The deacylase sirtuin 5 reduces malonylation in nonmitochondrial metabolic pathways in diabetic kidney disease.

Early diabetic kidney disease (DKD) is marked by dramatic metabolic reprogramming due to nutrient excess, mitochondrial dysfunction, and increased renal energy requirements from hyperfiltration. We hypothesized that changes in metabolism in DKD may be regulated by Sirtuin 5 (SIRT5), a deacylase that removes posttranslational modifications derived from acyl-coenzyme A and has been demonstrated to regulate numerous metabolic pathways. We found decreased malonylation in the kidney cortex (∼80% proximal tubules) of type 2 diabetic BKS db/db mice, associated with increased SIRT5 expression. We performed a proteomics analysis of malonylated peptides and found that proteins with significantly decreased malonylated lysines in the db/db cortex were enriched in nonmitochondrial metabolic pathways: glycolysis and peroxisomal fatty acid oxidation. To confirm relevance of these findings in human disease, we analyzed diabetic kidney transcriptomic data from a cohort of Southwestern American Indians, which revealed a tubulointerstitial-specific increase in Sirt5 expression. These data were further corroborated by immunofluorescence data of SIRT5 from nondiabetic and DKD cohorts. Furthermore, overexpression of SIRT5 in cultured human proximal tubules demonstrated increased aerobic glycolysis. Conversely, we observed reduced glycolysis with decreased SIRT5 expression. These findings suggest that SIRT5 may lead to differential nutrient partitioning and utilization in DKD. Taken together, our findings highlight a previously unrecognized role for SIRT5 in metabolic reprogramming in DKD.

Sustainable, Insoluble, and Photonic Cellulose Nanocrystal Patches for Calcium Ion Sensing in Sweat.

Self-assembly of cellulose nanocrystals (CNCs) is invaluable for the development of sustainable optics and photonics. However, the functional failure of CNC-derived materials in humid or liquid environments inevitably impairs their development in biomedicine, membrane separation, environmental monitoring, and wearable devices. Here, a facile and robust method to fabricate insoluble hydrogels in a self-assembled CNC-polyvinyl alcohol (PVA) system is reported. Due to the reconstruction of inter- or intra-molecular hydrogen bond interactions, thermal dehydration makes an optimized CNC/PVA photonic film form a stable hydrogel network in an aqueous solution rather than dissolve. Notably, the resulting hydrogel exhibits superb mechanical performance (stress up to 3.3 Mpa and tough up to 0.73 MJ m-3 ) and reversible conversion between dry and wet states, enabling it convenient for specific functionalization. Sodium alginate (SA) can be adsorbed into the CNC photonic structure by swelling dry CNC/PVA film in a SA solution. The prepared hydrogel showcases the comprehensive properties of freezing resistance (-20°C), strong adhesion, satisfactory biocompatibility, and highly sensitive and selective Ca2+ sensing. The material could act as a portable wearable patch on the skin for the continuous analysis of calcium trends during different physical exercises, facilitating their development in precision nutrition and health monitoring.

Risk factor analysis and prediction of postoperative clinically relevant pancreatic fistula after distal pancreatectomy.

OBJECTIVE: Postoperative pancreatic fistula (POPF) following distal pancreatectomy (DP) is a serious complication. In the present study, we aimed to identify the risk factors associated with clinically relevant postoperative pancreatic fistula (CR-POPF) and establish a nomogram model for predicting CR-POPF after DP. METHODS: In total, 115 patients who underwent DP at the General Hospital of Northern Theater Command between January 2005 and December 2020 were retrospectively studied. Univariate and multivariable logistic regression analyses were used to identify the independent risk factors associated with CR-POPF. Then, a nomogram was formulated based on the results of multivariable logistic regression analysis. The predictive performance was evaluated with receiver operating characteristic (ROC) curves. Decision curve and clinical impact curve analyses were used to validate the clinical application value of the model. RESULTS: The incidence of CR-POPF was 33.0% (38/115) in the present study. Multivariate logistic regression analysis identified the following variables as independent risk factors for POPF: body mass index (BMI) (OR 4.658, P = 0.004), preoperative albumin level (OR 7.934, P = 0.001), pancreatic thickness (OR 1.256, P = 0.003) and pancreatic texture (OR 3.143, P = 0.021). We created a nomogram by incorporating the above mentioned risk factors. The nomogram model showed better predictive value, with a concordance index of 0.842, sensitivity of 0.710, and specificity of 0.870 when compared to each risk factor. Decision curve and clinical impact curve analyses also indicated that the nomogram conferred a high clinical net benefit. CONCLUSION: Our nomogram could accurately and objectively predict the risk of postoperative CR-POPF in individuals who underwent DP, which could help clinicians with early identification of patients who might develop CR-POPF and early development of a suitable fistula mitigation strategy and postoperative management.

A Tumor-Targeting Metal-Organic Nanoparticle Constructed by Dynamic Combinatorial Chemistry toward Accurately Redressing Carcinogenic Wnt Cascade.

Targeted and immunological therapy have revolutionized the malignancy treatment, but is suffering from the dose-limiting side effects and inadequate responsiveness. The emerging nanoscale infinite coordination polymers provide a feasible strategy for tumor targeting and immune sensitization. Herein, a "one-pot" self-assembled strategy based on dynamic combinatorial chemistry (DCC) principle is designed to construct a tumor-targeting metal-organic nanoparticle (MOICP) through a spontaneous co-assembling among three metal-organic coordination polymers tuned by a Wnt-inhibitor carnosic acid (CA). Responding to the tumor microenvironment, MOICP presents an optimized tumor-preferential accumulation and the satisfactory biosafety. MOICP is more active in vitro and in vivo than CA in suppressing of Wnt signaling pathway, and potently inhibits tumor growth in a patient-derived xenograft model of Wnt-activated pancreatic carcinoma. Moreover, MOICP reverses the lack of intratumoral infiltration of T lymphocytes, and hence augments the action of Anti-PD1 (programmed cell death protein 1) immunotherapy in B16F10 melanoma allograft mice model. This clinically viable MOICP can not only be applied to Wnt inhibition for cancer targeted therapy and immunotherapeutic sensitization, but also provides a de novo pattern for nanomedicine architecture with cargo-initiated co-self-assembly guided by DCC, thereby bringing new inspiration in general for disease intervention.

Quantitative analysis of γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline in HeLa cells using UHPLC-MS/MS.

γ-Glutamylpeptides have been identified as potential biomarkers for a number of diseases including cancer, diabetes, and liver disease. In this study, we developed and validated a novel quantitative analytical strategy for measuring γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline, all of which have been previously reported as potential biomarkers for prostate cancer in HeLa cells using ultra-high-performance liquid chromatography-tandem mass spectrometry. A BEH C18 column was used as the stationary phase. Mobile phase A was 99:1 water:formic acid and mobile phase B was acetonitrile. Chemical isotope labeling using benzoyl chloride was used as the internal standardization strategy. Sample preparation consisted of the addition of water to a frozen cell pellet, sonication, derivatization, centrifugation, and subsequent addition of an internal standard solution. The method was validated for selectivity, accuracy, precision, linearity, and stability. The determined concentrations of γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline in HeLa cells were 1.92 ± 0.06, 10.8 ± 0.4, and 1.96 ± 0.04 pmol/mg protein, respectively. In addition, the qualitative analysis of these analytes in human serum was achieved using a modified sample preparation strategy. To the best of our knowledge, this is the first report of the use of benzoyl chloride for chemical isotope labeling for metabolite quantitation in cells.

Integrative, genome-wide association study identifies chemicals associated with common women's malignancies.

BACKGROUND: Breast cancer, cervical cancer, and ovarian cancer are three of the most commonly diagnosed malignancies in women, and more cancer prevention research is urgently needed. METHODS: Summary data of a large genome-wide association study of female cancers were derived from the UK biobank. We performed a transcriptome-wide association study and a gene set enrichment analysis to identify correlations between chemical exposure and aberrant expression, repression, or mutation of genes related to cancer using the Comparative Toxicogenomics Database. RESULTS: We identified five chemicals (NSC668394, glafenine, methylnitronitrosoguanidine, fenofibrate, and methylparaben) that were associated with the incidence of both breast cancer and cervical cancer. CONCLUSION: Using a transcriptome-wide association study and gene set enrichment analysis we identified environmental chemicals that are associated with an increased risk of breast cancer, cervical cancer, and ovarian cancer.

Alternol eliminates excessive ATP production by disturbing Krebs cycle in prostate cancer.

BACKGROUND: Alternol is a natural compound isolated from fermentation products of a mutant fungus. Our previous studies demonstrated that Alternol specifically kills cancer cells but spares benign cells. METHODS: To investigate the mechanism underlying alternol-induced cancer cell-specific killing effect, we took a comprehensive strategy to identify Alternol's protein targets in prostate cancer cells, including PC-3, C4-2, and 22RV1, plus benign BPH1 cell lines. Major experimental techniques included biotin-streptavidin pulldown assay coupled with mass-spectrometry, in vitro enzyme activity assay for Krebs cycle enzymes and gas chromatography-mass spectrometry (GC-MS) for metabolomic analysis. RESULTS: Among 14 verified protein targets, four were Krebs cycle enzymes, fumarate hydratase (FH), malate dehydrogenase-2 (MDH2), dihydrolipoamide acetyltransferase (DLAT) in pyruvate dehydrogenase complex (PDHC) and dihydrolipoamide S-succinyltransferase (DLST) in a-ketoglutarate dehydrogenase complex (KGDHC). Functional assays revealed that PDHC and KGDHC activities at the basal level were significantly higher in prostate cancer cells compared to benign prostate BPH1 cells, while alternol treatment reduced their activities in cancer cells close to the levels in BPH1 cells. Although FH and MDH2 activities were comparable among prostate cancer and benign cell lines at the basal level, Alternol treatment largely increased their activities in cancer cells. Metabolomic analysis revealed that Alternol treatment remarkably reduced the levels of malic acid, fumaric acid, and isocitric acid and mitochondrial respiration in prostate cancer cells. Alternol also drastically reduced mitochondrial respiration and ATP production in PC-3 cells in vitro or in xenograft tissues but not in BPH1 cells or host liver tissues. CONCLUSIONS: Alternol interacts with multiple Krebs cycle enzymes, resulting in reduced mitochondrial respiration and ATP production in prostate cancer cells and xenograft tissues, providing a novel therapeutic strategy for prostate cancer treatment.

Characterization of a novel p110ß-specific inhibitor BL140 that overcomes MDV3100-resistance in castration-resistant prostate cancer cells.

BACKGROUND: Our previous studies demonstrated that the class IA PI3K/p110ß is critical in castration-resistant progression of prostate cancer (CRPC) and that targeting prostate cancer with nanomicelle-loaded p110ß-specific inhibitor TGX221 blocked xenograft tumor growth in nude mice, confirming the feasibility of p110ß-targeted therapy for CRPCs. To improve TGX221's aqueous solubility, in this study, we characterized four recently synthesized TGX221 analogs. METHODS: TGX221 analog efficacy were examined in multiple prostate cancer cell lines with the SRB cell growth assay, Western blot assay for AKT phosphorylation and cell cycle protein levels. Target engagement with PI3K isoforms was evaluated with cellular thermal shift assay. PI3K activity was determined with the Kinase-Glo Plus luminescent kinase assay. Cell cycle distribution was evaluated with flow cytometry after propidium iodide staining. RESULTS: As expected, replacing either one of two major functional groups in TGX221 by more hydrophilic groups dramatically improved the aqueous solubility (about 40-fold) compared to TGX221. In the CETSA assay, all the analogs dramatically shifted the melting curve of p110ß protein while none of them largely affected the melting curves of p110α, p110γ, or Akt proteins, indicating target-specific engagement of these analogs with p110ß protein. However, functional evaluation showed that only one of the analogs BL140 ubiquitously inhibited AKT phosphorylation in all CRPC cell lines tested with diverse genetic abnormalities including AR, PTEN, and p53 status. BL140 was superior than GSK2636771 (IC50 5.74 vs 20.49 nM), the only p110ß-selective inhibitor currently in clinical trials, as revealed in an in vitro Kinase-Glo assay. Furthermore, BL140 exhibited a stronger inhibitory effect than GSK2636771 on multiple CRPC cell lines including a MDV3100-resistant C4-2B cell subline, indicating BL140 elimination of MDV3100 resistance. Mechanistic studies revealed that BL140 blocked G1 phase cell cycle entry by reducing cyclin D1 but increasing p27kip1 protein levels. CONCLUSION: These studies suggested that BL140 is a promising p110ß-specific inhibitor with multiple superb properties than GSK2636771 worthy for further clinical development.

The role of RCAS1 as a biomarker in diagnosing CRC and monitoring tumor recurrence and metastasis.

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) plays an important role in tumor progression by helping tumor cell to escape from host immunological surveillance or modifying the characteristics of connective tissue around. RCAS1 may appropriately reflect the development and prognosis of tumor. In the study, we sought to identify the clinical significance of RCAS1 in colorectal cancer (CRC) diagnosis and tumor recurrence monitoring. Immunohistochemistry (IHC) with tissue array slides was preformed to analyze RCAS1 protein expression in CRC, colorectal polyps, and normal colon tissues. RCAS1 levels in colorectal cancer were significantly higher than those in colorectal polyps and normal colon tissues (P<0.001). Silencing RCAS1 gene in human colonic adenocarcinoma cells decreased cell proliferation and enhanced apoptosis through the p53 signaling pathway. Further analysis by an enzyme-linked immunosorbent assay (ELISA) showed that serum RCAS1 levels in CRC are significantly higher than in healthy controls and polyps (P<0.05), in which the highest serum RCAS1 level is reported in the recurrence group. The serum RCAS1 levels have a significant correlation with clinical stage and pathologic grading. Furthermore, the positive rate of serum RCAS1 in CRC was 82.1 %, which was higher than carcinoembryonic antigen (CEA). Especially in CEA-negative cases, the sensitivity of RCAS1 was 88.2 %. Finally, CRC patients who were followed up showed a serum RCAS1 level which significantly decreased after surgery (P<0.001) and obviously increased in the recurrence group. Taken together, our data demonstrated that RCAS1 is not only a supplementary serological biomarker for CRC diagnosis but also useful for monitoring tumor recurrence. RCAS1 might be a supplementary serological marker for CRC.

Natural compound Alternol actives multiple endoplasmic reticulum stress-responding pathways contributing to cell death.

Background: Alternol is a small molecular compound isolated from the fermentation of a mutant fungus obtained from Taxus brevifolia bark. Our previous studies showed that Alternol treatment induced reactive oxygen species (ROS)-dependent immunogenic cell death. This study conducted a comprehensive investigation to explore the mechanisms involved in Alternol-induced immunogenic cell death. Methods: Prostate cancer PC-3, C4-2, and 22RV1 were used in this study. Alternol interaction with heat shock proteins (HSP) was determined using CETSA assay. Alternol-regulated ER stress proteins were assessed with Western blot assay. Extracellular adenosine triphosphate (ATP) was measured using ATPlite Luminescence Assay System. Results: Our results showed that Alternol interacted with multiple cellular chaperone proteins and increased their expression levels, including endoplasmic reticulum (ER) chaperone hypoxia up-regulated 1 (HYOU1) and heat shock protein 90 alpha family class B member 1 (HSP90AB1), as well as cytosolic chaperone heat shock protein family A member 8 (HSPA8). These data represented a potential cause of unfolded protein response (UPR) after Alternol treatment. Further investigation revealed that Alternol treatment triggered ROS-dependent (ER) stress responses via R-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α). The double-stranded RNA-dependent protein kinase (PKR) but not activating transcription factor 6 (ATF6) cascades, leading to ATF-3/ATF-4 activation, C/EBP-homologous protein (CHOP) overexpression, and X-box binding protein XBP1 splicing induction. In addition, inhibition of these ER stress responses cascades blunted Alternol-induced extracellular adenosine triphosphate (ATP) release, one of the classical hallmarks of immunogenic cell death. Conclusion: Taken together, our data demonstrate that Alternol treatment triggered multiple ER stress cascades, leading to immunogenic cell death.

Natural compound Alternol exerts a broad anti-cancer spectrum and a superior therapeutic safety index in vivo.

Introduction: Alternol is a natural compound isolated from the fermentation of a mutated fungus. We have demonstrated its potent anti-cancer effect via the accumulation of radical oxygen species (ROS) in prostate cancer cells in vitro and in vivo. In this study, we tested its anti-cancer spectrum in multiple platforms. Methods: We first tested its anti-cancer spectrum using the National Cancer Institute-60 (NCI-60) screening, a protein quantitation-based assay. CellTiter-Glo screening was utilized for ovarian cancer cell lines. Cell cycle distribution was analyzed using flow cytometry. Xenograft models in nude mice were used to assess anti-cancer effect. Healthy mice were tested for the acuate systemic toxicity. Results: Our results showed that Alternol exerted a potent anti-cancer effect on 50 (83%) cancer cell lines with a GI50 less than 5 µM and induced a lethal response in 12 (24%) of those 50 responding cell lines at 10 µM concentration. Consistently, Alternol displayed a similar anti-cancer effect on 14 ovarian cancer cell lines in an ATP quantitation-based assay. Most interestingly, Alternol showed an excellent safety profile with a maximum tolerance dose (MTD) at 665 mg/kg bodyweight in mice. Its therapeutic index was calculated as 13.3 based on the effective tumor-suppressing doses from HeLa and PC-3 cell-derived xenograft models. Conclusion: Taken together, Alternol has a broad anti-cancer spectrum with a safe therapeutic index in vivo.

Jumonji domain-containing protein RIOX2 is overexpressed and associated with worse survival outcomes in prostate cancers.

Background: Histone demethylase RIOX2 was cloned as a c-Myc downstream gene involved in cell proliferation and has been implicated as an oncogenic factor in multiple tumor types. Its expression profiles and correlation with disease progression in prostate cancers are unknown. Methods: Transcriptomic profiles of Jumanji domain-containing protein genes were assessed using multiple public expression datasets generated from RNA-seq and cDNA microarray assays. RIOX2 protein expression was assessed using an immunohistochemistry approach on a tissue section array from benign and malignant prostate tissues. Gene expression profiles were analyzed using the bioinformatics software R package. Western blot assay examined androgen stimulation on RIOX2 protein expression in LNCaP cells. Results: Among 35 Jumanji domain-containing protein genes, 12 genes were significantly upregulated in prostate cancers compared to benign compartments. COX regression analysis identified that the ribosomal oxygenase 2 (RIOX2) gene was the only one significantly associated with disease-specific survival outcomes in prostate cancer patients. RIOX2 upregulation was confirmed at the protein levels using immunohistochemical assays on prostate cancer tissue sections. Meanwhile, RIOX2 upregulation was associated with clinicopathological features, including late-stage diseases, adverse Gleason scores, TP53 gene mutation, and disease-free status. In castration-resistant prostate cancers (CRPC), RIOX2 expression was positively correlated with AR signaling index but negatively correlated with the neuroendocrinal progression index. However, androgen treatment had no significant stimulatory effect on RIOX2 expression, indicating a parallel but not a causative effect of androgen signaling on RIOX2 gene expression. Further analysis discovered that RIOX2 expression was tightly correlated with its promoter hypomethylation and MYC gene expression, consistent with the notion that RIOX2 was a c-Myc target gene. Conclusion: The Jumanji domain-containing protein RIOX2 was significantly overexpressed in prostate cancer, possibly due to c-Myc upregulation. RIOX2 upregulation was identified as an independent prognostic factor for disease-specific survival.

Aberrant expression of multiple glycolytic enzyme genes is significantly associated with disease progression and survival outcomes in prostate cancers.

Prostate cancer is the leading cause of cancer death after lung cancer in men. Recent studies showed that aberrant metabolic pathways are involved in prostate cancer development and progression. In this study, we performed a systemic analysis of glycolytic enzyme gene expression using the TCGA-PRAD RNAseq dataset. Our analysis revealed that among 25 genes, only four genes (HK2/GPI/PFKL/PGAM5) were significantly upregulated while nine genes (HK1/GCK/PFKM/PFKP/ALDOC/PGK1/PGAM1/ENO2/PKM) were downregulated in primary prostate cancer tissues compared to benign compartments. Among these 13 altered genes, four genes (ENO2/ALDOC/GPI/GCK) exhibited strong diagnostic potential in distinguishing malignant and benign tissues. Meanwhile, GPI expression exerted as a prognostic factor of progression-free and disease-specific survival. PFKL and PGAM5 gene expressions were associated with AR signaling scores in castration-resistant patients, and AR-targeted therapy suppressed their expression. In LuCap35 xenograft tumors, PFKL and PGAM5 expression was significantly reduced after animal castration, confirming the AR dependency. Conversely, GCK/PKLR genes were significantly associated with neuroendocrinal progression, representing two novel neuroendocrinal biomarkers for prostate cancer. In conclusion, our results suggest that GPI expression is a strong prognostic factor for prostate cancer progression and survival while GCK/PKLR are two novel biomarkers of prostate cancer progression to neuroendocrinal status.

Risk Factor Analysis and Prediction of Severe Hypocalcemia after Total Parathyroidectomy without Auto-Transplantation in Patients with Secondary Hyperparathyroidism.

Objective: Our study aimed to develop and validate a nomogram to predict severe hypocalcemia (SH) before total parathyroidectomy (TPTX) without auto-transplantation in patients with secondary hyperparathyroidism. Methods: A total of 299 consecutive patients who underwent TPTX without transplantation for secondary hyperparathyroidism were selected from the General Hospital of Northern Theater Command between January 2013 and December 2021. Of these, patients who underwent surgery between January 2013 and December 2020 formed the training cohort (n = 208) to develop a nomogram, and those who underwent surgery thereafter formed the validation cohort (n = 91) to validate the performance of this nomogram. Univariate and multivariate logistic regression analyses were used to identify the risk factors associated with SH, and then, a nomogram was constructed. Results: The incidence of postoperative SH was 27.9% and 35.2% in the training and validation cohorts, respectively. The preoperative factors associated with SH were younger age, lower serum calcium (Ca) level, higher intact parathyroid hormone (iPTH) level, and higher serum alkaline phosphatase (ALP) level. Incorporating these 4 factors, the nomogram achieved good concordance indexes of 0.866 (95%CI, 0.816-0.916) and 0.867 (95% CI, 0.793-0.941) in predicting SH in the training and validation cohorts, respectively, and had well-fitted calibration curves. The positive predictive values of the nomogram were 64.7% (54.1%-78.4%) and 75.0% (58.6%-88.5%), and negative predictive values of the nomogram were 90.0% (82.9%-93.6%) and 86.4% (73.5%-94.0%) for the training and validation cohorts, respectively. Conclusions: We developed and validated a nomogram for the prediction of SH in patients who underwent TPTX without auto-transplantation for secondary hyperparathyroidism. Our nomogram may facilitate the identification of high-risk SH in patients after TPTX and optimization of preoperative decision-making.

Recurrent renal secondary hyperparathyroidism caused by supernumerary mediastinal parathyroid gland and parathyromatosis: A case report.

Background: Surgical parathyroidectomy (PTX) is necessary for patients with severe and progressive secondary hyperparathyroidism (SHPT) refractory to medical treatment. Recurrence of SHPT after PTX is a serious clinical problem. Both supernumerary mediastinal parathyroid gland and parathyromatosis are the rare causes of recurrent renal SHPT. We report a rare case of recurrent renal SHPT due to supernumerary mediastinal parathyroid gland and parathyromatosis. Case presentation: A 53-year-old man underwent total parathyroidectomy with autotransplantation due to the drug-refractory SHPT 17 years ago. In the last 11 months, the patient experienced symptoms including bone pain and skin itch, and the serum intact parathyroid hormone (iPTH) level elevated to 1,587 pg/ml. Ultrasound detected two hypoechoic lesions located at the dorsal area of right lobe of the thyroid gland, and both lesions presented as characteristics of hyperparathyroidism in contrast-enhanced ultrasound. 99mTc-MIBI/SPECT detected a nodule in the mediastinum. A reoperation involved a cervicotomy for excising parathyromatosis lesions and the surrounding tissue and a thoracoscopic surgery for resecting a mediastinal parathyroid gland. According to a histological examination, two lesions behind the right thyroid lobe and one lesion in the central region had been defined as parathyromatosis. A nodule in the mediastinum was consistent with hyperplastic parathyroid. The patient remained well for 10 months with alleviated symptoms and stabilized iPTH levels in the range of 123-201 pg/ml. Conclusion: Although rare, recurrent SHPT may be caused by a coexistence of both supernumerary parathyroid glands and parathyromatosis, which should receive more attention. The combination of imaging modalities is important for reoperative locations of parathyroid lesions. To successfully treat parathyromatosis, all the lesions and the surrounding tissue must be excised. Thoracoscopic surgery is a reliable and safe approach for the resection of ectopic mediastinal parathyroid glands.

Cardiorespiratory dose comparison among six radiotherapy regimens for patients with left-sided breast cancer.

There is uncertainty regarding the benefits and drawbacks of various radiation protocols for the treatment of left-sided breast cancer. To address this issue, we conducted a Bayesian network analysis. First, we searched several electronic databases for eligible literature. Next, we pooled the data from twelve studies concerning three-dimensional conformal radiation therapy (3D-CRT), intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT), combined with either deep inspiratory breath-holding (DIBH) or free-breathing (FB) modalities. The integrated cardiac and pulmonary dosimetric indexes for all included treatments were compared using Bayesian networks. A direct meta-analysis indicated that for the two methods of 3D-CRT and IMRT, DIBH technology was more effective than FB in reducing the radiation dose to the heart and lungs. Additionally, according to the network results, DIBH was superior to FB in all six treatment options, regardless of whether the plan was 3D-CRT, IMRT, or VMAT. Besides, the combined data indicated that the FB-3D-CRT regimen had the weakest dosimetric advantage of all the treatments. Excluding FB-3D-CRT, each of the other five treatments had its own specific benefits. This is the first Bayesian study of several radiotherapy regimens for breast cancer patients on the left side, and the findings can be used to select appropriate radiotherapy programs for breast cancer patients.

Exopolysaccharide-producing bacteria enhanced Pb immobilization and influenced the microbiome composition in rhizosphere soil of pakchoi (Brassica chinensis L.).

Lead (Pb) contamination of planting soils is increasingly serious, leading to harmful effects on soil microflora and food safety. Exopolysaccharides (EPSs) are carbohydrate polymers produced and secreted by microorganisms, which are efficient biosorbent materials and has been widely used in wastewater treatment to remove heavy metals. However, the effects and underlying mechanism of EPS-producing marine bacteria on soil metal immobilization, plant growth and health remain unclear. The potential of Pseudoalteromonas agarivorans Hao 2018, a high EPS-producing marine bacterium, to produce EPS in soil filtrate, immobilize Pb, and inhibit its uptake by pakchoi (Brassica chinensis L.) was studied in this work. The effects of strain Hao 2018 on the biomass, quality, and rhizospheric soil bacterial community of pakchoi in Pb-contaminated soil were further investigated. The results showed that Hao 2018 reduced the Pb concentration in soil filtrate (16%-75%), and its EPS production increased in the presence of Pb2+. When compared to the control, Hao 2018 remarkably enhanced pakchoi biomass (10.3%-14.3%), decreased Pb content in edible tissues (14.5%-39.2%) and roots (41.3%-41.9%), and reduced the available Pb content (34.8%-38.1%) in the Pb-contaminated soil. Inoculation with Hao 2018 raised the pH of the soil, the activity of several enzymes (alkaline phosphatase, urease, and dehydrogenase), the nitrogen content (NH4 +-N and NO3 --N), and the pakchoi quality (Vc and soluble protein content), while also raising the relative abundance of bacteria that promote plant growth and immobilize metals, such as Streptomyces and Sphingomonas. In conclusion, Hao 2018 reduced the available Pb in soil and pakchoi Pb absorption by increasing the pH and activity of multiple enzymes and regulating microbiome composition in rhizospheric soil.

Lipidomic approaches to dissect dysregulated lipid metabolism in kidney disease.

Dyslipidaemia is a hallmark of chronic kidney disease (CKD). The severity of dyslipidaemia not only correlates with CKD stage but is also associated with CKD-associated cardiovascular disease and mortality. Understanding how lipids are dysregulated in CKD is, however, challenging owing to the incredible diversity of lipid structures. CKD-associated dyslipidaemia occurs as a consequence of complex interactions between genetic, environmental and kidney-specific factors, which to understand, requires an appreciation of perturbations in the underlying network of genes, proteins and lipids. Modern lipidomic technologies attempt to systematically identify and quantify lipid species from biological systems. The rapid development of a variety of analytical platforms based on mass spectrometry has enabled the identification of complex lipids at great precision and depth. Insights from lipidomics studies to date suggest that the overall architecture of free fatty acid partitioning between fatty acid oxidation and complex lipid fatty acid composition is an important driver of CKD progression. Available evidence suggests that CKD progression is associated with metabolic inflexibility, reflecting a diminished capacity to utilize free fatty acids through ß-oxidation, and resulting in the diversion of accumulating fatty acids to complex lipids such as triglycerides. This effect is reversed with interventions that improve kidney health, suggesting that targeting of lipid abnormalities could be beneficial in preventing CKD progression.

Idarubicin combats abiraterone and enzalutamide resistance in prostate cells via targeting XPA protein.

Although second-generation therapies like abiraterone (ABI) and enzalutamide (ENZ) benefit patients with castration-resistant prostate cancer (CRPC), drug resistance frequently occurs, eventually resulting in therapy failure. In this study, we used two libraries, FDA-approved drug library and CRISP/Cas9 knockout (GeCKO) library to screen for drugs that overcome treatment resistance and to identify the potential drug-resistant genes involved in treatment resistance. Our screening results showed that the DNA-damaging agent idarubicin (IDA) overcame abiraterone and enzalutamide resistance in prostate cancer cells. IDA treatment inhibited the DNA repair protein XPA expression in a transcription-independent manner. Consistently, XPA knockout sensitized prostate cancer cells to abiraterone and enzalutamide treatment. In conclusion, IDA combats abiraterone and enzalutamide resistance by reducing XPA protein level in prostate cancer.