Long-term dynamic changes and influencing factors of corneal morphology after multiple intravitreal injections of anti-VEGF drugs.

To observe alterations in corneal morphology caused by repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF). Prospective cohort study. Seventy-seven eyes were treated with intravitreal injection of anti-VEGF from June 2021 to March 2023. There were 25 eyes of neovascular age-related macular degeneration (nAMD), 24 eyes of diabetic macular edema (DME), and 28 eyes of retinal vein occlusion (RVO). Aflibercept was used in 37 eyes and Ranibizumab was used in 40 eyes. 3 + PRN was used. Corneal endothelium and corneal thickness were measured using a corneal endothelial microscope. The data related to central corneal thickness, corneal endothelial cell density (ECD), average cell size, coefficient of variation (CV), proportion of hexagonal cells (Hex%) was collected. A comparison was also made between baseline and the dynamic changes of all indexes 1 year following the last injection. It was observed that in comparison to baseline, ECD and Hex% decreased significantly after the 3rd injection of Aflibercept and Ranibizumab. However, ECD did not decrease further and remained at the same level as after the last injection. Hex% and average cell size increased to a certain extent in comparison to the last injection. All the changes were found to be statistically significant (P < .01). After 3 injections, ECD in DME group was markedly lower than that in nAMD and RVO group, but the CV in DME group was higher than that in nAMD as well as RVO groups, and all the differences were statistically significant (P < .05). Following intravitreal anti-VEGF therapy, DME is more likely than other disorders to result in a decrease in ECD. Repeated intravitreal injections of anti-VEGF drugs can reduce the Hex% and ECD to a certain extent. After the last injection, Hex% can progressively recover, and ECD can remain stable without further declining. After injections, ECD in DME group was found to be significantly lower than that in nAMD and RVO groups, but CV in DME group was significantly higher in comparison to the other 2 groups. In patients with macular edema, repeated intravitreal injections of anti-VEGF may have certain effects on corneal morphology. Patients with diabetes mellitus in particular should pay special attention to corneal safety following repeated intravitreal injections if they have significantly reduced ECD at baseline.

Severe gastrointestinal involvements in patients with adult dermatomyositis with anti-NXP2 antibody.

OBJECTIVE: Gastrointestinal (GI) involvements were scarcely reported in adult anti-nuclear matrix protein 2 (NXP2) dermatomyositis (NXP2+DM). In this study, we investigated the clinical, pathological and molecular features as well as treatment options of this rare yet life-threatening disease. METHODS: We retrospectively collected the data of the cohort of NXP2+ DM from 2012 to 2022 in our hospital. RNA sequencing was performed in intestinal samples of perforated patients compared with healthy controls data set. RESULTS: A total of 56 patients with adult NXP2+DM were collected including 10 cases with GI involvements. Abdominal pain and melena were the initial manifestations for GI involvements with a median 10-month time lag after the diagnosis of NXP2+DM when myositis largely subsided. Within weeks, GI perforation occurred in 8 of 10 patients, while five patients underwent eight surgical interventions subsequently. The short-term mortality was observed in four patients. NXP2+DM with GI involvements presented with more extramuscular systemic manifestations such as interstitial lung disease and subcutaneous calcinosis. The GI pathological features encompassed vasculitis/vasculopathy with high MxA expression, intestinal smooth muscle necrosis and serosal calcinosis. Gene expression profile validated the type-I interferon activation and revealed that epithelial mesenchymal transition and focal adhesion pathway may also contribute. Finally, vedolizumab, an anti-α4ß7-integrin monoclonal antibody, exhibited promising therapeutic signals which should be further investigated. CONCLUSIONS: GI involvement is a unique complication in patients with adult NXP2+DM. Timely recognition and targeted therapy may turn out to be lifesaving.

Discovery of novel oridonin sulfamide derivatives as potent NLRP3 inhibitors by a visible-light photocatalysis-enabled peripheral editing.

The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1ß and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, ß-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.

Clinical phenotypes and prognoses of microscopic polyangiitis based on kidney biopsies.

BACKGROUND: To classify the different clinical phenotypes and compare the distinct prognoses of microscopic polyangiitis (MPA). METHODS: A retrospective analysis of 436 patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) from 2015 to 2022 was conducted in our center, of which 90 patients were diagnosed with MPA and underwent renal biopsy. RESULTS: Among the 90 MPA patients, 63% were female, and the median age at onset was 63 years (25th-75th percentile: 58-68). The median follow-up time was 26 months (25th-75th percentile: 10-53). We identified four subtypes: renal impairment type (cluster 1, 39%), pure type (cluster 2, 22%), systemic inflammation type (cluster 3, 26%), and rapid progress type (cluster 4, 13%). Cluster 1, characterized by renal dysfunction at onset (80%), demonstrated poor prognoses with only 26% achieved complete remission (CR), 11% dying, and 19% developing renal failure. In contrast, patients in cluster 2, exclusively female, most had only kidney involvement showed the best prognoses with 55% achieving CR and none experiencing death or renal failure within 10 years. Cluster 3 mostly consisted of males; high fever and C-reactive protein levels were the primary characteristics. These cases exhibited moderate prognoses with 53% achieving CR, 9% dying, and 4% developing renal failure. Finally, patients in cluster 4, which was characterized by rapidly progressive glomerulonephritis, had the worst prognoses, with none achieving CR, 8% dying, and 75% developing renal failure despite aggressive treatment. CONCLUSIONS: MPA is classified into four subtypes with distinct clinical manifestations and prognoses.

A tRF-5a fragment that regulates radiation resistance of colorectal cancer cells by targeting MKNK1.

Radiotherapy serves as a crucial strategy in the treatment of colorectal cancer (CRC). However, its efficacy is often hindered by the challenge of radiation resistance. Although the literature suggests that some tRNA-derived small RNAs (tsRNAs) are associated with various cancers, studies reporting the relationship of tsRNAs with cancer cell radiosensitivity have not been published yet. In our study, we utilized tsRNAs sequencing to predict differentially expressed tsRNAs in two CRC cells and their radioresistant cells, and 10 tsRNAs with significant differences in expression were validated by qPCR. The target genes of tRF-16-7X9PN5D were predicted and verified by the bioinformatics, dual-luciferase reporter gene assay and western blotting analyses. Wound healing, colony formation, transwell invasion and CCK-8 assays were performed to detect the effects of tRF-16-7X9PN5D on cell function and radiosensitivity. Western blotting evaluated the relationship between tRF-16-7X9PN5D and the MKNK-eIF4E axis. Our findings demonstrated that tRF-16-7X9PN5D expression was substantially downregulated in radioresistant CRC cells. Furthermore, tRF-16-7X9PN5D could promote CRC cells' ability to proliferate, migrate, invade and obtain radiation resistance by targeting MKNK1. Finally, tRF-16-7X9PN5D could regulate eIF4E phosphorylation via MKNK1. This investigation indicated that tRF-16-7X9PN5D has an essential regulatory role in the radiation resistance of CRC by directly targeting MKNK1, and may be a new pathway for regulating the CRC radiosensitivity.

Effect of repeated intravitreal anti-vascular endothelial growth factor drugs on corneal nerves.

To investigate the potential effect of repeated intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) drugs on corneal nerves. A total of 64 patients were treated with intravitreal injection of anti-VEGF drugs. There were 19 cases of neovascular age-related macular degeneration (AMD), 20 cases of diabetic macular edema (DME) and 25 cases of retinal vein occlusion (RVO). Twenty-nine cases were treated with aflibercept (2 mg/0.05 mL) whereas 35 cases were managed with ranibizumab (0.5 mg/0.05 mL). A corneal confocal microscope was used to collect images of corneal subbasal nerve plexus, and Image J was used for image analysis. The changes in corneal nerve were compared between 1 month after each injection and before injection. There were no significant differences in the density and length of corneal nerve at specific time after the surgery in comparison with baseline in patients who were given 3 intravitreal injections. There was no significant correlation between the numbers of injections and the changes of the corneal nerves. After 3rd injection, the nerve length of the DME group was markedly lower than that of AMD and RVO groups, the difference was statistically significant (P < .05). The nerve density of the DME group was not significantly different from that of AMD and RVO groups, whereas the nerve length and nerve density of the AMD and RVO groups were not statistically significant between each other also. The corneal nerve length after the 2nd and 3rd injections of Aflibercept were lower than that before surgery, the difference was statistically significant. There were no significant differences in nerve density and nerve length at each time point after Ranibizumab injection. The length and density of the corneal nerve after multiple injections in contralateral eye displayed no significant changes compared with the baseline. Repeated intravitreal anti-VEGF drug can reduce the length of corneal nerves. For patients who need repeated intravitreal injections of anti-VEGF drugs, especially in DM, attention should be paid on the changes affecting the corneal nerves. It is also needed to strengthen the local anti-inflammatory therapy to avoid infection and to use artificial tears to protect the microenvironment of the ocular surface after the surgery.

Genomic profiling of ovarian clear cell carcinoma in Chinese patients reveals potential prognostic biomarkers for survival.

INTRODUCTION: Ovarian clear cell carcinoma (OCCC) has distinct clinical and molecular features and heterogeneous prognosis. Insights into the somatic genomic abnormalities of OCCC provide the basis for deeper understanding and potential therapeutic avenues. Herein, we performed extensive genomic profiling in Chinese patients to illustrate the mutation landscape and genetic prognostic biomarkers of OCCC. PATIENTS AND METHODS: We used targeted DNA sequencing on 61 OCCC cases with a panel of 520 cancer-related genes. Correlations between clinicopathological features and survival were evaluated. Nomogram-based models were constructed to predict progress-free survival (PFS). RESULTS: We detected 763 somatic mutations spanning 286 genes. The most frequent genetic alterations, ARID1A (49%) and PIK3CA (48%), were concurrently mutated. Comprehensive copy number alterations (CNAs) were identified in chromosomes 20q13.2 and 8q. Most (73.7%) patients harboured potentially targetable driver mutations. The mean and median tumour mutational burden were 7.0 and 3.0 mutations/Mb, respectively. Microsatellite instability (high) was identified in 8.2% of patients. Mutation of the base-excision repair pathway was significantly higher in patients of stage II/III/IV. ATM mutation was associated with platinum sensitivity (p < .05). Survival analysis identified chr8q CNAs in all patients, PIK3CA mutations in stage I patients and SWI/SNF complex (ARID1A and SMARCA4) mutations in stage II/III/IV patients as potential prognosticators (p < .05). Integration of genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) improved the performance of a nomogram based on tumour stage and residual disease (concordance index 0.75 vs. 0.70, p < .05). CONCLUSIONS: We described somatic genomic alterations in Chinese OCCC patients and observed different genomic alterations between stage I and stage II/III/IV tumours. Genetic factors may supplement clinical factors in nomogram modelling for PFS prediction.Key MessagesWe performed extensive genomic profiling in a well-annotated cohort of 61 Chinese ovarian clear cell carcinoma (OCCC) patients.PIK3CA mutations were associated with worse overall survival (OS) in stage I OCCC, and SWI/SNF gene mutations were associated with improved OS in stage II/III/IV disease.We propose an easy-to-use nomogram using clinical factors (tumour stage and residual disease) and genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) to predict the progress-free survival (PFS) of OCCC.

Effect of ultrasound treatment on interactions of whey protein isolate with rutin.

Rutin is a biologically active polyphenol, but its poor water solubility and low bioavailability limit its application to the food industry. We investigated the effect of ultrasound treatment on the properties of rutin (R) and whey protein isolate (WPI) using spectral and physicochemical analysis. The results revealed that there was covalent interaction between whey protein isolate with rutin, and the binding degree of whey isolate protein with rutin increased with ultrasound treatment. Additionally, solubility and surface hydrophobicity of WPI-R complex improved with ultrasonic treatment, and a maximum solubility of 81.9 % at 300 W ultrasonic power. The ultrasound treatment caused the complex to develop a more ordered secondary structure, resulting in a three-dimensional network structure with small and uniform pore sizes. This research could provide a theoretical reference for studying protein-polyphenol interactions and their applications in food delivery systems.

WDFY4 polymorphisms in Chinese patients with anti-MDA5 dermatomyositis is associated with rapid progressive interstitial lung disease.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+DM), is susceptible to development of rapidly progressive interstitial lung disease (RPILD), which has been predominantly reported in East Asia. A Japanese genome-wide study has identified a WDFY4 variant rs7919656 linkage. We sought to evaluate this genetic marker and exploit its possible clinical relevance in Chinese MDA5+DM. METHODS: We genotyped and compared the minor allele A frequency of WDFY4 rs7919656 in patients with MDA5+DM (n = 254) including 190 clinically amyopathic dermatomyositis (CADM), MDA5-DM (n = 53), anti-synthetases syndrome (ASyS, n = 72) and healthy controls (n = 192). Association of the WDFY4 variant with clinical phenotype was evaluated using logistic regression. RESULTS: Although the minor allele A frequencies of WDFY4 rs7919656 in MDA5+DM and CADM were comparable to that in healthy controls, we observed a significant correlation between the WDFY4 variant (GA+AA genotype) and the incidence of RPILD in MDA5+DM (OR: 2.11; 95% CI: 1.21, 3.69; P = 0.007). Moreover, this variant was an independent risk factor for RPILD in multivariate analysis (OR: 4.98; 95% CI: 1.59, 17.19; P = 0.008), along with other well-recognized risk factors, i.e. forced vital capacity % predicted, diffusing capacity for carbon monoxide % predicted, serum ferritin and prednisolone exposure. In addition, this variant was associated with higher expression of WDFY4 in PBMCs of MDA5+DM, especially those with RPILD. WDFY4 overexpression was also observed in lung biopsy of MDA5+DM-RPILD bearing the variant genotype. CONCLUSION: We found that the WDFY4 variant was associated with an increased risk of RPILD, not with disease susceptibility in Chinese MDA5+DM.

High eukaryotic initiation factor 5A2 expression predicts poor prognosis and may participate in the SNHG16/miR-10b-5p/EIF5A2 regulatory axis in head and neck squamous cell carcinoma.

BACKGROUND: This study attempted to investigate the significance of eukaryotic initiation factor 5A2 (EIF5A2) in the prognosis and regulatory network of head and neck squamous cell carcinoma (HNSCC). METHODS: EIF5A2 expression, prognostic information, and methylation levels of HNSCC were collected from the Cancer Genome Atlas (TCGA) database. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot analyses were performed to determine EIF5A2 levels in HNSCC and normal tissue samples. R software was employed for expression analysis and prognosis assessment of EIF5A2 in HNSCC. A competing endogenous RNA (ceRNA) network was generated with the starBase database. Gene set enrichment analysis (GSEA) was used to determine the enriched physiological functions and network related to high expression of EIF5A2 in HNSCC. Immune infiltration-related outcomes were acquired from the CIBERSORT and Tumor Immune Estimation Resource (TIMER) database. RESULTS: EIF5A2 overexpression was observed in HNSCC and linked to poor progression-free survival and overall survival time. Cox regression analyses showed that EIF5A2 level was a stand-alone indicator of HNSCC patients' prognosis. A ceRNA network analysis highlighted the SNHG16/miR-10b-5p/EIF5A2 axis in EIF5A2 regulation. The GSEA results indicated that EIF5A2 was involved in complex signaling pathways. The CIBERSORT and TIMER databases revealed significant associations between EIF5A2 expression and immune cell infiltration. CONCLUSION: EIF5A2 overexpression may be a risk factor for prognosis in HNSCC and may be regulated by the SNHG16/miR-10b-5p/EIF5A2 axis.

Longitudinal study of patients with antimelanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease.

OBJECTIVES: To describe the 8-year longitudinal study and long-term prognosis of a large inception cohort of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (MDA5+) DM-interstitial lung disease (ILD) patients. METHODS: In total, 216 patients diagnosed with MDA5+ DM-ILD were enrolled and followed up to analyse long-term survival rate. Demographic and clinical variables were collected at baseline and each temporal end point. Seventy patients who survived the first year were analysed for the long-term serological and respiratory outcomes. RESULTS: A total of 85 patients (39.3%) died during the follow-up period up to 96 months, with 89% of the deaths occurring in the first year after diagnosis. Long-term outcome was reported in 70 patients. Serological markers including anti-MDA5 antibody showed significant improvement with time. Radiographic findings and pulmonary function also improved notably in the follow-up period, especially in rapidly progressive ILD group, as measured by high-resolution computed tomography imaging scores, the estimated forced vital capacity, estimated diffusing capacity of lung carbon monoxide and dyspnoea scores. Early application of anti-fibrosis therapy helped to improve long-term pulmonary function. CONCLUSIONS: MDA5+ DM-ILD patients had a high mortality rate despite aggressive treatment. Patients who survived the first year usually showed a significant improvement in serological markers and pulmonary function during the long-term follow-up.

Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications.

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM) is an autoimmune condition associated with rapidly progressive interstitial lung disease and high mortality. The aetiology and pathogenesis of MDA5+ DM are still largely unknown. Here we describe the immune signatures of MDA5+ DM via single-cell RNA sequencing, flow cytometry and multiplex immunohistochemistry in peripheral B and T cells and in affected lung tissue samples from one patient. We find strong peripheral antibody-secreting cell and CD8+ T cell responses as cellular immune hallmarks, and over-stimulated type I interferon signaling and associated metabolic reprogramming as molecular immune signature in MDA5+ DM. High frequency of circulating ISG15+ CD8+ T cells at baseline predicts poor one-year survival in MDA5+ DM patients. In affected lungs, we find profuse immune cells infiltration, which likely contributes to the pro-fibrotic response via type I interferon production. The importance of type I interferons in MDA5+ DM pathology is further emphasized by our observation in a retrospective cohort of MDA5+ DM patients that combined calcineurin and Janus kinase inhibitor therapy show superior efficacy to calcineurin inhibitor monotherapy. In summary, this study reveals key immune-pathogenic features of MDA5+ DM and provides a potential basis for future tailored therapies.

Application of a fluorine strategy in the lead optimization of betulinic acid to the discovery of potent CD73 inhibitors.

The ecto-5'-nucleotidase (CD73) is an important enzyme in the adenosine pathway and catalyzes the extracellular hydrolysis of adenosine monophosphate (AMP) yielding adenosine which is involved in the inflammation and immunosuppression. Inhibitors of CD73 have potential as novel immunotherapy agents for the treatment of cancer and infection. In this study, we discovered a series of fluorinated betulinic acid derivatives as potent CD73 inhibitors by a fluorine scanning strategy. Among these, three compounds ZM522, ZM553 and ZM557 exhibited inhibitory activity with IC50 values of 0.56 uM, 0.74 uM and 0.47 uM, respectively. In addition, these compounds showed a 7-fold, 5-fold and 8-fold increase in activity compared to the positive control drug α, ß-methylene adenosine diphosphate (APCP) against the human CD73 enzyme. Two of these (ZM522 and ZM553) also exhibited effective interferon gamma (INF-γ) elevation and indicated the regulation of rescued T cell activation. Therefore, our study provides both a lead optimization strategy and potential compounds for further development of small molecule CD73 inhibitors.

Inhibition of the PIN1-NRF2/GPX4 axis imparts sensitivity to cisplatin in cervical cancer cells.

The incidence of cervical cancer (CC) ranks the fourth in female malignant tumors globally. Chemoresistance is one of the main causes of treatment failure in advanced recurrent CC. Prolyl isomerase 1 (PIN1) is overexpressed in a variety of tumors, and is closely associated with the malignant potential of tumor cells, such as transformation, proliferation, invasion and metastasis. In the present study, we demonstrate that cell death induced by suppression of PIN1 could be inhibited by ferrostatin-1 (Fer-1) and ferroptosis biomarkers including lactate dehydrogenase (LDH) release, lipid peroxidation and malondialdehyde (MDA) are upregulated by downregulating PIN1. We then discover that abrogation of PIN1 greatly decreases the level of glutathione peroxidase 4 (GPX4) and the level of PIN1 is positively correlated with the level of GPX4. Furthermore, the knockdown of PIN1 promotes ferroptosis induced by RSL3. The mechanism involves PIN1 silencing which downregulates GPX4 by decreasing the level of nuclear factor E2-related factor 2 (NRF2). Furthermore, overexpression of NRF2 inhibits RSL3-mediated ferroptosis of CC cells when PIN1 is silenced. In addition, our results indicate that cisplatin (DDP) induces ferroptosis, which is restrained by overexpression of PIN1. The PIN1 inhibitor, KPT-6566, promotes the cytotoxic effect of DDP. The present study reveals that PIN1 affects ferroptosis and sensitivity to DDP in CC cells via the NRF2/GPX4 axis, thereby identifying PIN1 as a potential therapeutic target for CC.

Two Distinct Immune Cell Signatures Predict the Clinical Outcomes in Patients With Amyopathic Dermatomyositis With Interstitial Lung Disease.

OBJECTIVE: Amyopathic dermatomyositis (ADM) is a heterogeneous and life-threatening autoimmune disease with a high mortality rate. In particular, anti-melanoma differentiation-associated protein 5 antibody-positive patients are at a high risk of developing rapidly progressive interstitial lung disease (RPILD). This study was undertaken to identify immunologic signatures among patients who have ADM with ILD (ADM-ILD) and to discover the biomarkers predicting prognosis. METHODS: The landscape of 42 immune cell phenotypes in the peripheral blood of 82 ADM-ILD patients and 82 age- and sex-matched healthy donors was assessed by multicolor flow cytometry. Patients were stratified using an unsupervised machine learning method (hierarchical clustering analysis) by immune cell subsets. Multiple Wilcoxon's signed rank tests and supervised machine learning methods were performed to identify important immune cell subsets. Kaplan-Meier survival analysis with log rank tests was used to create survival curves. RESULTS: We identified 2 distinct clusters correlating with different disease activities and clinical outcomes in ADM-ILD. Cluster 1 was enriched in the activated CD45RA+HLA-DR+CD8+ T cells with decreased CD56dim natural killer cell proportions and showed a higher prevalence of RPILD and higher mortality. In contrast, the other subgroup, cluster 2 (the nonactivated T cell-dominant cluster), displayed favorable clinical outcomes with high survival rates. Our data also revealed that immunophenotype was an independent risk factor associated with 1-year survival. CONCLUSION: Peripheral immunologic features may have the potential to stratify patients with ADM-ILD according to different disease severity and clinical outcomes, which may have implications for outcome prediction, pathogenesis study, and therapy selection.

Trisomy 8 Associated Clonal Cytopenia Featured With Acquired Auto-Inflammation and Its Response to JAK Inhibitors.

Objects: It has been recognized the nexus between trisomy 8 and auto-inflammatory features in myelodysplasia syndrome (MDS). Recent research about VEXAS syndrome proved clonal hematopoiesis could interfere with innate immune system far before occurrence of hematological malignancies. We reported a case series of clonal cytopenia with auto-inflammatory features in trisomy 8 patients. Methods: A total of six patients with isolated trisomy 8 excluded from MDS was retrospectively collected from the Department of Rheumatology, Renji Hospital, Shanghai. The clinical presentations and treatment outcomes were presented. Results: We report patients with trisomy 8 shared the auto-inflammatory features of recurrent fever, arthralgia, gastrointestinal involvement, and elevated inflammatory markers, especially hyperferritinemia, in addition to hematological findings such as macrocytic anemia and cytopenia of other lineages but without myelodysplasia. The symptoms of this disorder responded to the treatment of glucocorticoids but difficult to taper. JAK inhibitors were introduced to four patients with enhanced response along with glucocorticoids sparing effect and good tolerance. Conclusion: Clonal cytopenia harboring trisomy 8 presenting with auto-inflammatory features was identified. JAK inhibitor may be a promising anti-inflammatory option.

Short-term, low-dose etoposide in refractory adult-onset Still's disease-associated macrophage activation syndrome.

INTRODUCTION: In this study, we modified the classical regimen of the hemophagocytic lymphohistiocytosis-04 protocol and evaluated the efficacy and safety of short-term, low-dose etoposide in patients with refractory macrophage activation syndrome (MAS) associated with adult-onset Still's disease (AOSD). METHODS: A total of 17 patients with refractory AOSD-associated MAS were enrolled and received short-term, low-dose etoposide (100 mg twice a week for four times). Another 11 patients, who were not treated with etoposide, were included as historical controls. Patient information, such as clinical manifestations, laboratory results, treatments, and short-term prognosis, were recorded and analyzed. RESULTS: In this case series, 88.24% of the patients with MAS who were treated with short-term, low-dose etoposide had a favorable response in 3 weeks, which was significantly higher (p = 0.017) than that in the patients with MAS who were treated without etoposide (45.45%). The 90-day survival rate after the onset of MAS was significantly higher (p = 0.0029) among the patients in the short-term etoposide group (16/17, 94.12%) than in the control group (5/11, 45.45%). CONCLUSION: The regimen of short-term (2 weeks), low-dose etoposide was highly effective in the treatment for patients with refractory AOSD-associated MAS with an acceptable safety profile. Key Points • There is no high level evidence to guide the management of refractory MAS-associated AOSD patients. • This study was the first to propose and confirm the efficacy and safety of short-term, low-dose etoposide in the treatment of refractory MAS-associated AOSD patients.

The frequency and clinical implication of mismatch repair protein deficiency in Chinese patients with ovarian clear cell carcinoma.

BACKGROUND: The aim of the present study was to assess the prevalence of deficient mismatch repair (MMR) in Chinese ovarian clear cell carcinoma (CCC) patients and its association with clinicopathologic features. METHODS: Immunohistochemistry with four antibodies against MLH1, PMS2, MSH2 and MSH6 was performed on whole section slides, and the results were correlated with clinicopathologic variables. RESULTS: A total of 108 cases were included in the present study with a median age of 52 years at first diagnosis. Early-stage disease and platinum-sensitive recurrence accounted for 62.3 and 69.6%, respectively, of the total cases. Overall, the estimated 5-year overall survival was 70.3 and 20.7% in patients with early- and late-stage tumors, respectively. Deficient MMR was identified in 5.6% (6/108) of the cohort and included MSH2/MSH6 (n = 4) and MLH1/PMS2 (n = 2). The average age of the six patients with deficient MMR was 45.6 years, and the rate of MMR-deficient tumors in women ≤50 years was relatively higher than that in women over 50 years (10.0% vs. 2.9%; P = 0.266). Half of the patients with deficient MMR were diagnosed with synchronous (endometrial or colorectal) and metachronous (endometrial) cancer, which was significantly more than their intact counterparts (P = 0.002). All six patients with deficient MMR had early-stage tumors, and the majority (83.3%) were platinum sensitive. The median progression-free survival was slightly higher in patients with defective MMR expression than in their intact counterparts (30 months vs. 27 months), but significance was not achieved (P = 0.471). CONCLUSIONS: Young ovarian CCC patients with concurrent diagnosis of endometrial and colorectal cancer are more likely to have MMR-deficient tumors, thereby warranting additional studies to determine whether patients harboring MMR abnormalities have a favorable prognosis.

Identification of epigenetic genes for predicting prognosis and immunotherapy response of ovarian cancer.

BACKGROUND: Epigenetic factors play a critical role in tumour development and progression. The aim of this study was to construct and validate a robust epigenetic gene set-based signature for predicting prognosis of ovarian cancer. METHODS: By using LASSO Cox regression model, we screened out the most useful prognostic epigenetic factors and a prognostic signature was developed based on them. Survival receiver operating characteristic was used to test the prognostic accuracy of signature in training and validation sets. The associations between the risk scores and immune cell infiltration, tumour purity, immune checkpoint inhibitor genes expression were also assessed in ovarian cancer . RESULTS: A total of 26 epigenetic factors were identified to develop the prognostic signature. In the training set, the prognosis of high-risk patients was strikingly poorer than that of low-risk patients (hazard ratio: 2.11, 95% confidence interval: 1.65-2.72, P < 0.001). Similar results were further observed in the internal validation set (hazard ratio: 1.69, 95% confidence interval: 1.07-2.63, P = 0.020) and external validation set (hazard ratio:1.95, 95% confidence interval: 1.41-2.69; P < 0.001). Survival receiver operating characteristic at 5 year showed the epigenetic signature (area under the curve = 0.700) performed better than other clinical features in predicting prognosis. Distinct difference in immune activation related pathways, immune cells infiltration, tumour purity reflected by immune and stromal score and immune checkpoint inhibitor genes gene expression was observed between high- and low-risk samples. CONCLUSIONS: This study constructed an epigenetic signature that was capable of predicting postoperative outcomes and may also serve as potential biomarker for immunotherapy responses for ovarian cancer.