Insulin resistance during androgen deprivation therapy in men with prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. METHODS: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. RESULTS: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p = .47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass. CONCLUSIONS: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT.

FGFR2 fusion/rearrangement is associated with favorable prognosis and immunoactivation in patients with intrahepatic cholangiocarcinoma.

Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC). This study aims to explore the association of FGFR2 status with the prognosis and immune cell infiltration profiles of patients with ICC. A total of 226 ICC tissue samples from patients who received surgery at the Department of Liver Surgery at Zhongshan Hospital, Fudan University, were collected retrospectively and assigned to a primary cohort (n = 152) and validation cohort (n = 74) group. Fluorescence in situ hybridization was performed to determine FGFR2 status. Multiplex immunofluorescence (mIF) staining and immunohistochemistry were performed to identify immune cells. Thirty-two (14.2%) ICC tissues presented with FGFR2 fusion/rearrangement. FGFR2 fusion/rearrangement was associated with low levels of carcinoembryonic antigen (CEA, P = .026) and gamma glutamyl transferase (γ-GGT, P = .003), low TNM (P = .012), CNLC (P = .008) staging as well as low tumor cell differentiation (P = .016). Multivariate COX regression analyses revealed that FGFR2 fusion/rearrangement was an independent protective factor for both overall survival (OS) and relapse-free survival in patients with ICC. Furthermore, correlation analysis revealed that an FGFR2 fusion/rearrangement was associated with low levels of Tregs and N2 neutrophils and high levels of N1 neutrophils infiltrating into tumors but not with CD8+ T-cell or macrophage tumor infiltration. FGFR2 fusion/rearrangement may exert a profound impact on the prognosis of ICC patients and reprogram the tumor microenvironment to be an immune-activated state. FGFR2 status may be used for ICC prognostic stratification and as an immunotherapeutic target in patients with ICC.

Supermolecular Confined Silicon Phosphorescence Nanoprobes for Time-Resolved Hypoxic Imaging Analysis.

Room temperature phosphorescence (RTP) nanoprobes play crucial roles in hypoxia imaging due to their high signal-to-background ratio (SBR) in the time domain. However, synthesizing RTP probes in aqueous media with a small size and high quantum yield remains challenging for intracellular hypoxic imaging up to present. Herein, aqueous RTP nanoprobes consisting of naphthalene anhydride derivatives, cucurbit[7]uril (CB[7]), and organosilicon are reported via supermolecular confined methods. Benefiting from the noncovalent confinement of CB[7] and hydrolysis reactions of organosilicon, such small-sized RTP nanoprobes (5-10 nm) exhibit inherent tunable phosphorescence (from 400 to 680 nm) with microsecond second lifetimes (up to ∼158.7 µs) and high quantum yield (up to ∼30%). The as-prepared RTP nanoprobes illustrate excellent intracellular hypoxia responsibility in a broad range from ∼0.1 to 21% oxygen concentrations. Compared to traditional fluorescence mode, the SBR value (∼108.69) of microsecond-range time-resolved in vitro imaging is up to 2.26 times greater in severe hypoxia (<0.1% O2), offering opportunities for precision imaging analysis in a hypoxic environment.

Chemokine CCL21 determines immunotherapy response in hepatocellular carcinoma by affecting neutrophil polarization.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is poor and great heterogeneity among individuals. Chemokines are highly correlated with tumor immune response. Here, we aimed to identify an effective chemokine for predicting the efficacy of immunotherapy in HCC. METHODS: Chemokine C-C motif ligand 21 (CCL21) was screened by transcriptomic analysis in tumor tissues from HCC patients with different responses to ICIs. The least absolute shrinkage and selection operator (LASSO) regression analysis was conducted to construct a predictive nomogram. Neutrophils in vitro and HCC subcutaneous tumor model in vivo were applied to explore the role of CCL21 on the tumor microenvironment (TME) of HCC. RESULTS: Transcriptome analysis showed that CCL21 level was much higher in HCC patients with response to immunotherapy. The predictive nomogram was constructed and validated as a classifier. CCL21 could inhibit N2 neutrophil polarization by suppressing the activation of nuclear factor kappa B (NF-κB) pathway. In addition, CCL21 enhanced the therapeutic efficacy of ICIs. CONCLUSION: CCL21 may serve as a predictive biomarker for immunotherapy response in HCC patients. High levels of CCL21 in TME inhibit immunosuppressive polarization of neutrophils. CCL21 in combination with ICIs may offer a novel therapeutic strategy for HCC.

Association between plant-based dietary pattern and biological aging trajectory in a large prospective cohort.

BACKGROUND: Aging is a dynamic and heterogeneous process that may better be captured by trajectories of aging biomarkers. Biological age has been advocated as a better biomarker of aging than chronological age, and plant-based dietary patterns have been found to be linked to aging. However, the associations of biological age trajectories with mortality and plant-based dietary patterns remained unclear. METHODS: Using group-based trajectory modeling approach, we identified distinctive aging trajectory groups among 12,784 participants based on a recently developed biological aging measure acquired at four-time points within an 8-year period. We then examined associations between aging trajectories and quintiles of plant-based dietary patterns assessed by overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) among 10,191 participants who had complete data on dietary intake, using multivariable multinomial logistics regression adjusting for sociodemographic and lifestyles factors. Cox proportional hazards regression models were applied to investigate the association between aging trajectories and all-cause mortality. RESULTS: We identified three latent classes of accelerated aging trajectories: slow aging, medium-degree, and high-degree accelerated aging trajectories. Participants who had higher PDI or hPDI had lower odds of being in medium-degree (OR = 0.75, 95% CI: 0.65, 0.86 for PDI; OR = 0.73, 95% CI: 0.62, 0.85 for hPDI) or high-degree (OR = 0.63, 95% CI: 0.46, 0.86 for PDI; OR = 0.62, 95% CI: 0.44, 0.88 for hPDI) accelerated aging trajectories. Participants in the highest quintile of uPDI were more likely to be in medium-degree (OR = 1.72, 95% CI: 1.48, 1.99) or high-degree (OR = 1.70, 95% CI: 1.21, 2.38) accelerated aging trajectories. With a mean follow-up time of 8.40 years and 803 (6.28%) participants died by the end of follow-up, we found that participants in medium-degree (HR = 1.56, 95% CI: 1.29, 1.89) or high-degree (HR = 3.72, 95% CI: 2.73, 5.08) accelerated aging trajectory groups had higher risks of death than those in the slow aging trajectory. CONCLUSIONS: We identified three distinctive aging trajectories in a large Asian cohort and found that adopting a plant-based dietary pattern, especially when rich in healthful plant foods, was associated with substantially lowered pace of aging.

Detection of Entangled States Supported by Reinforcement Learning.

Discrimination of entangled states is an important element of quantum-enhanced metrology. This typically requires low-noise detection technology. Such a challenge can be circumvented by introducing nonlinear readout process. Traditionally, this is realized by reversing the very dynamics that generates the entangled state, which requires a full control over the system evolution. In this Letter, we present nonlinear readout of highly entangled states by employing reinforcement learning to manipulate the spin-mixing dynamics in a spin-1 atomic condensate. The reinforcement learning found results in driving the system toward an unstable fixed point, whereby the (to be sensed) phase perturbation is amplified by the subsequent spin-mixing dynamics. Working with a condensate of 10 900 ^{87}Rb atoms, we achieve a metrological gain of 6.97_{-1.38}^{+1.30} dB beyond the classical precision limit. Our work will open up new possibilities in unlocking the full potential of entanglement caused quantum enhancement in experiments.

Two-Layered Biomimetic Flexible Self-Powered Electrical Stimulator for Promoting Wound Healing.

The repair of wound damage has been a common problem in clinic for a long time. Inspired by the electroactive nature of tissues and the electrical stimulation of wounds in clinical practice, the next generation of wound therapy with self-powered electrical stimulator is expected to achieve the desired therapeutic effect. In this work, a two-layered self-powered electrical-stimulator-based wound dressing (SEWD) was designed through the on-demand integration of the bionic tree-like piezoelectric nanofiber and the adhesive hydrogel with biomimetic electrical activity. SEWD has good mechanical properties, adhesion properties, self-powered properties, high sensitivity, and biocompatibility. The interface between the two layers was well integrated and relatively independent. Herein, the piezoelectric nanofibers were prepared by P(VDF-TrFE) electrospinning, and the morphology of the nanofibers was controlled by adjusting the electrical conductivity of the electrospinning solution. Benefiting from its bionic dendritic structure, the prepared piezoelectric nanofibers had better mechanical properties and piezoelectric sensitivity than native P(VDF-TrFE) nanofibers, which can convert tiny forces into electrical signals as a power source for tissue repair. At the same time, the designed conductive adhesive hydrogel was inspired by the adhesive properties of natural mussels and the redox electron pairs formed by catechol and metal ions. It has bionic electrical activity matching with the tissue and can conduct the electrical signal generated by the piezoelectric effect to the wound site so as to facilitate the electrical stimulation treatment of tissue repair. In addition, in vitro and in vivo experiments demonstrated that SEWD converts mechanical energy into electricity to stimulate cell proliferation and wound healing. The proposed healing strategy for the effective treatment of skin injury was provided by developing self-powered wound dressing, which is of great significance to the rapid, safe, and effective promotion of wound healing.

The application of "S.I.S" technique improves long-term continence after robotic radical prostatectomy.

AIMS: To propose a novel S.I.S technique during the robotic-assisted radical prostatectomy (RARP), encompassing pubourethral suspension, posterior wall intensification, and bladder neck stripping, and to present functional and oncological outcomes with a special focus on long-term continence. METHODS: From January 1, 2018, to December 31, 2019, consecutive patients who underwent RARP were retrospectively investigated and separated into the S.I.S group and the conventional group. Preoperative patient characteristics, tumor status, and perioperative parameters were collected, followed by the assessment of self-reported status on continence, using an International Consultation on Incontinence Modular Questionnaire-urinary incontinence short form (ICIQ-UI-SF). Statistical comparisons were performed on variables between the two surgery groups, and multivariate logistic regression analysis was used to determine predictive factors for postoperative incontinence severity. RESULTS: A total of 602 subjects were analyzed with a median follow-up of 24 months. There was no significant difference regarding baseline characteristics and perioperative parameters, except for a more advanced tumor stage in the S.I.S group. The application of the S.I.S technique did not jeopardize the positive surgical margin rate at the bladder neck or long-term tumor control. Notably, the patient-reported degree of incontinence was significantly reduced with the assistance of S.I.S technique, as evidenced by the diminished severe-to-very severe cases. On multivariate analysis, both preoperative body mass index and use of S.I.S modification were independent predictive factors for the long-term incontinence severity. CONCLUSIONS: The application of S.I.S technique during RARP is feasible and superior compare with the conventional approach, with a significantly alleviated long-term incontinence severity, without compromising cancer control.

Site specificity determinants for prelamin A cleavage by the zinc metalloprotease ZMPSTE24.

The integral membrane zinc metalloprotease ZMPSTE24 is important for human health and longevity. ZMPSTE24 performs a key proteolytic step in maturation of prelamin A, the farnesylated precursor of the nuclear scaffold protein lamin A. Mutations in the genes encoding either prelamin A or ZMPSTE24 that prevent cleavage cause the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS) and related progeroid disorders. ZMPSTE24 has a novel structure, with seven transmembrane spans that form a large water-filled membrane chamber whose catalytic site faces the chamber interior. Prelamin A is the only known mammalian substrate for ZMPSTE24; however, the basis of this specificity remains unclear. To define the sequence requirements for ZMPSTE24 cleavage, we mutagenized the eight residues flanking the prelamin A scissile bond (TRSY↓LLGN) to all other 19 amino acids, creating a library of 152 variants. We also replaced these eight residues with sequences derived from putative ZMPSTE24 cleavage sites from amphibian, bird, and fish prelamin A. Cleavage of prelamin A variants was assessed using an in vivo yeast assay that provides a sensitive measure of ZMPSTE24 processing efficiency. We found that residues on the C-terminal side of the cleavage site are most sensitive to changes. Consistent with other zinc metalloproteases, including thermolysin, ZMPSTE24 preferred hydrophobic residues at the P1' position (Leu647), but in addition, showed a similar, albeit muted, pattern at P2'. Our findings begin to define a consensus sequence for ZMPSTE24 that helps to clarify how this physiologically important protease functions and may ultimately lead to identifying additional substrates.

Tailored Polymeric Hole-Transporting Materials Inducing High-Quality Crystallization of Perovskite for Efficient Inverted Photovoltaic Devices.

For achieving high-performance p-i-n perovskite solar cells (PSCs), hole transporting materials (HTMs) are critical to device functionality and represent a major bottleneck to further enhancing device stability and efficiency in the inverted devices. Three dopant-free polymeric HTMs are developed based on different linkage sites of triphenylamine and phenylenevinylene repeating units in their main backbone structures. The backbone curvatures of the polymeric HTMs affect the morphology and hole mobility of the polymers and further change the crystallinity of perovskite films. By using PTA-mPV with moderate molecular curvature, p-i-n PSCs with high efficiency of 19.5% and long-term stability can be achieved. The better performance is attributed to the more effective hole extraction ability, higher charge-carrier mobility, and lower interfacial charge recombination. Furthermore, these three polymeric HTMs are synthesized without any noble metal catalyst, and show great advantages in future application owing to the low-cost.

Potential therapies and diagnosis based on Golgi-targeted nano drug delivery systems.

With the rapid development of nanotechnology, organelle-targeted nano drug delivery systems (NDDSs) have emerged as a potential method which can transport drugs specifically to the subcellular compartments like nucleus, mitochondrion, lysosome, endoplasmic reticulum (ER) and Golgi apparatus (GA). GA not only plays a key role in receiving, modifying, packaging and transporting proteins and lipids, but also contributes to a set of cellular processes. Golgi-targeted NDDSs can alter the morphology of GA and will become a promising strategy with high specificity, low-dose administration and decreased occurrence of side effects. In this review, Golgi-targeted NDDSs and their applications in disease therapies and diagnosis such as cancer, metastasis, fibrosis and neurological diseases are introduced. Meanwhile, modifications of NDDSs to achieve targeting strategies, Golgi-disturbing agents to change the morphology of GA, special endocytosis to achieve endosomal/lysosomal escape strategies are also involved.

Swellable PVA/PVP hydrogel microneedle patches for the extraction of interstitial skin fluid toward minimally invasive monitoring of blood glucose level.

Interstitial skin fluid (ISF) is an emerging alternative source of blood samples that has attracted great interest from researchers. It is a very promising way to use microneedle patches for extracting ISF. However, the recovery of ISF still faces great challenges, such as long extraction time and low extraction volume, which may affect the analysis of biomarkers. Traditional centrifugation methods cannot completely recover ISF, which leads to inaccuracy in ISF detection. In this paper, the prepared polyvinyl alcohol/polyvinylpyrrolidone (PVA/PVP) microneedle patches had the ability to insert into the skin in a dry state; at the same time, the microneedle patches had good swelling properties and could extract ISF in a short time without any additional devices. Due to the thermal degradation of PVA, the way of gentle heating was used to recover ISF, which could greatly improve the accuracy of detection. By comparing the D-glucose content assay kit with the blood glucose concentration of rats detected using a commercial glucometer, the detection accuracy of the microneedle patches was verified. The microneedle patches can be used to sample ISF and analyze the level of biomarkers in ISF, and are expected to provide a basis for the prevention and diagnosis of clinical diseases in the future.

An mALBI-Child-Pugh-based nomogram for predicting post-hepatectomy liver failure grade B-C in patients with huge hepatocellular carcinoma: a multi-institutional study.

OBJECTIVE: Post-hepatectomy liver failure (PHLF) is a severe complication in patients with hepatocellular carcinoma (HCC) who underwent hepatectomy. This study aims to develop a nomogram of PHLF grade B-C in patients with huge HCC (diameter ≥ 10 cm). METHODS: We retrospectively collected clinical information of 514 and 97 patients who underwent hepatectomy for huge HCC at two medical centers between 2016 and 2021. Univariate and multivariate analysis were carried out to screen the independent risk factors of PHLF grade B-C, which were visualized as a nomogram. RESULTS: Three Hundred Forty Three Thousand One Hundred Seventy One  and 97 HCC patients were included in the training cohort, internal validation cohort, and external validation cohort, with probabilities of PHLF grade B-C of 15.1%, 12.9%, and 22.7%, respectively. Pre-operative modified albumin-bilirubin (mALBI) grade (p < 0.001), Child-Pugh classification (p = 0.044), international normalized ratio (INR) (p = 0.005), cirrhosis (p = 0.019), and intraoperative blood loss (p = 0.004) were found to be independently associated with PHLF grade B-C in the training cohort. All the five independent factors were considered in the establishment of the nomogram model. In the internal validation cohort and external validation cohort, the area under receiver operating characteristic curve for the nomogram in PHLF grade B-C prediction reached 0.823 and 0.740, respectively. Divided into different risk groups according to the optimal cut-off value, patients in the high-risk group reported significantly higher frequency of PHLF grade B-C than those in the low-risk group, both in the training cohort and the validation cohort (p < 0.001). CONCLUSIONS: The proposed noninvasive nomogram based on mALBI-Child-Pugh and three other indicators achieved optimal prediction performance of PHLF grade B-C in patients with huge HCC.

The value of clinical-ultrasonographic feature model to predict the severity of secondary hyperparathyroidism.

OBJECTIVES: To analyze conventional ultrasound (CUS) and contrast-enhanced ultrasound (CEUS) features in patients with secondary hyperparathyroidism (SHPT) and to evaluate the clinical-ultrasonographic feature based model for predicting the severity of SHPT. METHODS: From February 2016 to March 2021, a total of 59 patients (age 51.3 ± 11.7 years, seCr 797.8 ± 431.7 µmol/L, iPTH 1535.1 ± 1063.9 ng/L) with SHPT (including 181 parathyroid glands (PTGs)) without the history of intact parathyroid hormone (iPTH)-reducing drugs using were enrolled. The patients were divided into the mild SHPT group (mSHPT, iPTH <800 ng/L) and the severe SHPT group (sSHPT, iPTH ≥ 800 ng/L) according to the serum iPTH level. The clinical test data of patients were collected and CUS and CEUS examinations were performed for every patient. Multivariable logistic regression model according to clinical-ultrasonographic features was adopted to establish a nomogram. We performed K-fold cross-validation on this nomogram model and nomogram performance was determined by its discrimination, calibration, and clinical usefulness. RESULTS: There were 19 patients in the mSHPT group and 40 patients in the sSHPT group. Multivariable logistic regression indicated serum calcium, serum phosphorus and total volume of PTGs were independent predictors related with serum iPTH level. Even though CEUS score of wash-in and wash-out were showed related to severity of SHPT in univariate logistic regression analysis, they were not predictors of SHPT severity (p = 0.539, 0.474 respectively). The nomogram developed by clinical and ultrasonographic features showed good calibration and discrimination. The accuracy and the area under the curve (AUC), positive predictive value (PPV), negative predictive value (NPV) and accuracy of this model were 0.888, 92.5%, 63.2% and 83.1%, respectively. When applied to internal validation, the score revealed good discrimination with stratified fivefold cross-validation in the cohort (mean AUC = 0.833). CONCLUSIONS: The clinical-ultrasonographic features model has good performance for predicting the severity of SHPT.

Research on Cyanobacterial-Bloom Detection Based on Multispectral Imaging and Deep-Learning Method.

Frequent outbreaks of cyanobacterial blooms have become one of the most challenging water ecosystem issues and a critical concern in environmental protection. To overcome the poor stability of traditional detection algorithms, this paper proposes a method for detecting cyanobacterial blooms based on a deep-learning algorithm. An improved vegetation-index method based on a multispectral image taken by an Unmanned Aerial Vehicle (UAV) was adopted to extract inconspicuous spectral features of cyanobacterial blooms. To enhance the recognition accuracy of cyanobacterial blooms in complex scenes with noise such as reflections and shadows, an improved transformer model based on a feature-enhancement module and pixel-correction fusion was employed. The algorithm proposed in this paper was implemented in several rivers in China, achieving a detection accuracy of cyanobacterial blooms of more than 85%. The estimate of the proportion of the algae bloom contamination area and the severity of pollution were basically accurate. This paper can lay a foundation for ecological and environmental departments for the effective prevention and control of cyanobacterial blooms.

Overexpressing PhytochromeInteractingFactor 8 of Myrothamnus flabellifolia Enhanced Drought and Salt Tolerance in Arabidopsis.

Myrothamnus flabellifolia is the only woody resurrection plant found in the world and can survive from long-term desiccation. Therefore, M. flabellifolia could be considered as a valuable resource for study of plant adaptation to abiotic stress. However, few genes related to its drought tolerance have been functionally characterized and the molecular mechanisms underlying the stress tolerance of M. flabellifolia are largely unknown. The phytochrome interacting factor (PIF) family is a group of basic helix-loop-helix (bHLH) transcription factors and functions as the core regulator in plant growth and development. However, less is known of its participation in abiotic stress response. In this study, we isolated and characterized a dehydration-inducible PIF gene MfPIF8 from M. flabellifolia. Heterologous expression of MfPIF8 in Arabidopsis enhanced tolerance to drought and salinity stresses at seedling and adult stages. It significantly increased primary root length and stomatal aperture (ration of length/width) under stress treatments and decreased water loss rate. Compared with WT, the transgenic lines overexpressing MfPIF8 exhibited higher chlorophyll content and lower malondialdehyde accumulation. The abilities of osmotic adjustment and reactive oxygen species scavenging were also enhanced in MfPIF8 transgenic lines. These results suggest that MfPIF8 may participate in the positive regulation of abiotic stress responses. Additional investigation of its mechanism is needed in the future.

Heterologous Expression of MfWRKY7 of Resurrection Plant Myrothamnus flabellifolia Enhances Salt and Drought Tolerance in Arabidopsis.

Drought and salinity have become major environmental problems that affect the production of agriculture, forestry and horticulture. The identification of stress-tolerant genes from plants adaptive to harsh environments might be a feasible strategy for plant genetic improvement to address the challenges brought by global climate changes. In this study, a dehydration-upregulated gene MfWRKY7 of resurrection Plant Myrothamnusflabellifolia, encoding a group IId WRKY transcription factor, was cloned and characterized. The overexpression of MfWRKY7 in Arabidopsis increased root length and tolerance to drought and NaCl at both seedling and adult stages. Further investigation indicated that MfWRKY7 transgenic plants had higher contents of chlorophyll, proline, soluble protein, and soluble sugar but a lower water loss rate and malondialdehyde content compared with wild-type plants under both drought and salinity stresses. Moreover, the higher activities of antioxidant enzymes and lower accumulation of O2- and H2O2 in MfWRKY7 transgenic plants were also found, indicating enhanced antioxidation capacity by MfWRKY7. These findings showed that MfWRKY7 may function in positive regulation of responses to drought and salinity stresses, and therefore, it has potential application value in genetic improvement of plant tolerance to abiotic stress.

Assessing population diversity in phase III trials of cancer drugs supporting Food and Drug Administration approval in solid tumors.

Our study aimed to assess inequities in the clinical trial participation for the selected patient groups. We searched the Food and Drug Administration (FDA) database and extracted phase-III clinical trial data from MEDLINE for each approved drug by the FDA between January 1, 2006, and June 30, 2020. We analyzed the inclusion/exclusion criteria, participation according to gender, ethnic group, performance score, the positivity of HBV and HCV, and HIV, having comorbidities and brain metastasis. We compared the findings with that of the general population by retrieving data from the Surveillance, Epidemiology and End Results (SEER) database. We identified 142 phase III pivotal oncology trials that enrolled 105 397 patients. The proportion of female patients in trials was lower than their relative prevalence in the general population from SEER region (36% vs 49.6%, P < .001). The rates of black patients included were lower than their relative prevalence from SEER region (2.1% vs 9.8%, P < .001). 1.3% and 0.8% of patients had HBV and HCV infections, respectively. The patients' numbers with organ dysfunction were not established due to insufficient data from clinical trials. 1.6% of all patients had controlled brain metastasis. Black patients, women and patients with brain metastasis or with HBV and HCV were underrepresented. Our study underscores the importance of expanding the inclusion/exclusion criteria of pivotal oncology trials to be more representative of patients seen in clinical practice.

Circular RNA circ_0068,888 protects against lipopolysaccharide-induced HK-2 cell injury via sponging microRNA-21-5p.

Our previous findings revealed that hsa_circ_0068,888 was markedly down-regulated in the plasma of patients with sepsis-associated acute kidney injury (AKI). However, its molecular mechanism in AKI remains unclear. Herein, we explored the role of hsa_circ_0068,888 in AKI. Human renal proximal tubular cell line HK-2 was stimulated with lipopolysaccharide (LPS) to mimic AKI in vitro. Decreased hsa_circ_0068,888 expression was observed in AKI cell model. The overexpression of hsa_circ_0068,888 significantly increased the viability of LPS-stimulated HK-2 cells, whereas hsa_circ_0068,888 downregulation showed the opposite effect. Furthermore, LPS triggered inflammatory response and oxidative stress, which was inhibited by hsa_circ_0068,888 overexpression and enhanced by hsa_circ_0068,888 down-regulation. Hsa_circ_0068,888 overexpression suppressed the activation of nuclear factor-κB (NF-κB) pathway triggered by LPS as evidenced by decreased p-p65 protein level and nuclear translocation of p65 in hsa_circ_0068,888 overexpressed cells. Additionally, we proved that hsa_circ_0068,888 targeted microRNA-21-5p (miR-21-5p). The expression of miR-21-5p was markedly increased and was negatively regulated by hsa_circ_0068,888 in LPS-stimulated HK-2 cells. Furthermore, we demonstrated that miR-21-5p overexpression reversed the effects on cell viability, inflammatory response, oxidative stress, and NF-κB pathway induced by hsa_circ_0068,888 overexpression in LPS-stimulated HK-2 cells. Overall, these results implied that hsa_circ_0068,888 shows a protective effect on AKI by sponging miR-21-5p. Hence, up-regulation of hsa_circ_0068,888 might be a potential strategy in treatment for AKI.

Characterization of type-2 diacylglycerol acyltransferases in Haematococcus lacustris reveals their functions and engineering potential in triacylglycerol biosynthesis.

BACKGROUND: Haematococcus lacustris is an ideal source of astaxanthin (AST), which is stored in oil bodies containing esterified AST (EAST) and triacylglycerol (TAG). Diacylglycerol acyltransferases (DGATs) catalyze the last step of acyl-CoA-dependent TAG biosynthesis and are also considered as crucial enzymes involved in EAST biosynthesis in H. lacustris. Previous studies have identified four putative DGAT2-encoding genes in H. lacustris, and only HpDGAT2D allowed the recovery of TAG biosynthesis, but the engineering potential of HpDGAT2s in TAG biosynthesis remains ambiguous. RESULTS: Five putative DGAT2 genes (HpDGAT2A, HpDGAT2B, HpDGAT2C, HpDGAT2D, and HpDGAT2E) were identified in H. lacustris. Transcription analysis showed that the expression levels of the HpDGAT2A, HpDGAT2D, and HpDGAT2E genes markedly increased under high light and nitrogen deficient conditions with distinct patterns, which led to significant TAG and EAST accumulation. Functional complementation demonstrated that HpDGAT2A, HpDGAT2B, HpDGAT2D, and HpDGAT2E had the capacity to restore TAG synthesis in a TAG-deficient yeast strain (H1246) showing a large difference in enzymatic activity. Fatty acid (FA) profile assays revealed that HpDGAT2A, HpDGAT2D, and HpDGAT2E, but not HpDGAT2B, preferred monounsaturated fatty acyl-CoAs (MUFAs) for TAG synthesis in yeast cells, and showed a preference for polyunsaturated fatty acyl-CoAs (PUFAs) based on their feeding strategy. The heterologous expression of HpDGAT2D in Arabidopsis thaliana and Chlamydomonas reinhardtii significantly increased the TAG content and obviously promoted the MUFAs and PUFAs contents. CONCLUSIONS: Our study represents systematic work on the characterization of HpDGAT2s by integrating expression patterns, AST/TAG accumulation, functional complementation, and heterologous expression in yeast, plants, and algae. These results (1) update the gene models of HpDGAT2s, (2) prove the TAG biosynthesis capacity of HpDGAT2s, (3) show the strong preference for MUFAs and PUFAs, and (4) offer target genes to modulate TAG biosynthesis by using genetic engineering methods.