Genotyping-by-Sequencing Analysis Reveals Associations between Agronomic and Oil Traits in Gamma Ray-Derived Mutant Rapeseed (Brassica napus L.).

Rapeseed (Brassica napus L.) holds significant commercial value as one of the leading oil crops, with its agronomic features and oil quality being crucial determinants. In this investigation, 73,226 single nucleotide polymorphisms (SNPs) across 95 rapeseed mutant lines induced by gamma rays, alongside the original cultivar ('Tamra'), using genotyping-by-sequencing (GBS) analysis were examined. This study encompassed gene ontology (GO) analysis and a genomewide association study (GWAS), thereby concentrating on agronomic traits (e.g., plant height, ear length, thousand-seed weight, and seed yield) and oil traits (including fatty acid composition and crude fat content). The GO analysis unveiled a multitude of genes with SNP variations associated with cellular processes, intracellular anatomical structures, and organic cyclic compound binding. Through GWAS, we detected 320 significant SNPs linked to both agronomic (104 SNPs) and oil traits (216 SNPs). Notably, two novel candidate genes, Bna.A05p02350D (SFGH) and Bna.C02p22490D (MDN1), are implicated in thousand-seed weight regulation. Additionally, Bna.C03p14350D (EXO70) and Bna.A09p05630D (PI4Kα1) emerged as novel candidate genes associated with erucic acid and crude fat content, respectively. These findings carry implications for identifying superior genotypes for the development of new cultivars. Association studies offer a cost-effective means of screening mutants and selecting elite rapeseed breeding lines, thereby enhancing the commercial viability of this pivotal oil crop.

Health shocks, health and labor market dynamics, and the socioeconomic-health gradient in older Singaporeans.

Health disparities by socioeconomic status (SES) are potentially shaped by how an individual's health status and work capacity are affected by the incidence of illness, and how these effects vary across SES groups. We examine the impact of illness on the dynamics of health status, work activity and income in older Singaporeans to gain new insights on how ill health shapes the socioeconomic health gradient. Our data comprise of 60 monthly waves (2015-2019) of panel survey data containing 445,464 person-observations from 11,827 unique respondents from Singapore. We apply a matched event-study difference-in-differences research design to track how older adults' health and work changes following the diagnosis of heart disease and cancer. Our focus is how the dynamics of health and work differ for different SES groups, which we measure by post-secondary education attainment. We find that the dynamics of how self-assessed health recovers following the diagnosis of a new heart disease or cancer do not vary significantly across SES groups. Work activity however varies significantly, with less well-educated males and females being significantly less likely to be in active employment and have income from work, and are marginally more likely to be in retirement following the onset of ill health. By contrast, more well-educated males work more, and earn more a year after the health shock than they did before they fell ill. Occupational differences likely played a role in how work activity of less well-educated men decline more after an acute health event compared with more well-educated men. Understanding the drivers of the socioeconomic health gradient necessitates a focus on individual-level factors, as well as system-level influences, that affect health and work.

The incidence and predictors of antibiotic-associated encephalopathy: a multicenter hospital-based study.

This study aimed to evaluate the incidence and likelihood of antibiotic-associated encephalopathy (AAE), comparing rates among the classes of antibiotics in monotherapy or in combination therapy. We also investigated the associations between the incidence of AAE and the glomerular filtration rate (GFR) and electroencephalogram features. Consecutive admissions that used any kind of antibiotics to treat infectious diseases were identified from six hospitals. We classified antibiotics according to three distinct pathophysiologic mechanisms and clinical subtypes. We searched for the incidence of AAE as the primary outcome. A total of 97,433 admission cases among 56,038 patients was identified. Cases that received type 1 antibiotics had significantly more frequent AAE compared to those that received type 2 antibiotics (adjusted odds ratio [OR], 2.62; 95% confidence interval [CI] 1.15-5.95; P = 0.021). Combined use of type 1 + 2 antibiotics was associated with a significantly higher incidence of AAE compared to the use of type 2 antibiotics alone (adjusted OR, 3.44; 95% CI 1.49-7.93; P = 0.004). Groups with GFR < 60 mL/min/1.73 m2 had significantly higher incidence rates of AAE compared to those with GFRs ≥ 90 mL/min/1.73 m2 among cases that received type 1 + 2 antibiotics. Detection of spike-and-wave or sharp-and-wave patterns on electroencephalogram was significantly more common in the combination therapy group. Combination use of antibiotics was associated with a higher incidence of AAE compared to monotherapy. The incidence of AAE significantly increased as renal function decreased, and epileptiform discharges were more likely to be detected in cases receiving combined antibiotics.

Risk of epilepsy in gonadal teratoma: a nationwide population-based study.

Epilepsy is a common neurological disease. Systemic tumors are associated with an increased risk of epileptic events. Paraneoplastic encephalitis related to gonadal teratoma is frequently accompanied by seizures and life-threatening status epilepticus (SE). However, the risk of epilepsy in gonadal teratoma has not been studied. This study aims to investigate the relationship between epileptic events and gonadal teratoma. This retrospective cohort study used the Korean National Health Insurance (KNHI) database. The study population was divided into two study arms (ovarian teratoma vs. control and testicular teratoma vs. control) with 1:2 age and gender-matched control groups without a history of gonadal teratoma or other malignancy. Participants with other malignancies, neurologic disorders, and metastatic brain lesions were excluded. We observed the occurrence of epileptic events during the observation period (2013-2018) and investigated the risk of epileptic events in each gonadal teratoma group compared to controls. In addition, the influence of malignancy and tumor removal was investigated. The final analysis included 94,203 women with ovarian teratoma, 2314 men with testicular teratoma, and controls. Ovarian teratoma is associated with a higher risk of epilepsy without SE (HR, 1.244; 95% CI 1.112-1.391) and epilepsy with SE (HR, 2.012; 95% CI 1.220-3.318) compared to the control group. The risk of epilepsy without SE was higher in malignant ovarian teratoma (HR, 1.661; 95% CI 1.358-2.033) than in benign (HR, 1.172; 95% CI 1.037-1.324). Testicular teratoma did not show significant relations with epileptic events. The risk of epileptic events showed a tendency to decrease after removing the ovarian teratoma. This study found that ovarian teratoma is associated with a higher risk of epileptic events, especially in malignant tumors, whereas testicular teratoma did not show significant differences in epileptic events compared to the control group. This study adds to the current understanding of the association between gonadal teratoma and epileptic events.

Enhancement of the Anticancer Ability of Natural Killer Cells through Allogeneic Mitochondrial Transfer.

An in vitro culture period of at least 2 weeks is required to produce sufficient natural killer (NK) cells for immunotherapy, which are the key effectors in hematological malignancy treatment. Mitochondrial damage and fragmentation reduce the NK cell immune surveillance capacity. Thus, we hypothesized that the transfer of healthy mitochondria to NK cells could enhance their anticancer effects. Allogeneic healthy mitochondria isolated from WRL-68 cells were transferred to NK cells. We evaluated NK cells' proliferative capacity, cell cycle, and cytotoxic capacity against various cancer cell types by analyzing specific lysis and the cytotoxic granules released. The relationship between the transferred allogenic mitochondrial residues and NK cell function was determined. After mitochondrial transfer, the NK cell proliferation rate was 1.2-fold higher than that of control cells. The mitochondria-treated NK cells secreted a 2.7-, 4.1-, and 5-fold higher amount of granzyme B, perforin, and IFN-γ, respectively, when co-cultured with K562 cells. The specific lysis of various solid cancer cells increased 1.3-1.6-fold. However, once allogeneic mitochondria were eliminated, the NK cell activity returned to the pre-mitochondrial transfer level. Mitochondria-enriched NK cells have the potential to be used as a novel solid cancer treatment agent, without the need for in vitro cytokine-induced culture.

Glucosinolate Diversity Analysis in Choy Sum (Brassica rapa subsp. chinensis var. parachinensis) Germplasms for Functional Food Breeding.

The aim of this study was to analyze glucosinolates (GSLs) in germplasm that are currently conserved at the RDA-Genebank. The analysis focused on the glucosinolate diversity among the analyzed germplasms, with the goal of identifying those that would be most useful for future breeding efforts to produce nutritionally rich Choy sum plants. In total, 23 accessions of Choy sums that possessed ample background passport information were selected. On analyzing the glucosinolate content for 17 different glucosinolates, we observed aliphatic GSLs to be the most common (89.45%) and aromatic GSLs to be the least common (6.94%) of the total glucosinolates detected. Among the highly represented aliphatic GSLs, gluconapin and glucobrassicanapin were found to contribute the most (>20%), and sinalbin, glucoraphanin, glucoraphasatin, and glucoiberin were detected the least (less than 0.05%). We identified one of the accessions, IT228140, to synthesize high quantities of glucobrassicanapin and progoitrin, which have been reported to contain several therapeutic applications. These conserved germplasms are potential bioresources for breeders, and the availability of information, including therapeutically important glucosinolate content, can help produce plant varieties that can naturally impact public health.

Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidity.

Immunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of antibody molecules could be induced on a surface where target antigen molecules are abundant, and that it could be an effective way to greatly enhance the antigen-binding avidity. A thermodynamic simulation showed that quite low homodimerization affinity of a catenator, e.g. dissociation constant of 100 µM, can enhance nanomolar antigen-binding avidity to a picomolar level, and that the fold enhancement sharply depends on the density of the antigen. In a proof-of-concept experiment where antigen molecules are immobilized on a biosensor tip, the C-terminal fusion of a pair of weakly homodimerizing proteins to three different antibodies enhanced the antigen-binding avidity by at least 110 or 304 folds from the intrinsic binding avidity. Compared with the mother antibody, Obinutuzumab(Y101L) which targets CD20, the same antibody with fused catenators exhibited significantly enhanced binding to SU-DHL5 cells. Together, the homodimerization-induced antibody catenation would be a new powerful approach to improve antibody applications, including the detection of scarce biomarkers and targeted anticancer therapies.

Lipid ROS- and Iron-Dependent Ferroptotic Cell Death in Unicellular Algae Chlamydomonas reinhardtii.

The phenomenon of heat stress leading to ferroptosis-like cell death has recently been observed in bacteria as well as plant cells. Despite recent findings, the evidence of ferroptosis, an iron-dependent cell death remains unknown in microalgae. The present study aimed to investigate if heat shock could induce reactive oxygen species (ROS) and iron-dependent ferroptotic cell death in Chlamydomonas reinhardtii in comparison with RSL3-induced ferroptosis. After RSL3 and heat shock (50 °C) treatments with or without inhibitors, Chlamydomonas cells were evaluated for cell viability and the induction of ferroptotic biomarkers. Both the heat shock and RSL3 treatment were found to trigger ferroptotic cell death, with hallmarks of glutathione-ascorbic acid depletion, GPX5 downregulation, mitochondrial dysfunction, an increase in cytosolic calcium, ROS production, lipid peroxidation, and intracellular iron accumulation via heme oxygenase-1 activation (HO-1). Interestingly, the cells preincubated with ferroptosis inhibitors (ferrostatin-1 and ciclopirox) significantly reduced RSL3- and heat-induced cell death by preventing the accumulation of Fe2+ and lipid ROS. These findings reveal that ferroptotic cell death affects the iron homeostasis and lipid peroxidation metabolism of Chlamydomonas, indicating that cell death pathways are evolutionarily conserved among eukaryotes.

Computational design of an apoptogenic protein that binds BCL-xL and MCL-1 simultaneously and potently.

One of the hallmarks of cancer cells is their ability to evade apoptosis, which confers survival advantages and resistance to anti-cancer drugs. Cancers often exhibit overexpression of anti-apoptotic BCL-2 proteins, the loss of which triggers apoptosis. In particular, the inhibition of both BCL-xL and MCL-1, but neither one individually, synergistically enhances apoptotic cell death. Here, we report computational design to produce a protein that inhibits both BCL-xL and MCL-1 simultaneously. To a reported artificial three-helix bundle whose second helix was designed to bind MCL-1, we added a fourth helix and designed it to bind BCL-xL. After structural validation of the design and further structure-based sequence design, we produced a dual-binding protein that interacts with both BCL-xL and MCL-1 with apparent dissociation constants of 820 pM and 196 pM, respectively. Expression of this dual binder in a subset of cancer cells induced apoptotic cell death at levels significantly higher than those induced by the pro-apoptotic BIM protein. With a genetic fusion of a mitochondria-targeting sequence or the BH3 sequence of BIM, the activity of the dual binder was enhanced even further. These data suggest that targeted delivery of this dual binder alone or as a part of a modular protein to cancers in the form of protein, mRNA, or DNA may be an effective way to induce cancer cell apoptosis.

Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson's disease.

Intraneuronal inclusions of misfolded α-synuclein (α-syn) and prion-like spread of the pathologic α-syn contribute to progressive neuronal death in Parkinson's disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting α-synucleinopathy has been developed. In this study, we provide evidence that astrocytes, especially those cultured from the ventral midbrain (VM), show therapeutic potential to alleviate α-syn pathology in multiple in vitro and in vivo α-synucleinopathic models. Regulation of neuronal α-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal α-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which α-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular α-syn aggregates. In addition to the aggregated form of α-syn, VM astrocytes reduced total α-syn protein loads both by actively scavenging extracellular α-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of α-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated α-syn pathology and protected the midbrain dopamine neurons from neurodegeneration. We further showed that cografting of VM astrocytes could be exploited in stem cell-based therapy for PD, in which host-to-graft transmission of α-syn pathology remains a critical concern for long-term cell therapeutic effects.

Adeno-associated virus (AAV) 9-mediated gene delivery of Nurr1 and Foxa2 ameliorates symptoms and pathologies of Alzheimer disease model mice by suppressing neuro-inflammation and glial pathology.

There is a compelling need to develop disease-modifying therapies for Alzheimer's disease (AD), the most common neuro-degenerative disorder. Together with recent progress in vector development for efficiently targeting the central nervous system, gene therapy has been suggested as a potential therapeutic modality to overcome the limited delivery of conventional types of drugs to and within the damaged brain. In addition, given increasing evidence of the strong link between glia and AD pathophysiology, therapeutic targets have been moving toward those addressing glial cell pathology. Nurr1 and Foxa2 are transcription/epigenetic regulators that have been reported to cooperatively regulate inflammatory and neurotrophic response in glial cells. In this study, we tested the therapeutic potential of Nurr1 and Foxa2 gene delivery to treat AD symptoms and pathologies. A series of functional, histologic, and transcriptome analyses revealed that the combined expression of Nurr1 and Foxa2 substantially ameliorated AD-associated amyloid ß and Tau proteinopathy, cell senescence, synaptic loss, and neuro-inflammation in multiple in vitro and in vivo AD models. Intra-cranial delivery of Nurr1 and Foxa2 genes using adeno-associated virus (AAV) serotype 9 improved the memory and cognitive function of AD model mice. The therapeutic benefits of gene delivery were attained mainly by correcting pathologic glial function. These findings collectively indicate that AAV9-mediated Nurr1 and Foxa2 gene transfer could be an effective disease-modifying therapy for AD.

The influence of endogenous and exogenous hormonal factors on migraine in spontaneous postmenopausal women: A nationwide population-based study in South Korea.

BACKGROUND: Hormonal and menstrual factors are known to influence migraines in women. However, studies in the postmenopausal period are relatively insufficient for clinical translation. This study investigated the influence of endogenous and exogenous hormonal factors on migraines in spontaneous menopausal women. METHODS: We obtained and analyzed the data related to hormonal factors from the Korean Health Examination database. A migraine diagnosis was identified using the Korean National Health Insurance Service database between 2009 and 2018. We observed migraine occurrence in spontaneous postmenopausal women. Study populations were divided into two groups depending on new diagnosis of migraine during the follow up periods. We investigated the association between endogenous and exogenous hormonal factors and migraine. RESULTS: 1,114,742 spontaneous postmenopausal women were enrolled. Migraine risk tended to increase in the shorter lifetime number of years of menstruation group compared to the group with lifetime number of years of menstruation ≥40 years. All of the hormone replacement therapy (HRT) groups showed higher risk compared with the non-HRT group. Migraine risk tends to increase with greater postmenopausal years compared to the postmenopausal <5 years group. CONCLUSION: Our study suggests that female hormonal factors, including endogenous and exogenous estrogen exposure, may be associated with migraine occurrence in spontaneous menopausal women.

Influence of Root Color and Tissue on Phytochemical Contents and Antioxidant Activities in Carrot Genotypes.

This study monitored changes in major carotenoids (lutein, ⍺-carotene, and ß-carotene), free sugars (fructose, glucose, and sucrose), ascorbic acid, vitamin E, phytosterols (campesterol, stigmasterol, and ß-sitosterol), fatty acid composition, total phenol content (TPC), total flavonoid content (TFC), total anthocyanin content, and antioxidant activities (AA); ferric-reducing antioxidant power (FRAP) and 2,2'-azino-bis (3-ethylbenzothiazoline-6sulfonic acid) [ABTS] assays, in the inner and outer root tissues of nine carrot genotypes with orange, white, and purple roots. The results showed a differential accumulation of bioactive compounds and antioxidant activities depending on root tissue and color. Carotenoids, free sugars, and total phytosterol contents were higher in genotypes with orange roots than in other genotypes. Ascorbic acid, TPC, TFC, total anthocyanin, and AA were highest in purple-colored carrots while vitamin E content was higher in white/purple carrots. Root color was highly related to the accumulation of individual carotenoids, vitamin E isomers, and total anthocyanin content most prominently among the analyzed bioactive compounds and AA. Free sugar and carotenoid contents were relatively higher in outer tissues than in inner tissues. Furthermore, ascorbic acid, TPC, TFC, and AA were statistically higher or similar in outer tissues when compared to inner tissues in all genotypes. In contrast, trends in vitamin E and phytosterol content were inconsistent between the inner and outer tissues, depending on the genotype. Although fatty acid composition was affected by both root color and tissue, the results were not significant. Thus, the phytochemical profile and content were highly dependent on root color and tissue in carrot genotypes. This may be useful in the food processing and pharmaceutical industries for the extraction of targeted bioactive compounds.

The Influence of Amyloid Burden on Cognitive Decline over 2 years in Older Adults with Subjective Cognitive Decline: A Prospective Cohort Study.

BACKGROUND: Subjective cognitive decline (SCD) is a self-perceived cognitive worsening without objective cognitive impairment. Due to its heterogeneity and potential risk of Alzheimer's disease (AD), baseline biomarkers to predict progression are clinically important. In the present study, cognitive trajectories during a 24-month period were compared between amyloid-positive SCD (A+SCD) and amyloid-negative SCD (A-SCD) subjects, and biomarkers associated with memory decline were investigated. METHODS: Data from a prospective cohort study in Korea between 2016 and 2019 were analyzed. SCD subjects ≥50 years of age were eligible. All participants underwent neuropsychological tests, brain magnetic resonance imaging, and florbetaben positron emission tomography scans. Amyloid burden and regional volumes were measured. Cognitive changes corrected for age were compared between A+SCD and A-SCD groups. Biomarkers associated with memory decline were assessed. RESULTS: Forty-seven SCD subjects (69.9 ± 6.7 years, mini-mental state examination (MMSE) score 27.5) were enrolled, and 31 completed at least 1 annual follow-up (mean follow-up: 24.7 months). Baseline characteristics except age, hippocampal atrophy, and white matter hyperintensities were similar between A+SCDs (n = 12, 25.6%) and A-SCDs (n = 35). A+SCD subjects showed greater decline in the verbal memory function compared with the A-SCD subjects after adjustment for age. MMSE scores decreased more in the A+SCD (1.1 in the A+SCD; 0.55 in the A-SCD), although it was not statistically significant. Amyloid burden and baseline memory score were associated with memory decline. CONCLUSIONS: Within SCD, A+SCD subjects showed faster memory decline compared with the A-SCD subjects and amyloid burden might be associated with future memory decline in SCD.

Metabolic Analysis of the Development of the Plant-Parasitic Cyst Nematodes Heterodera schachtii and Heterodera trifolii by Capillary Electrophoresis Time-of-Flight Mass Spectrometry.

The cyst nematodes Heterodera schachtii and Heterodera trifolii, whose major hosts are sugar beet and clover, respectively, damage a broad range of plants, resulting in significant economic losses. Nematodes synthesize metabolites for organismal development and social communication. We performed metabolic profiling of H. schachtii and H. trifolii in the egg, juvenile 2 (J2), and female stages. In all, 392 peaks were analyzed by capillary electrophoresis time-of-flight mass spectrometry, which revealed a lot of similarities among metabolomes. Aromatic amino acid metabolism, carbohydrate metabolism, choline metabolism, methionine salvage pathway, glutamate metabolism, urea cycle, glycolysis, gluconeogenesis, coenzyme metabolism, purine metabolism, pyrimidine metabolism, and tricarboxylic acid (TCA) cycle for energy conversion (ß-oxidation and branched-chain amino acid metabolism) energy storage were involved in all stages studied. The egg and female stages synthesized higher levels of metabolites compared to the J2 stage. The key metabolites detected were glycerol, guanosine, hydroxyproline, citric acid, phosphorylcholine, and the essential amino acids Phe, Leu, Ser, and Val. Metabolites, such as hydroxyproline, acetylcholine, serotonin, glutathione, and glutathione disulfide, which are associated with growth and reproduction, mobility, and neurotransmission, predominated in the J2 stage. Other metabolites, such as SAM, 3PSer, 3-ureidopropionic acid, CTP, UDP, UTP, 3-hydroxy-3-methylglutaric acid, 2-amino-2-(hydroxymethyl-1,3-propanediol, 2-hydroxy-4-methylvaleric acid, Gly Asp, glucuronic acid-3 + galacturonic acid-3 Ser-Glu, citrulline, and γ-Glu-Asn, were highly detected in the egg stage. Meanwhile, nicotinamide, 3-PG, F6P, Cys, ADP-Ribose, Ru5P, S7P, IMP, DAP, diethanolamine, p-Hydroxybenzoic acid, and γ-Glu-Arg_divalent were unique to the J2 stage. Formiminoglutamic acid, nicotinaminde riboside + XC0089, putrescine, thiamine 2,3-dihydroxybenzoic acid, 3-methyladenine, caffeic acid, ferulic acid, m-hydrobenzoic acid, o- and p-coumaric acid, and shikimic acid were specific to the female stage. Overall, highly similar identities and quantities of metabolites between the corresponding stages of the two species of nematode were observed. Our results will be a valuable resource for further studies of physiological changes related to the development of nematodes and nematode-plant interactions.

Phylogeography and Antioxidant Activity of Proso Millet (Panicum miliaceum L.).

Proso millet (Panicum miliaceum L.) or broomcorn millet is among the most important food crops to be domesticated by humans; it is widely distributed in America, Europe, and Asia. In this study, we genotyped 578 accessions of P. miliaceum using 37 single-sequence repeat (SSR) markers, to study the genetic diversity and population structure of each accession. We also investigated total phenolic content (TPC) and superoxide dismutase (SOD) activity and performed association analysis using SSR markers. The results showed that genetic diversity and genetic distance were related to geographic location and the fixation index (Fst). Population structure analysis divided the population into three subpopulations. Based on 3 subpopulations, the population is divided into six clusters in consideration of geographical distribution characteristics and agronomic traits. Based on the genetic diversity, population structure, pairwise Fst, and gene flow analyses, we described the topological structure of the six proso millet subpopulations, and the geographic distribution and migration of each cluster. Comparison of the published cluster (cluster 1) with unique germplasms in Japan and South Korea suggested Turkey as a possible secondary center of origin and domestication (cluster 3) for the cluster. We also discovered a cluster domesticated in Nepal (cluster 6) that is adapted to high-latitude and high-altitude cultivation conditions. Differences in phenotypic characteristics, such as TPC, were observed between the clusters. The association analysis showed that TPC was associated with SSR-31, which explained 7.1% of the total variance, respectively. The development of markers associated with TPC and SOD will provide breeders with new tools to improve the quality of proso millet through marker-assisted selection.

LEP as a potential biomarker in prognosis of breast cancer: Systemic review and meta analyses (PRISMA).

PURPOSE: Obesity strongly affects the prognosis of various malignancies, including breast cancer. Leptin (LEP) may be associated with obesity and breast cancer prognosis. The purpose of our study was to determine the prognostic value of LEP in breast cancer. METHOD: We conducted a multi-omic analysis to determine the prognostic role of LEP. Different public bioinformatics platforms (Oncomine, Gene Expression Profiling Interactive Analysis, University of California Santa Cruz Xena, bc-GenExMiner, PrognoScan database, R2-Kaplan-Meier Scanner, UALCAN, Search Tool for the Retrieval of Interacting Genes/Proteins database , and The Database for Annotation, Visualization and Integrated Discovery) were used to evaluate the roles of LEP. Clinicopathological variables were evaluated. RESULTS: LEP was downregulated in breast cancer tissues compared to levels in normal tissues. By co-expressed gene analysis, a positive correlation between LEP and SLC19A3 was observed. Based on the clinicopathological analysis, low LEP expression was associated with older age, higher stage, lymph node status, human epidermal growth factor receptor 2 (HER2) status, estrogen receptor (ER+) positivity, and progesterone receptor (PR+) positivity. Kaplan-Meier survival analysis showed that low LEP expression indicated a poorer prognosis. LEP is hypermethylated in breast cancer tissues in PrognoScan and R2-Kaplan Meier Scanner, and low LEP expression was correlated with poor prognosis. LEP protein-protein interactions were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins database. Gene ontology analysis results showed that cellular component is mainly associated with the endosome lumen, cytosol, and secretory granules and is upregulated. For the biological process energy reserve, metabolic processes exhibited the greatest regulation compared to the others. In molecular function, it was mainly enriched in a variety of combinations, but hormone activity showed the highest regulation. CONCLUSION: Our study provides evidence for the prognostic role of LEP in breast cancer and as a novel potential therapeutic target in such malignancies. Nevertheless, further validation is required.

Survival Analysis after Living Donor Liver Transplantation for Hepatocellular Carcinoma: A Single Center Cohort Study.

BACKGROUND: Living-donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) has been used as a curative treatment option for hepatocellular carcinoma (HCC) because of a shortage of deceased donors. This study aimed to investigate survival outcomes after LDLT for HCC. METHOD: This study included 359 patients undergoing LDLT for HCC. We analyzed overall survival (OS) and recurrence-free survival (RFS) and the prognostic factors related to them. RESULTS: The 5-year OS and RFS rates of patients within the Milan criteria (WM) were better than those of patients beyond the Milan criteria (BM) (87.3% vs. 64.1% and 87.6% vs. 57.8%, respectively, both p < 0.05). Alpha-fetoprotein level (AFP) > 400 ng/mL (hazard ratio (HR), 2.07; 95% CI, 1.28-3.36; p < 0.05) and HCC of BM (HR, 2.61; 95% CI, 1.60-4.26; p < 0.05) at immediate pretransplant were independent risk factors of OS. AFP > 400 ng/mL (HR, 2.16; 95% CI, 1.34-3.49; p < 0.05) and HCC of BM (HR, 3.01; 95% CI, 1.81-5.01; p < 0.05) were also independent risk factors of RFS. In pathologic findings of explanted liver, tumor size, Edmondson-Steiner grade III-IV, and microvascular invasion were independent risk factors of both OS and RFS (p < 0.05). CONCLUSIONS: BM and AFP > 400 ng/mL at immediate pretransplant are unfavorable predictors of survival outcomes after LDLT for HCC.