Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study.

Therapies that demonstrate durable, long-term responses with manageable safety and tolerability are needed for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]), an anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer, demonstrated single-agent antitumor activity in the pivotal phase II LOTIS-2 study in heavily pretreated patients with R/R DLBCL. Here we present updated efficacy and safety analyses from LOTIS-2, performed for all patients and in subsets of patients with a complete response (CR), including patients with CR who were event-free (no progressive disease or death) for ≥1 year and ≥2 years from cycle 1, day 1 of treatment. Lonca was administered every 3 weeks (0.15 mg/kg for 2 cycles; 0.075 mg/kg for subsequent cycles). As of the final data cutoff (September 15, 2022; median follow-up: 7.8 months [range, 0.3-42.6]), 70 of 145 (48.3%) patients achieved an overall response. Thirty-six (24.8%) patients achieved CR, of which 16 (44%) and 11 (31%) were event-free for ≥1 year and ≥2 years, respectively. In the all-treated population, the median overall survival was 9.5 months; the median progression-free survival was 4.9 months. Among patients with CR, median overall survival and progression-free survival were not reached, with 24-month overall and progression-free survival rates of 68.2% (95% CI: 50.0-81.0) and 72.5% (95% CI: 48.2-86.8), respectively. No new safety concerns were detected. With additional follow-up, Lonca continued to demonstrate durable, long-term responses with manageable safety and tolerability in patients with CR (clinicaltrials gov. Identifier: NCT03589469).

Comparison of the effect of levonorgestrel-intrauterine system with or without oral megestrol acetate on fertility-preserving treatment in patients with atypical endometrial hyperplasia: A prospective, open-label, randomized controlled phase II study.

OBJECTIVE: To compare the effects of levonorgestrel-intrauterine system (LNG-IUS) with or without oral megestrol acetate (MA) versus MA alone on fertility-preserving treatment in patients with atypical endometrial hyperplasia (AEH). METHODS: This was a single-center phase II study with an open-label, randomized, controlled trial conducted between July 2017 and June 2020 at the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. A total of 180 patients (18-45 years) with primary AEH were randomly assigned (1:1:1) to the MA (N = 60), LNG-IUS (N = 60), or MA + LNG-IUS (N = 60) groups, in which the patients received MA (160 mg orally daily), LNG-IUS, or MA + LNG-IUS (MA 160 mg orally daily plus LNG-IUS), respectively. The primary endpoint was complete response (CR) rate at 16 weeks of treatment. The secondary endpoints were CR rate at 32 weeks of treatment, adverse events, and recurrence and pregnancy rates. All analyses were conducted in a modified intention to treat (ITT) population who underwent randomization and in whom treatment was initiated. RESULTS: The Kaplan-Meier estimate of 16-week CR rates (with 95% confidence interval) were 19.2% (9.0-29.4%) in the MA group, 35.0% (22.8-47.2%) in the LNG-IUS group, and 29.4% (17.2-41.6%) in the MA + LNG-IUS groups. Side effects such as weight gain, increased nocturnal urine, night sweat, insomnia and edema face seemed to occur less frequently in LNG-IUS group compared with MA group. No difference was found among groups regarding second endpoints. CONCLUSIONS: LNG-IUS or LNG-IUS plus MA did not show significant therapeutic benefit compared with MA alone. Further studies including sufficient sample-size are needed to validate these findings due to the underpowered design of this trial. FUNDING: This study was supported by the National Key Research and Development Program of China (Grant No 2019YFC1005200 and 2019YFC1005204), Shanghai Medical Centre of Key Programs for Female Reproductive Diseases (Grant No. 2017ZZ010616), Shanghai sailing program (Grant No. 19YF1404200), and Shen Kang clinical project (SHDC22021219). Trial registrationClinicalTrials.govNCT03241888. https://www. CLINICALTRIALS: gov/ct2/show/NCT03241888?term=NCT03241888&draw=2&rank=1.

Accuracy improvement in plastics classification by laser-induced breakdown spectroscopy based on a residual network.

The whole ecosystem is suffering from serious plastic pollution. Automatic and accurate classification is an essential process in plastic effective recycle. In this work, we proposed an accurate approach for plastics classification using a residual network based on laser-induced breakdown spectroscopy (LIBS). To increasing efficiency, the LIBS spectral data were compressed by peak searching algorithm based on continuous wavelet, then were transformed to characteristic images for training and validation of the residual network. Acrylonitrile butadiene styrene (ABS), polyamide (PA), polymethyl methacrylate (PMMA), and polyvinyl chloride (PVC) from 13 manufacturers were used. The accuracy of the proposed method in few-shot learning was evaluated. The results show that when the number of training image data was 1, the verification accuracy of classification by plastic type under residual network still kept 100%, which was much higher than conventional classification algorithms (BP, kNN and SVM). Furthermore, the training and testing data were separated from different manufacturers to evaluate the anti-interference properties of the proposed method from various additives in plastics, where 73.34% accuracy was obtained. To demonstrate the superiority of classification accuracy in the proposed method, all the evaluations were also implemented by using conventional classification algorithm (kNN, BP, SVM algorithm). The results confirmed that the residual network has a significantly higher accuracy in plastics classification and shows great potential in plastic recycle industries for pollution mitigation.

Complete Genome Sequence of Pantoea stewartii subsp. indologenes ZJ-FGZX1, a Lucky Bamboo Pathogen.

The phytopathogen Pantoea stewartii subsp. indologenes causes Stewart's wilt disease in lucky bamboo. Here, we report the complete genome of P. stewartii subsp. indologenes ZJ-FGZX1, which represents the first whole-genome sequence of an isolate from China. The assembled genome consisted of three contigs, with one circular chromosome of 4,550,072 bp and two circular plasmids of 326,337 and 106,454 bp. The complete genome will provide a valuable resource for further studies on bacterial blight worldwide.

MicroRNA-144-3p suppressed TGF-ß1-induced lung cancer cell invasion and adhesion by regulating the Src-Akt-Erk pathway.

Lung cancer remains a leading cause to cancer-related death worldwide. The anti-cancer ability of microRNA-144-3p has been reported in many cancer types. This study focused on the mechanisms underlying miR-144-3p in inhibiting lung cancer. The expression levels of miR-144-3p and steroid receptor coactivator (Src) in different lung cancer cell lines and those in bronchial epithelial cells (16HBE) were compared. miR-144-3p mimic and siSrc were transfected into A549 cells. Under the conditions of transforming growth factor-ß1 (TGF-ß1). Small interfering transfection or TGF-ß1 treatment, cell invasive and adhesive abilities were analyzed by Transwell and cell adhesion assays. miR-144-3p inhibitor and siSrc were co-transfected into A549 cells and the changes in cell invasion and adhesion were detected. The activation of Src-protein kinase B-extracellular-regulated protein kinases (Src-Akt-Erk) pathway was determined using Western blot. The downregulated miR-144-3p and upregulated Src were generally detected in lung cancer cell lines and were the most significant genes in A549 cells. Both miR-144-3p overexpression and Src inhibition could obviously inhibit the invasion and adhesion abilities of A549 cells in the presence or absence of the effects of TGF-ß1. The inhibition of Src could block the promotive effects of miR-144-3p inhibitor and TGF-ß1 on cell invasion and adhesion. Furthermore, we found that miR-144-3p could negatively regulate the phosphorylation levels of Akt and Erk. Our data indicated the essential role of Src in the mechanisms underlying TGF-ß1-induced cell invasion and adhesion of lung cancer, and that miR-144-3p could effectively suppress TGF-ß1-induced aggressive lung cancer cells by regulating Src expression.

Small non-coding RNA and colorectal cancer.

Colorectal cancer (CRC) is the third most common malignance. Although great efforts have been made to understand the pathogenesis of CRC, the underlying mechanisms are still unclear. It is now clear that more than 90% of the total genome is actively transcribed, but lack of protein-coding potential. The massive amount of RNA can be classified as housekeeping RNAs (such as ribosomal RNAs, transfer RNAs) and regulatory RNAs (such as microRNAs [miRNAs], PIWI-interacting RNA [piRNAs], tRNA-derived stress-induced RNA, tRNA-derived small RNA [tRFs] and long non-coding RNAs [lncRNAs]). Small non-coding RNAs are a group of ncRNAs with the length no more than 200 nt and they have been found to exert important regulatory functions under many pathological conditions. In this review, we summarize the biogenesis and functions of regulatory sncRNAs, such as miRNAs, piRNA and tRFs, and highlight their involvements in cancers, particularly in CRC.

Pairing and Exchanging between Daypyrum villosum Chromosomes 6V#2 and 6V#4 in the Hybrids of Two Different Wheat Alien Substitution Lines.

Normal pairing and exchanging is an important basis to evaluate the genetic relationship between homologous chromosomes in a wheat background. The pairing behavior between 6V#2 and 6V#4, two chromosomes from different Dasypyrum villosum accessions, is still not clear. In this study, two wheat alien substitution lines, 6V#2 (6A) and 6V#4 (6D), were crossed to obtain the F1 hybrids and F2 segregating populations, and the testcross populations were obtained by using the F1 as a parent crossed with wheat variety Wan7107. The chromosomal behavior at meiosis in pollen mother cells (PMCs) of the F1 hybrids was observed using a genomic in situ hybridization (GISH) technique. Exchange events of two alien chromosomes were investigated in the F2 populations using nine polymerase chain reaction (PCR) markers located on the 6V short arm. The results showed that the two alien chromosomes could pair with each other to form ring- or rod-shaped bivalent chromosomes in 79.76% of the total PMCs, and most were pulled to two poles evenly at anaphase I. Investigation of the F2 populations showed that the segregation ratios of seven markers were consistent with the theoretical values 3:1 or 1:2:1, and recombinants among markers were detected. A genetic linkage map of nine PCR markers for 6VS was accordingly constructed based on the exchange frequencies and compared with the physical maps of wheat and barley based on homologous sequences of the markers, which showed that conservation of sequence order compared to 6V was 6H and 6B > 6A > 6D. In the testcross populations with 482 plants, seven showed susceptibility to powdery mildew (PM) and lacked amplification of alien chromosomal bands. Six other plants had amplification of specific bands of both the alien chromosomes at multiple sites, which suggested that the alien chromosomes had abnormal separation behavior in about 1.5% of the PMCs in F1, which resulted in some gametes containing two alien chromosomes. In addition, three new types of chromosome substitution were developed. This study lays a foundation for alien allelism tests and further assessment of the genetic relationship among 6V#2, 6V#4, and their wheat homoeologous chromosomes.

CXCL13 expression is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer.

BACKGROUND: Chemokine (C-X-C motif) ligand 13 (CXCL13/BLC/BCA-1) is a cytokine from C-X-C chemokine family, which is selectively chemotactic for B cells. Previous research has demonstrated that high CXCL13 expression is correlated to poor prognosis in various cancers. However, the association between CXCL13 expression and gastric cancer is still unclear. METHODS: Intratumoral CXCL13 expression was evaluated by immunohistochemistry using a semi-quantitative method (modified H-score) in a testing set of 214 and a validation set of 227 randomly selected gastric cancer patients resected in 2008 in one institution. The median value was used as the cut-off point. We performed correlative analysis of CXCL-13 expression with clinicopathological variables, Kaplan-Meier analysis for association with overall survival (OS), and multivariate modeling. RESULTS: High CXCL13 expression was associated with larger tumor diameter and shorter OS. By multivariate analysis, CXCL13 expression was associated with OS independently from clinicopathological factors. Within the T2-4 stage patients group, low CXCL13 expression was associated with longer survival, especially in the subgroup of patients (57.6%) who received adjuvant chemotherapy. CONCLUSIONS: Intratumoral CXCL13 expression appears as an independent prognostic marker for patients after gastric cancer resection. In addition, CXCL13 expression may serve as a predictive biomarker of response to postoperative adjuvant chemotherapy in these patients.

In vivo HMRS and lipidomic profiling reveals comprehensive changes of hippocampal metabolism during aging in mice.

Aging is characterized by various cellular changes in the brain. Hippocampus is important for systemic aging and lifespan control. There is still a lack of comprehensive overview of metabolic changes in hippocampus during aging. In this study, we first created an accelerated brain aging mice model through the chronic administration of d-galactose. We then performed a multiplatform metabolomic profiling of mice hippocampus using the combination of in vivo 9.4 T HMRS and in vitro LC-MS/MS based lipidomics. We found N-acetylaspartic acid (NAA), gama-aminobutyric acid (GABA), glutamate/glutamine, taurine, choline, sphingolipids (SMs), phosphatidylethanolamines (PEs), phosphatidylinositols (PIs), phosphatidylglycerols (PGs) and phosphatidylserines (PSs), all of them decreasing with the aging process in mice hippocampus. The changes of sphingolipids and phospholipids were not limited to one single class or molecular species. In contrast, we found the significant accumulation of lactate, myoinositol and phosphatidylcholines (PCs) along with aging in hippocampus. SM (d18:1/20:2), PE (36:2), PG (34:1), PI (36:4), PS (18:0/20:4) and PC (36:0) have the most significant changes along with aging. Network analysis revealed the striking loss of biochemical connectivity and interactions between hippocampal metabolites with aging. The correlation pattern between metabolites in hippocampus could function as biomarkers for aging or diagnosis of aging-related diseases.

Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.

BACKGROUND: Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity. METHODS: In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed. RESULTS: Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001). CONCLUSIONS: Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).

Submucosal tunneling endoscopic resection for simultaneous esophageal and cardia submucosal tumors originating from the muscularis propria layer (with video).

Submucosal tunneling endoscopic resection (STER) is a new treatment technique for upper gastrointestinal submucosal tumors (SMT) originating from the muscularis propria (MP) layer. In contrast to conventional endoscopic resection, the new therapy can maintain the mucosal integrity of the digestive tract, which effectively prevents mediastinitis and peritonitis. STER, although a known method, has not been widely adopted because of technical difficulties. Here, we describe the case of a 30-year-old patient presenting with two separate SMT originating from the esophageal and cardia MP layer. A 2-cm longitudinal mucosal incision was made approximately 5 cm proximal to the esophageal SMT, and the esophageal and cardia SMT were dissected successively in the same submucosal tunnel. In the relevant literature, this is the first case of STER for resecting esophageal and cardia SMT using the same submucosal tunnel.

RECK overexpression reduces invasive ability in ameloblastoma cells.

BACKGROUND: Ameloblastoma is a frequent odontogenic neoplasm characterized by local invasiveness and high risk of recurrence. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a tumor suppressor that inhibits metastasis and angiogenesis. The aim of this study was to investigate effects of RECK overexpression on invasive potential in ameloblastoma cells. METHODS: Lentiviral vectors containing human RECK gene were created and subsequently stably transfected into immortalized ameloblastoma cell line hTERT(+) -AM. Functional characteristics of hTERT(+) -AM cells with stable RECK overexpression included proliferation, migration, invasion, and regulation of matrix metalloproteinases (MMP)-2, MMP-9 measured by zymography or commercially available assays. RESULTS: The stable and higher expression of RECK mRNA and protein (P < 0.01) was detected in RECK-transfected hTERT(+) -AM cells. RECK overexpression caused a decrease in migration and invasion (P < 0.01) for hTERT(+) -AM cells and a decrease in activity of MMP-2, MMP-9 (P < 0.01). Proliferation was not affected by RECK overexpression (P > 0.05). CONCLUSIONS: Overexpression of RECK gene significantly inhibited cell invasive ability of hTERT(+) -AM cells, suggesting RECK may be a new target for ameloblastoma treatment.

Heparin is an effective treatment for preventing liver failure after hepatectomy.

BACKGROUND: Posthepatectomy liver failure (PHLF) is one of the most important causes of death following liver resection. Heparin, an established anticoagulant, can protect liver function through a number of mechanisms, and thus, prevent liver failure. AIM: To look at the safety and efficacy of heparin in preventing hepatic dysfunction after hepatectomy. METHODS: The data was extracted from Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) v1. 4 pinpointed patients who had undergone hepatectomy for liver cancer, subdividing them into two cohorts: Those who were injected with heparin and those who were not. The statistical evaluations used were unpaired t-tests, Mann-Whitney U tests, chi-square tests, and Fisher's exact tests to assess the effect of heparin administration on PHLF, duration of intensive care unit (ICU) stay, need for mechanical ventilation, use of continuous renal replacement therapy (CRRT), incidence of hypoxemia, development of acute kidney injury, and ICU mortality. Logistic regression was utilized to analyze the factors related to PHLF, with propensity score matching (PSM) aiming to balance the preoperative disparities between the two groups. RESULTS: In this study, 1388 patients who underwent liver cancer hepatectomy were analyzed. PSM yielded 213 matched pairs from the heparin-treated and control groups. Initial univariate analyses indicated that heparin potentially reduces the risk of PHLF in both matched and unmatched samples. Further analysis in the matched cohorts confirmed a significant association, with heparin reducing the risk of PHLF (odds ratio: 0.518; 95% confidence interval: 0.295-0.910; P = 0.022). Additionally, heparin treatment correlated with improved short-term postoperative outcomes such as reduced ICU stay durations, diminished requirements for respiratory support and CRRT, and lower incidences of hypoxemia and ICU mortality. CONCLUSION: Liver failure is an important hazard following hepatic surgery. During ICU care heparin administration has been proved to decrease the occurrence of hepatectomy induced liver failure. This indicates that heparin may provide a hopeful option for controlling PHLF.

Differences in drought characteristics, progression, and recession across ecosystem types in the pantropical region of the Lancang-Mekong River Basin.

Exploring the development and impacts of drought across different ecosystems can offer new insights for mitigating the adverse effects of drought events. Using the pantropical Lancang-Mekong River Basin as the study region, we investigated the agricultural, ecological, and hydrological drought characteristics and explored their drought progression and recession rates across four vegetation ecosystem types: tropical forests, subtropical forests, shrubs, and crops. We utilized newly developed drought indices based on the ERA5-Land reanalysis dataset, GOSIF chlorophyll fluorescence data, and modified Moderate Resolution Imaging Spectroradiometer (MODIS) land cover data. The results showed that agricultural and hydrological droughts exhibited increasing trends from 2001 to 2021, whereas ecological drought displayed a decreasing trend over the same period. The cropland region experienced the fewest drought events, shortest drought durations, slowest progression rates, and lowest recession rates. By contrast, the two evergreen, broadleaf forest ecosystems (subtropical and tropical forests) experienced the highest number of drought events and fastest progression and recession rates. The findings suggest a trade-off relationship between vegetation resistance and recovery, where faster drought onset is associated with faster drought recession for ecological drought. Given the more severe challenges posed by agricultural and hydrological droughts, the riparian countries in the Lancang-Mekong River Basin should adopt proactive financial and management measures to mitigate the adverse impacts of these drought types. The insights gained from this study can inform the development of targeted strategies for drought monitoring, preparedness, and response across diverse ecosystems.

Pathogenicity and horizontal transmission evaluation of a novel isolated African swine fever virus strain with a three-large-fragment-gene deletion.

African swine fever has caused substantial economic losses to China`s pig industry in recent years. Currently, the highly pathogenic African swine fever virus strain of genotype II is predominantly circulating in China, accompanied by a series of emerging isolates displaying unique genetic variations. The pathogenicity of these emerging strains is still unclear. Recently, a novel ASFV strain with a distinguishable three-large-fragment gene deletion was obtained from the field specimens, and its in vivo pathogenicity and transmission were evaluated in this study. The animal experiment involved inoculating a high dose of YNFN202103 and comparing its effects with those of the highly pathogenic strain GZ201801_2. Results showed that pigs infected by YNFN202103 exhibited significantly prolonged onset and survival time, lower viremia levels, and less severe histopathological lesions compared to GZ201801_2. These findings contributed valuable insights into the pathogenicity and transmission of ASFV and its prevention and eradication strategies in practical settings.

Recent trends in the transfer of graphene films.

Recent years have witnessed advances in chemical vapor deposition growth of graphene films on metal foils with fine scalability and thickness controllability. However, challenges for obtaining wrinkle-free, defect-free and large-area uniformity remain to be tackled. In addition, the real commercial applications of graphene films still require industrially compatible transfer techniques with reliable performance of transferred graphene, excellent production capacity, and suitable cost. Transferred graphene films, particularly with a large area, still suffer from the presence of transfer-related cracks, wrinkles and contaminants, which would strongly deteriorate the quality and uniformity of transferred graphene films. Potential applications of graphene films include moisture barrier films, transparent conductive films, electromagnetic shielding films, and optical communications; such applications call different requirements for the performance of transferred graphene, which, in turn, determine the suitable transfer techniques. Besides the reliable transfer process, automatic machines should be well developed for the future batch transfer of graphene films, ensuring the repeatability and scalability. This mini-review provides a summary of recent advances in the transfer of graphene films and offers a perspective for future directions of transfer techniques that are compatible for industrial batch transfer.

Polyacrylonitrile as an Efficient Transfer Medium for Wafer-Scale Transfer of Graphene.

The disparity between growth substrates and application-specific substrates can be mediated by reliable graphene transfer, the lack of which currently strongly hinders the graphene applications. Conventionally, the removal of soft polymers, that support the graphene during the transfer, would contaminate graphene surface, produce cracks, and leave unprotected graphene surface sensitive to airborne contaminations. In this work, it is found that polyacrylonitrile (PAN) can function as polymer medium for transferring wafer-size graphene, and encapsulating layer to deliver high-performance graphene devices. Therefore, PAN, that is compatible with device fabrication, does not need to be removed for subsequent applications. The crack-free transfer of 4 in. graphene onto SiO2/Si wafers, and the wafer-scale fabrication of graphene-based field-effect transistor arrays with no observed clear doping, uniformly high carrier mobility (≈11 000 cm2 V-1 s-1), and long-term stability at room temperature, are achieved. This work presents new concept for designing the transfer process of 2D materials, in which multifunctional polymer can be retained, and offers a reliable method for fabricating wafer-scale devices of 2D materials with outstanding performance.

Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

Cilostazol promotes mitochondrial biogenesis in human umbilical vein endothelial cells through activating the expression of PGC-1α.

Mitochondrial dysfunction is frequently observed in vascular diseases. Cilostazol is a drug approved by the US Food and Drug Administration for the treatment of intermittent claudication. Cilostazol increases intracellular cyclic adenosine monophosphate (cAMP) levels through inhibition of type III phosphodiesterase. The effects of cilostazol in mitochondrial biogenesis in human umbilical vein endothelial cells (HUVECs) were investigated in this study. Cilostazol treated HUVECs displayed increased levels of ATP, mitochondrial DNA/nuclear DNA ratio, expressions of cytochrome B, and mitochondrial mass, suggesting an enhanced mitochondrial biogenesis induced by cilostazol. The promoted mitochondrial biogenesis could be abolished by Protein kinase A (PKA) specific inhibitor H-89, implying that PKA pathway played a critical role in increased mitochondrial biogenesis after cilostazol treatment. Indeed, expression levels of peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), NRF 1 and mitochondrial transcription factor A (TFAM) were significantly increased in HUVECs after incubation with cilostazol at both mRNA levels and protein levels. Importantly, knockdown of PGC-1α could abolish cilostazol-induced mitochondrial biogenesis. Enhanced expression of p-CREB and PGC-1α induced by cilostazol could be inhibited by H-89. Moreover, the increased expression of PGC-1α induced by cilostazol could be inhibited by downregulation of CREB using CREB siRNA at both mRNA and protein levels. All the results indicated that cilostazol promoted mitochondrial biogenesis through activating the expression of PGC-1α in HUVECs, which was mediated by PKA/CREB pathway.

Ischaemic colitis during pegylated interferon-alpha monotherapy for chronic hepatitis B: A case report.

RATIONALE: Pegylated interferon-alpha (PEG-IFN-α) is available for the treatment of hepatitis B virus infection, which is better than interferon-alpha (IFN-α) for the inhibition of hepatitis B virus replication. Ischemic colitis has been described from non-pegylated IFN-α, which occurs mainly in patients with hepatitis C virus infection. This is the first case of ischemic colitis during pegylated IFN-α monotherapy for chronic hepatitis B. PATIENT CONCERNS: A 35-year-old Chinese man presented with complaints of acute lower abdominal pain and haematochezia, who was receiving PEG-IFN-α-2a monotherapy for chronic hepatitis B. DIAGNOSES: Colonoscopy revealed scattered ulcers and severe mucosal inflammation with edema in the left hemi colon and necrotizing changes in the descending portion. Biopsies revealed focal mucosal chronic inflammation and mucosal erosion. Therefore, the patient was diagnosed with ischemic colitis based on clinical and testing results. INTERVENTIONS: PEG-IFN-α therapy was discontinued and switched to symptomatic management. OUTCOMES: The patient was discharged from the hospital after recovery. Follow-up colonoscopy revealed normal. The temporal association between the resolution of ischemic colitis and cessation of PEG-IFN-α treatment strongly favors the diagnosis of interferon-induced ischemic colitis. LESSONS: Ischaemic colitis is a severe emergency complication of interferon therapy. Physicians should consider this complication in any patient taking PEG-IFN-α who develops abdominal discomfort and hematochezia.