecules are also demonstrated with this method.

Enantioselective C(sp3)-C(sp3) Reductive Cross-Electrophile Coupling of Unactivated Alkyl Halides with α-Chloroboronates via Dual Nickel/Photoredox Catalysis.

Substantial advances in enantioconvergent C(sp3)-C(sp3) bond formations have been made with nickel-catalyzed cross-coupling of racemic alkyl electrophiles with organometallic reagents or nickel-hydride-catalyzed hydrocarbonation of alkenes. Herein, we report an unprecedented enantioselective C(sp3)-C(sp3) reductive cross-coupling by the direct utilization of two different alkyl halides with dual nickel/photoredox catalysis system. This highly selective coupling of racemic α-chloroboronates and unactivated alkyl iodides furnishes chiral secondary alkyl boronic esters, which serve as useful and important intermediates in the realm of organic synthesis and enable a desirable protocol to fast construction of enantioenriched complex molecules.

Special issue "The advance of solid tumor research in China": Multi-omics analysis based on 1311 clear cell renal cell carcinoma samples identifies a glycolysis signature associated with prognosis and treatment response.

In clear cell renal cell carcinoma (ccRCC), glycolysis is enhanced mainly because of the increased expression of key enzymes in glycolysis. Hence, the discovery of new molecular biomarkers for glycolysis may help guide and establish a precise system of diagnosis and treatment for ccRCC. Expression profiles of 1079 tumor samples of ccRCC patients (including 311 patients treated with everolimus or nivolumab) were downloaded from public databases. Proteomic profiles of 232 ccRCC samples were obtained from Fudan University Shanghai Cancer Center (FUSCC). Biological changes, tumor microenvironment and prognostic differences were explored between samples with various glycolysis characteristics. There were significant differences in CD8+ effector T cells, epithelial-to-mesenchymal transition and pan-fibroblast TGFb between the Low and High glyScore groups. The tumor mutation burden of the Low glyScore group was lower than that of the High glyScore group. And higher glyScore was significantly associated with worse overall survival (OS) in 768 ccRCC patients (P < .0001). External validation in FUSCC cohort also indicated that glyScore was of strong ability for predicting OS (P < .05). GlyScore may serve as a biomarker for predicting everolimus response in ccRCC patients due to its significant associations with progression-free survival (PFS). And glyScore may also predict overall survival in patients treated with nivolumab. We calculated the glyScore in ccRCC and the defined glyScore was of strong ability for predicting OS. In addition, glyScore may also serve as a biomarker for predicting PFS in patients treated with everolimus and could predict OS in patients treated with nivolumab.

Identification and functional characterization of the dirigent gene family in Phryma leptostachya and the contribution of PlDIR1 in lignan biosynthesis.

BACKGROUND: Furofuran lignans, the main insecticidal ingredient in Phryma leptostachya, exhibit excellent controlling efficacy against a variety of pests. During the biosynthesis of furofuran lignans, Dirigent proteins (DIRs) are thought to be dominant in the stereoselective coupling of coniferyl alcohol to form ( ±)-pinoresinol. There are DIR family members in almost every vascular plant, but members of DIRs in P. leptostachya are unknown. To identify the PlDIR genes and elucidate their functions in lignan biosynthesis, this study performed transcriptome-wide analysis and characterized the catalytic activity of the PlDIR1 protein. RESULTS: Fifteen full-length unique PlDIR genes were identified in P. leptostachya. A phylogenetic analysis of the PlDIRs classified them into four subfamilies (DIR-a, DIR-b/d, DIR-e, and DIR-g), and 12 conserved motifs were found among them. In tissue-specific expression analysis, except for PlDIR7, which displayed the highest transcript abundance in seeds, the other PlDIRs showed preferential expression in roots, leaves, and stems. Furthermore, the treatments with signaling molecules demonstrated that PlDIRs could be significantly induced by methyl jasmonate (MeJA), salicylic acid (SA), and ethylene (ETH), both in the roots and leaves of P. leptostachya. In examining the tertiary structure of the protein and the critical amino acids, it was found that PlDIR1, one of the DIR-a subfamily members, might be involved in the region- and stereo-selectivity of the phenoxy radical. Accordingly, LC-MS/MS analysis demonstrated the catalytic activity of recombinant PlDIR1 protein from Escherichia coli to direct coniferyl alcohol coupling into ( +)-pinoresinol. The active sites and hydrogen bonds of the interaction between PlDIR1 and bis-quinone methide (bisQM), the intermediate in ( +)-pinoresinol formation, were analyzed by molecular docking. As a result, 18 active sites and 4 hydrogen bonds (Asp-42, Ala-113, Leu-138, Arg-143) were discovered in the PlDIR1-bisQM complex. Moreover, correlation analysis indicated that the expression profile of PlDIR1 was closely connected with lignan accumulations after SA treatment. CONCLUSIONS: The results of this study will provide useful clues for uncovering P. leptostachya's lignan biosynthesis pathway as well as facilitate further studies on the DIR family.

Class switching is differentially regulated in RBC alloimmunization and vaccination.

BACKGROUND: Studies of human patients have shown that most anti-RBC alloantibodies are IgG1 or IgG3 subclasses, although it is unclear why transfused RBCs preferentially drive these subclasses over others. Though mouse models allow for the mechanistic exploration of class-switching, previous studies of RBC alloimmunization in mice have focused more on the total IgG response than the relative distribution, abundance, or mechanism of IgG subclass generation. Given this major gap, we compared the IgG subclass distribution generated in response to transfused RBCs relative to protein in alum vaccination, and determined the role of STAT6 in their generation. STUDY DESIGN AND METHODS: WT mice were either immunized with Alum/HEL-OVA or transfused with HOD RBCs and levels of anti-HEL IgG subtypes were measured using end-point dilution ELISAs. To study the role of STAT6 in IgG class-switching, we first generated and validated novel STAT6 KO mice using CRISPR/cas9 gene editing. STAT6 KO mice were then transfused with HOD RBCs or immunized with Alum/HEL-OVA, and IgG subclasses were quantified by ELISA. RESULTS: When compared with antibody responses to Alum/HEL-OVA, transfusion of HOD RBCs induced lower levels of IgG1, IgG2b, and IgG2c but similar levels of IgG3. Class switching to most IgG subtypes remained largely unaffected in STAT6 deficient mice in response to HOD RBC transfusion, with the one exception being IgG2b. In contrast, STAT6 deficient mice showed altered levels of all IgG subtypes following Alum vaccination. DISCUSSION: Our results show that anti-RBC class-switching occurs via alternate mechanisms when compared with the well-studied immunogen alum vaccination.

C Allele of the PPARδ+294T>C Polymorphism Confers a Higher Risk of Hypercholesterolemia, but not Obesity and Insulin Resistance: A Systematic Review and Meta-Analysis.

The relationships of the PPARα Leu162Val and PPARδ+294 T>C polymorphisms with metabolic indexes have been reported to be inconsistent and even contradictory. The meta-analysis was conducted to clarify the relationships between the two variants and the indexes of obesity, insulin resistance, and blood lipids. PubMed, Google Scholar, Embase, and Cochrane Library were searched for eligible studies. Standardized mean difference with 95% confidence interval was calculated to estimate the differences in the metabolic indexes between the genotypes of the Leu162Val and+294 T>C polymorphisms. Heterogeneity among studies was assessed by Cochran's x2-based Q-statistic test. Publication bias was identified by using Begg's test. Forty-one studies (44 585 subjects) and 33 studies (23 018 subjects) were identified in the analyses for the Leu162Val and+294 T>C polymorphisms, respectively. C allele carriers of the+294 T>C polymorphism had significantly higher levels of total cholesterol and low-density lipoprotein cholesterol than TT homozygotes in the whole population. Notably, C allele carriers of the+294 T>C polymorphism had significantly higher levels of triglycerides and total cholesterol in East Asians, but lower levels of triglycerides in West Asians than TT homozygotes. Regarding the Leu162Val polymorphism, it was found that Val allele carriers had significantly higher levels of blood glucose than Leu/Leu homozygotes only in European Caucasians. The meta-analysis demonstrates that C allele of the+294 T>C polymorphism in PPARδ gene confers a higher risk of hypercholesterolemia, which may partly explain the relationship between this variant and coronary artery disease.

Association of computed tomography-based body composition with survival in metastatic renal cancer patient received immunotherapy: a multicenter, retrospective study.

OBJECTIVES: To investigate the association of computed tomography-assessed body composition with survival outcomes of metastatic renal cell carcinoma (mRCC) received immunotherapy. METHODS: In this multicenter, retrospective study, we reviewed 251 mRCC patients who received anti-PD1 from five centers. We analyzed the relationship between BMI, skeletal muscle area (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and subcutaneous adipose percentage (SAT%) with progression-free survival (PFS) and overall survival (OS). The spatial localization T cells was investigated by multiplex immunofluorescence. RESULTS: Among 224 evaluable patients, 23 (10.3%) patients were underweight, 118 (52.7%) had normal weight, 65 (29%) were overweight, and 18 patients (8%) were obese. The median age was 55 years and most patients were male (71%). No significant improvement in PFS (HR, 0.61; 95% CI, 0.27-1.42) or OS (HR, 1.09; 95% CI, 0.38-3.13) was observed for the obese patients. Besides, SM, VAT, and SAT were not associated with survival outcomes (all p > 0.05). Interestingly, SAT% independently predicted PFS (as continuous variable, HR: 0.02; 95% CI, 0.01-0.11) and OS (HR:0.05; 95% CI, 0.01-0.39), which remained significant in multivariate modeling (as continuous variable, adjusted HR for PFS, 0.01; 95% CI, 0.00-0.04; adjusted HR for OS, 0.08; 95% CI, 0.01-0.72). These associations were consistent in subgroup analysis of different gender, BMI, PD-L1 positive, and sarcopenia group. Tumor of high SAT% patients had a higher intratumoral PD1+ CD8+ T cell density and ratio. CONCLUSION: High SAT% predicts better outcomes in mRCC patients treated with anti-PD1 and T cell location may account for the better response. KEY POINTS: • CT-based subcutaneous adipose percentage independently predicted progression-free survival and overall survival. • Patients with a higher subcutaneous adipose percentage had a higher intratumoral PD1+ CD8+ T cell density and ratio.

Identification of prognostic and therapeutic biomarkers in type 2 papillary renal cell carcinoma.

BACKGROUND: Papillary renal cell carcinoma (PRCC) can be divided into type 1 (PRCC1) and type 2 (PRCC2) and PRCC2 share a more invasive phenotype and worse prognosis. This study aims to identify potential prognostic and therapeutic biomarkers in PRCC2. METHODS: A cohort from The Cancer Genome Atlas and two datasets from Gene Expression Omnibus were examined. Common differentially expressed genes (DEGs) were screened and potential biomarkers were explored by using Kaplan-Meier method and cox regression analysis. Functional enrichment analysis was utilized to evaluate the potential biological functions. Tumor infiltrating immune cells were estimated by CIBERSORT algorithm. Ninety-two PRCC2 samples from Fudan University Shanghai Cancer Center were obtained, and immunostaining was performed to validate prognostic and therapeutic significance of the potential biomarker. RESULTS: PRCC2 has worse overall survival and shares distinct molecular characteristics from PRCC1. There was significant higher expression level of Targeting protein for Xklp2 (TPX2) in PRCC2 compared with normal tissues. Higher expression level of TPX2 was significantly associated with worse overall survival in PRCC2 and kinesin family genes expression were found significantly elevated in high risk PRCC2. Abundance of tumor infiltrating M1 macrophage was significantly higher in PRCC2 and it was also associated with worse overall survival. In the FUSCC cohort, higher TPX2 expression was significantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater efficacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater efficacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%). CONCLUSIONS: TPX2 was a prognostic and therapeutic biomarker in PRCC2. Higher abundance of tumor infiltrating M1 macrophage was significantly associated with worse overall survival in PRCC2. mTOR inhibitors may have good efficacy in patients with high-risk PRCC2.

Improving the Treatment Effect of Carotenoids on Alzheimer's Disease through Various Nano-Delivery Systems.

Natural bioactive compounds have recently emerged as a current strategy for Alzheimer's disease treatment. Carotenoids, including astaxanthin, lycopene, lutein, fucoxanthin, crocin and others are natural pigments and antioxidants, and can be used to treat a variety of diseases, including Alzheimer's disease. However, carotenoids, as oil-soluble substances with additional unsaturated groups, suffer from low solubility, poor stability and poor bioavailability. Therefore, the preparation of various nano-drug delivery systems from carotenoids is a current measure to achieve efficient application of carotenoids. Different carotenoid delivery systems can improve the solubility, stability, permeability and bioavailability of carotenoids to a certain extent to achieve Alzheimer's disease efficacy. This review summarizes recent data on different carotenoid nano-drug delivery systems for the treatment of Alzheimer's disease, including polymer, lipid, inorganic and hybrid nano-drug delivery systems. These drug delivery systems have been shown to have a beneficial therapeutic effect on Alzheimer's disease to a certain extent.