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The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies; however, the underlying mechanism remains underexplored. In this study, we discovered that impaired macrophage phagocytosis contributed to the psychological stress-evoked tumor susceptibility, and the stress hormone glucocorticoid (GC) was identified as a principal detrimental factor. Mechanistically, GC disturbed the balance of the “eat me” signal receptor (low-density lipoprotein receptor-related protein-1, LRP1) and the “don't eat me” signal receptor (signal regulatory protein alpha, SIRPα). Further analysis revealed that GC led to a direct, glucocorticoid receptor (GR)-dependent trans-repression of LRP1 expression, and the repressed LRP1, in turn, resulted in the elevated gene level of SIRPα by down-regulating miRNA-4695-3p. These data collectively demonstrate that stress induces the imbalance of the LRP1/SIRPα axis and entails the disturbance of tumor cell clearance by macrophages. Our findings provide the mechanistic insight into psychological stress-evoked tumor susceptibility and indicate that the balance of LRP1/SIRPα axis may serve as a potential therapeutic strategy for tumor treatment.

Key Points Isolated and comutated DDX41 myeloid neoplasms have different characteristics.DDX41-mutated AML has a relatively favorable outcome comparable to core binding factor AML., Visual Abstract, DDX41 mutations (germline and somatic) are associated with late onset myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Myeloid neoplasms (MN) with germline predisposition was identified as a distinct category in the 2016 WHO classification revision, including MN with germline DDX41 mutation. We retrospectively analyzed the molecular findings and clinical characteristics of thirty-three DDX41-mutated (mDDX41) patients at our institution. We identified 14 distinct pathogenic DDX41 variants in 32 patients and 8 DDX41 variants of unknown significance (VUS) in 9 patients. Five (16%) patients had a second DDX41 somatic mutation p.R525H and 13 (40%) had at least one additional oncogenic co-mutation in other genes. The median age at the time of diagnosis was 66 years, with male predominance (72%) and the majority of patients had normal cytogenetics (91%). Two-year overall survival (OS) was 86% and 6 (21%) MDS/AML patients with relatively preserved hematopoietic function were observed without further intervention. In comparison to AML patients with prognostically more favorable subtypes [t(8;21), n=27 and inv(16), n=40], mDDX41 patients in our cohort showed similarly favorable OS. Our study highlights that mDDX41-MN patients often have an indolent course and mDDX41-AML has comparable OS to favorable-risk AML.

Histiocytic neoplasms, including Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), present a diagnostic challenge due to nonspecific fibroinflammatory infiltrates and a diverse clinical presentation. The pathologist can play a key role in classification of these disorders through multidisciplinary collaboration and correlation of pathologic features with clinical and radiologic findings. The histopathologic differential diagnosis is broad, requiring knowledge of the possible diagnoses at each specific anatomic site, and a careful assessment to exclude other inflammatory and neoplastic disorders. An immunohistochemistry panel including CD163, CD1a, langerin, S100, Factor XIIIa, OCT2, and BRAF V600E can provide definitive diagnosis in LCH and RDD, whereas ECD requires classic clinical features as well as confirmation of an activating MAPK pathway mutation by genetic studies.

Background Auriculocondylar syndrome (ACS) is a rare disorder characterized by micrognathia, mandibular condyle hypoplasia, and auricular abnormalities. Only 6 pathogenic variants of GNAI3 have been identified associated with ACS so far. Here, we report a case of prenatal genetic diagnosis of ACS carrying a novel GNAI3 variant. Case presentation A woman with 30 weeks of gestation was referred to genetic counseling for polyhydramnios and fetal craniofacial anomaly. Severe micrognathia and mandibular hypoplasia were identified on ultrasonography. The mandibular length was 2.4 cm, which was markedly smaller than the 95th percentile. The ears were low-set with no cleft or notching between the lobe and helix. The face was round with prominent cheeks. Whole-exome sequencing identified a novel de novo missense variant of c.140G > A in the GNAI3 gene. This mutation caused an amino acid substitution of p.Ser47Asn in the highly conserved G1 motif, which was predicted to impair the guanine nucleotide-binding function. All ACS cases with GNAI3 mutations were literature reviewed, revealing female-dominated severe cases and right-side-prone deformities. Conclusion Severe micrognathia and mandibular hypoplasia accompanied by polyhydramnios are prenatal indicators of ACS. We expanded the mutation spectrum of GNAI3 and summarized clinical features to promote awareness of ACS.

Background Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. Methods Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. Results Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10–2.58)] and subtypes ALL [1.49 (0.87–2.56)] and AML [2.70 ([0.93–7.86)], but not with any cancer [1.13 (0.85–1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06–2.34)], ALL [1.43 (0.94–2.19)], AML [2.37 (1.10–5.12)] and any cancer [1.33 (1.09–1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. Conclusions Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

Background Deletion and duplication of the 3.7 Mb region in 17p11.2 result in two syndromes, Smith-Magenis syndrome and Potocki-Lupski syndrome, which are well-known development disorders. The purpose of this study was to determine the prevalence, genetic characteristics and clinical phenotypes of 17p11.2 deletion/duplication in Chinese children with development delay and in fetuses with potential congenital defects. Methods 7077 children with development delay and/or intellectual disability were screened by multiplex ligation-dependent probe amplification P245 assay. 7319 fetuses with potential congenital defects were tested using next generation sequencing technique. Results 417 of 7077 pediatric patients were determined to carry chromosome imbalance. 28 (28/7077, 0.4%) cases had imbalance at chromosome 17p11.2. Among them, 12 cases (42.9%) had heterozygous deletions and 16 cases (57.1%) had heterozygous duplications. The clinical phenotypes were variable, including neurobehavioral disorders, craniofacial/skeletal anomalies, immunologic defects, ocular problems and organ malformations. 263 of 7319 fetuses were recognized to have genomic copy number variations. Only 2 of them were found to harbor 17p11.2 imbalance. The fetus with deletion presented with ventricular septal defect and the fetus with duplication had cerebral ventricle dilation. Conclusion Our study highlights the phenotypic variability associated with 17p11.2 variations in China. The results further expand the phenotypic spectrum of SMS/PTLS and increase awareness of these disruptive mutations among clinicians.

Patients with asymptomatic/smouldering Waldenstrom macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and β2 -microglobulin (β2 M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and β2 M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.

The temporo-spatial organization of different cells in the tumor microenvironment (TME) is the key to understanding their complex communication networks and the immune landscape that exists within compromised tissues. Multi-omics profiling of single-interacting cells in the native TME is critical for providing further information regarding the reprograming mechanisms leading to immunosuppression and tumor progression. This requires new technologies for biomolecular profiling of phenotypically heterogeneous cells on the same tissue sample. Here, we developed a new methodology for comprehensive lipidomic and metabolomic profiling of individual cells on frozen-hydrated tissue sections using water gas cluster ion beam secondary ion mass spectrometry ((H2O)n-GCIB-SIMS) (at 1.6 μm beam spot size), followed by profiling cell-type specific lanthanide antibodies on the same tissue section using C60-SIMS (at 1.1 μm beam spot size). We revealed distinct variations of distribution and intensities of >150 key ions (e.g., lipids and important metabolites) in different types of the TME individual cells, such as actively proliferating tumor cells as well as infiltrating immune cells. The demonstrated feasibility of SIMS imaging to integrate the multi-omics profiling in the same tissue section at the single-cell level will lead to new insights into the role of lipid reprogramming and metabolic response in normal regulation or pathogenic discoordination of cell-cell interactions in a variety of tissue microenvironments.

Xuan-qiang Tu,1,* Ze-hua Lai,1,* Yu Zhang,2 Kai-qi Ding,1 Fei-yue Ma,3 Guo-Yuan Yang,1 Ji-rong He,3 Li-li Zeng1 1Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Neurology and Institute of Neurology, Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Neurology and Institute of Neurology, Ruijin Hospital Luwan Branch, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-li Zeng No. 197 Ruijin Second Road, Huangpu District, Shanghai, 200025, People’s Republic of ChinaTel +86-13816290607Email llzeng@126.comJi-rong He No. 149 Chongqing South Road, Huangpu District, Shanghai, People’s Republic of ChinaTel +86-13162762045Email kyo3shao@aliyun.comObjective: This study aimed to explore the correlation between white matter hyperintensity (WMH) and post-stroke depression (PSD) at 3 months, and to further investigate sex differences in the pathogenesis of PSD.Methods: A total of 238 consecutive patients with acute cerebral infarction were recruited. PSD was assessed at 2 weeks and at 3 months after stroke onset. All stroke cases were divided into four subgroups according to the diagnosis of depression at two time nodes: continuous depression; depression remission; late-onset PSD; and continuous non-depression. The Fazekas and Scheltens visual rating scales were adopted to assess WMH.Results: Logistic regression revealed that the presence of periventricular white matter hyperintensity (PVWMH) at baseline in male patients was an independent risk factor for PSD at 3 months. Further subgroup analysis revealed that PVWMH was associated with late-onset PSD in males, but not with continuous depression 3 months after stroke. Male acute stroke patients with PVWMH at baseline were more likely to develop PSD at 3 months, especially late-onset PSD.Conclusion: Our data suggest that sex differences may influence the pathogenesis of PSD.Keywords: sex difference, acute cerebral infarction, leukoencephalopathy, affective disorder, post-stroke depression

t(6;9)(p22;q34.1)/DEK-NUP214 is a recurrent genetic abnormality that occurs in 1-2% of patients with acute myeloid leukemia (AML), and rarely in myelodysplastic syndrome (MDS). It has been suggested by others that all myeloid neoplasms with t(6;9)/DEK-NUP214 may be considered as AML, even when blast count is

Comparative data guiding initial therapy for Waldenstrom macroglobulinemia (WM), an infrequently encountered non-Hodgkin lymphoma, are sparse. We evaluated three commonly used frontline regimens: rituximab-bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment-naive patients with WM, seen at Mayo Clinic between 11/01/2000 and 10/31/2019. The median follow-up was 4.5 (95%CI: 4-5) years. The R-Benda (n=83) cohort demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n=92, ORR: 78%) or BDR (n=45, ORR: 84%) cohorts, p=0.003. Similarly, longer progression-free survival (PFS) was evident with R-Benda use [median 5.2 versus 4.3 (DRC) and 1.8 years (BDR), p=0.0003].The time-to-next therapy (TTNT) favored R-Benda [median, not-reached, versus 4.4 (DRC) and 2.6 years (BDR), p=0.0002). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p=0.77. In a subset analysis of 142 patients genotyped for MYD88L265P mutation, the ORR, PFS and TTNT were unaffected by the MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R-Benda are superior compared to DRC or BDR in treatment-naive patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88L265P mutation status. This article is protected by copyright. All rights reserved.

Aims Exercise promotes functional recovery among stroke survivors and is recommended to be commenced as soon as is feasible. However, little is known about stroke survivors’ perception of participation in exercise or sitting Tai Chi, a more culturally appropriate and popular movement in China. To explore Chinese stroke survivors’ perceptions of participation in exercise or sitting Tai Chi. Methods and results Face-to-face semi-structured interviews and content analysis of transcripts were conducted with a purposive sample of 30 stroke survivors. The qualitative study explored perceptions of post-stroke participation in exercise or sitting Tai Chi. The consolidated criteria for reporting qualitative research checklist was used to report findings. Perceived facilitators of exercise participation were healthcare professionals’ encouragement and recommendations, family and peer support and survivors’ motivation, intention, and self-perceived benefits. Perceived barriers were fear of falling, physical discomfort, and challenges in standing. Despite some reservations, most participants were willing to try sitting Tai Chi. Conclusions Encouragement and support, motivation, and perceived benefits were important for exercise participation after stroke. With the premise that all medical and nursing students in China are trained in Tai Chi, for stroke survivors with no access to formal exercise programmes, sitting Tai Chi may offer an appropriate alternative.

The presence of increased multinucleated megakaryocytes (aka osteoclast-like) is considered a dysplastic feature in myelodysplastic syndrome; however, its clinical significance in isolation is uncertain. Herein, we report the clinicopathologic and genetic features of 18 such cases of 40,539 bone marrow biopsies spanning 10 years. All 18 patients had ≥25% multinucleated megakaryocytes in otherwise normal bone marrow biopsies, which were evaluated for plasma cell neoplasms (n=9), lymphoma (n=4), or anemia/neutropenia (n=5). None of the 17 patients tested showed acquired cytogenetic abnormalities. Sixteen patients underwent targeted gene panel next-generation sequencing: 9 patients had no pathogenic mutations; 3 harbored a single pathogenic mutation with variant allele frequencies of 7.5%, 7.6%, and 10.7%, likely representing clonal hematopoiesis of indeterminate potential; 1 had 2 pathogenic mutations, 1 of which had a variant allele frequency >20%. Fourteen of 18 patients had a follow-up period >6 months (median: 36.5 mo, range: 7 to 110 mo) and no patients developed a new-onset cytopenia, a progressive cytopenia, or a myeloid neoplasm. The patient with 2 mutations had persistent anemia, worrisome for an emerging MDS. However, given the absence of thrombocytopenia, increased multinucleated megakaryocytes in this patient could be an unrelated incidental finding. Our study indicates that increased multinucleated megakaryocytes as an isolated finding is a rare phenomenon, and this sole morphologic finding is not diagnostic of myelodysplastic syndrome. Diagnostic approaches in the presence of increased multinucleated megakaryocytes are proposed based on different clinical and pathologic scenarios.

Matrix metalloproteinase (MMP) secretion is highly associated with tumor invasion and metastasis; therefore, monitoring MMP secretion is important for disease progression study and therapy choosing. Though working well for intracellular MMP imaging, the performance of current MMP detection probes is impaired in secretion monitoring due to the diffusion of MMP in an extracellular environment after secretion and low secreted amount. Here, we design a cell membrane-anchored ratiometric upconversion nanoprobe (UCNPs-Cy3/Pep-QSY7/Ab) for in situ MMP secretion visualization. Anti-EGFR is functionalized on the nanoprobe to provide specific recognition to tumor cells and guarantee fast response to MMP2 in the local place of secretion. MMP-responsive cleavage of Pep-QSY7 results in Cy3 luminescence recovery at 580 nm, which is ratioed over an internal standard of UCNP emission at 654 nm for MMP2 detection. The presented cell membrane-anchored ratiometric upconversion nanoprobe demonstrated that satisfactory results for in situ monitoring of MMP2 secretion from MDA-MB-231 cells and MCF-7 cells, as well as in vivo imaging of metastatic lymph nodes, would provide a universal platform for protease secretion study and contribute to tumor invasiveness assessment.

Objectives SF3B1 mutations are the most common mutations in myelodysplastic syndromes (MDS). The International Working Group for the Prognosis of MDS (IWG-PM) recently proposed SF3B1-mutant MDS (SF3B1-mut-MDS) as a distinct disease subtype. We evaluated the spectrum and molecular landscape of SF3B1-mutated myeloid disorders and assessed the prognostication in MDS harboring SF3B1 mutations (MDS-SF3B1). Methods Cases were selected by retrospective review. Clinical course and laboratory and clinical findings were collected by chart review. SF3B1-mut-MDS was classified following IWG-PM criteria. Results SF3B1 mutations were identified in 75 of 955 patients, encompassing a full spectrum of myeloid disorders. In MDS-SF3B1, Revised International Prognostic Scoring System (IPSS-R) score greater than 3 and transcription factor (TF) comutations were adverse prognostic markers by both univariate and multivariate analyses. We confirmed the favorable outcome of IWG-PM-defined SF3B1-mut-MDS. Interestingly, it did not show sharp prognostic differentiation within MDS-SF3B1. Conclusions SF3B1 mutations occur in the full spectrum of myeloid disorders. We independently validated the favorable prognostication of IWG-PM-defined SF3B1-mut-MDS. However it may not provide sharp prognostication within MDS-SF3B1 where IPSS-R and TF comutations were prognostic-informative. Larger cohort studies are warranted to verify these findings and refine MDS-SF3B1 prognostication.

Summary Background & aims Maternal depression has been reported to be harmful to maternal and child health, and nutrition-mental health interactions may play a key role, but evidence from longitudinal studies throughout pregnancy remains insufficient. This study aimed to investigate the association of maternal dietary patterns with depressive symptoms throughout pregnancy. Methods This study was based in the Born in Guangzhou Cohort Study. Dietary patterns were defined by cluster analysis based on validated food frequency questionnaires in mid-pregnancy. A healthy diet score was also developed based on predefined criteria of existing dietary guidelines. Depressive symptoms were measured by Self-rating Depression Scale (SDS) in both early and late pregnancy, with SDS scores ≥53 defined as having depressive symptoms. Associations of dietary patterns with SDS scores were examined by linear-mixed models; associations of dietary patterns with the odds of having depressive symptoms were examined by mixed-effects logistic models. The associations of the healthy diet score with both dietary patterns and depressive symptoms were also explored. Results Six dietary patterns were identified in 17,430 pregnant women, namely ‘Varied’ (n = 3902, 22.4%), ‘Vegetables’ (n = 3269, 18.8%), ‘Meats’ (n = 2951, 16.9%), ‘Cereals’ (n = 2719, 15.6%), ‘Milk’ (n = 2377, 13.6%), and ‘Fruits’ (n = 2212, 12.7%). There were 19.3% and 15.7% of participants with depressive symptoms in early and late pregnancy, respectively. Compared with the ‘Varied’ pattern, all other patterns were associated with lower SDS scores during pregnancy except for ‘Cereals’ (‘Vegetables’: adjusted β [aβ] −0.78, 95% CI −1.16, −0.40; ‘Meats’: aβ −0.48, 95% CI −0.87, −0.09; ‘Milk’: aβ −0.52, 95% CI −0.94, −0.10; ‘Fruits’: aβ −0.85, 95% CI −1.27, −0.42). The ‘Vegetables’ (adjusted OR [aOR] 0.79, 95% CI 0.67, 0.93), ‘Milk’ (aOR 0.76, 95% CI 0.63, 0.91), and ‘Fruits’ (aOR 0.77, 95% CI 0.64, 0.93) patterns were associated with lower odds of having depressive symptoms during pregnancy than the ‘Varied’ pattern. Results for the healthy diet score revealed the healthiness of the ‘Vegetables’, ‘Fruits’, and ‘Milk’ patterns and supported an inverse association between healthy dietary patterns and depressive symptoms throughout pregnancy. Conclusions Diets rich in vegetables, fruits, nuts, and dairy products had an inverse association with depressive symptoms throughout pregnancy. Our findings add support to the existing dietary guidelines that healthy diets might also have potential benefits to maternal mental health.

Objective To examine the longitudinal associations of fetal growth with adverse child growth outcomes and to assess whether maternal metabolic factors modify the associations. Design Prospective cohort study. Setting Born in Guangzhou Cohort Study, China. Population A total of 4818 mother–child pairs. Methods Fetal growth was assessed according to estimated fetal weight (EFW) from 22 weeks of gestation until birth and the measurement of the birthweight. Fetal growth Z‐scores were computed from random effects in the multilevel linear spline models to represent fetal size in early pregnancy (22 weeks of gestation) and growth in mid‐pregnancy (22–27 weeks of gestation), early third trimester (28–36 weeks of gestation) and late third trimester (≥37 weeks of gestation). Main outcome measures Z‐scores for childhood stunting, low weight, overweight or obesity, length/height for age (LAZ/HAZ), weight for age (WAZ) and body mass index for age (BMIZ) at the age of 3 years. Adjusted associations were examined using multiple Poisson or linear regression models. Results Increased Z‐scores of fetal size in early pregnancy and growth in mid‐pregnancy and early third trimester were associated with a higher risk of childhood overweight or obesity (risk ratios 1.25–1.45). Fetal growth in each period was negatively associated with stunting and low weight, with the strongest associations observed for fetal size in early pregnancy and growth in mid‐pregnancy. The results for continuous outcomes (LAZ/HAZ, WAZ and BMIZ) were similar. The associations of fetal growth with overweight or obesity in childhood were stronger among mothers who were underweight and who were overweight or obese than among mothers of normal weight. Conclusions Accelerated fetal growth before 37 weeks of gestation is associated with children who are overweight or obese, whereas the critical period for stunting and low weight occurs before 28 weeks of gestation. Tweetable abstract Fetal growth during different periods is differentially associated with childhood stunting, underweight and overweight or obesity.

In this study, we present a case of a 22-year-old female with a family history of syncope, suffering from recurrent syncope since childhood. She had an obvious prolonged QTc interval of up to 651 ms, a bifid T wave pattern on electrocardiogram, and torsade de pointes, corresponding to a syncope episode. Additionally, her echocardiogram showed left ventricular non-compaction in the apex. After treatment with mexiletine, the QTc interval has been observed to shorten immediately, and the T wave morphology recovered. A similar effect was also observed in her mother and young sister. Administration of propranolol prolonged her QTc interval. Target sequencing of candidate genes revealed a missense mutation in the pore area of the hERG protein, coded by KCNH2. We diagnosed this as a case of type 2 long QT syndrome in which mexiletine could be effective in shortening the QTc interval.

Objectives To report our single-center experience of the management of children with prostatic utricle cysts. Methods We retrospectively analyzed 15 children who were incidentally found to have a prostatic utricle cyst and were admitted to our department between October 2013 and August 2020. Clinical characteristics and management were collected and catalogued. Results Recurrent genitourinary tract infections were the most frequent complaint, and two-thirds of patients also had hypospadias. A connection between the posterior urethra and the prostatic utricle cyst was found in all cases. Two patients directly had their progressively enlarging prostatic utricle cyst resected laparoscopically. Endoscopic techniques were used in 13 patients, two of whom underwent laparoscopic excision for repeated symptoms. The mean (range) follow-up period was 34.9 (2-82) months. No recurrences were observed in four patients who underwent prostatic utricle cyst excision and eight patients who received endoscopic treatment. Three patients had recurrent symptoms after endoscopic treatment and were managed by nonsurgical treatment. Conclusions Prostatic utricle cyst is a rare disease which can cause recurrent genitourinary tract infections. Extra attention should be paid to evaluation for prostatic utricle cyst in children with external genital anomalies. Retrograde urethrogram and magnetic resonance imaging are useful tools with which to distinguish prostatic utricle cyst from other cystic lesions that are located in the midline pelvis in male patients. Individualized treatment is appropriate when considering fertility preservation, recurrences and malignancy. Laparoscopic excision is feasible for symptomatic and large prostatic utricle cyst. Regular long-term monitoring is recommended for all patients with prostatic utricle cyst.

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2β (iPLA2β, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2β averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2β expression and a PD-relevant phenotype. Thus, iPLA2β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

During cancer therapy, phagocytic clearance of dead cells plays a vital role in immune homeostasis. The nonapoptotic form of cell death, ferroptosis, exhibits extraordinary potential in tumor treatment. However, the phagocytosis mechanism that regulates the engulfment of ferroptotic cells remains unclear. Here, we establish a novel pathway for phagocytic clearance of ferroptotic cells that is different from canonical mechanisms by using diverse ferroptosis models evoked by GPX4 dysfunction/deficiency. We identified the oxidized phospholipid, 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH), as a key eat-me signal on the ferroptotic cell surface. Enriching the plasma membrane with SAPE-OOH increased the efficiency of phagocytosis of ferroptotic cells by macrophage, a process that was suppressed by lipoprotein-associated phospholipase A2. Ligand fishing, lipid blotting, and cellular thermal shift assay screened and identified TLR2 as a membrane receptor that directly recognized SAPE-OOH, which was further confirmed by TLR2 inhibitors and gene silencing studies. A mouse mammary tumor model of ferroptosis verified SAPE-OOH and TLR2 as critical players in the clearance of ferroptotic cells in vivo. Taken together, this work demonstrates that SAPE-OOH on ferroptotic cell surface acts as an eat-me signal and navigates phagocytosis by targeting TLR2 on macrophages.

Benign clonal T-cell expansions in reactive immune responses often complicate the laboratory diagnosis T-cell neoplasia. We recently introduced a novel flow cytometry assay to detect T-cell clones in blood and bone marrow, based on the identification of a monophasic T-cell receptor (TCR) β chain constant region-1 (TRBC1) expression pattern within a phenotypically distinct TCRαβ T-cell subset. In routine laboratory practice, T-cell clones of uncertain significance (T-CUS) were detected in 42 of 159 (26%) patients without T-cell malignancy, and in 3 of 24 (13%) healthy donors. Their phenotype (CD8+/CD4−: 78%, CD4−/CD8−: 12%, CD4+/CD8+: 9%, or CD4+/CD8−: 2%) closely resembled that of 26 cases of T-cell large granular lymphocytic leukemia (T-LGLL) studied similarly, except for a much smaller clone size (p

A critical pathogenic factor in the development of lethal liver failure is cell death induced by the accumulation of lipid reactive oxygen species. In this study, we discovered and illuminated a new mechanism that led to alcoholic liver disease via ferroptosis, an iron-dependent regulated cell death. Study in vitro showed that both necroptosis inhibitor and ferroptosis inhibitors performed significantly protective effect on alcohol-induced cell death, while apoptosis inhibitor and autophagy inhibitor had no such effect. Our data also indicated that alcohol caused the accumulation of lipid peroxides and the mRNA expression of prostaglandin-endoperoxide synthase 2, reduced the protein expression of the specific light-chain subunit of the cystine/glutamate antiporter and glutathione peroxidase 4. Importantly, ferrostatin-1 significantly ameliorated liver injury that was induced by overdosed alcohol both in vitro and in vivo. These findings highlight that targeting ferroptosis serves as a hepatoprotective strategy for alcoholic liver disease treatment.

MiRNAs can be used as promising diagnostic biomarkers of heart failure, while lncRNAs act as competing endogenous RNAs of miRNAs. In this study, we collected peripheral blood monocytes from subjects with or without HF to explore the association between certain lncRNAs, miRNAs and HF. Heart failure patients with preserved or reduced ejection fraction were recruited for investigation. ROC analysis was carried out to evaluate the diagnostic values of certain miRNAs and lncRNAs in HF. Luciferase assays were used to study the regulatory relationship between above miRNAs and lncRNAs. LncRNA overexpression was used to explore the effect of certain miRNAs in H9C2 cells. Expression of miR‐30c was significantly decreased in the plasma and peripheral blood monocytes of patients suffering from heart failure, especially in these with reduced ejection fraction. On the contrary, the expression of lncRNA‐CASC7 was remarkably increased in the plasma and peripheral blood monocytes of patients suffering from heart failure. Both miR‐30c and lncRNA‐CASC7 expression showed a promising efficiency as diagnostic biomarkers of heart failure. Luciferase assays indicated that miR‐30c played an inhibitory role in lncRNA‐CASC7 and IL‐11 mRNA expression. Moreover, the overexpression of lncRNA‐CASC7 suppressed the expression of miR‐30c while evidently increasing the expression of IL‐11 mRNA and protein in H9C2 cells. This study clarified the relationship among miR‐30c, lncRNA‐CASC7 and IL‐11 expression and the risk of heart failure and showed that lncRNA‐CASC7 is potentially involved in the pathogenesis of HF via modulating the expression of miR‐30c.

GM1 ganglioside is particularly abundant in the mammalian central nervous system and has shown beneficial effects on neurodegenerative diseases. In this study, we investigated the therapeutic effect of GM1 ganglioside in experimental models of Parkinson’s disease (PD) in vivo and in vitro. Mice were injected with MPTP (30 mg·kg(-1)·d(−1), i.p.) for 5 days, resulting in a subacute model of PD. PD mice were treated with GM1 ganglioside (25, 50 mg·kg(−)(1)·d(−1), i.p.) for 2 weeks. We showed that GM1 ganglioside administration substantially improved the MPTP-induced behavioral disturbance and increased the levels of dopamine and its metabolites in the striatal tissues. In the MPP(+)-treated SH-SY5Y cells and α-synuclein (α-Syn) A53T-overexpressing PC12 (PC12(α-Syn A53T)) cells, treatment with GM1 ganglioside (40 μM) significantly decreased α-Syn accumulation and alleviated mitochondrial dysfunction and oxidative stress. We further revealed that treatment with GM1 ganglioside promoted autophagy, evidenced by the autophagosomes that appeared in the substantia nigra of PD mice as well as the changes of autophagy-related proteins (LC3-II and p62) in the MPP(+)-treated SH-SY5Y cells. Cotreatment with the autophagy inhibitor 3-MA or bafilomycin A1 abrogated the in vivo and in vitro neuroprotective effects of GM1 ganglioside. Using GM1 ganglioside labeled with FITC fluorescent, we observed apparent colocalization of GM1-FITC and α-Syn as well as GM1-FITC and LC3 in PC12(α-Syn A53T) cells. GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12(α-Syn A53T) cells and the MPP(+)-treated SH-SY5Y cells, which was inhibited by 3-MA. Taken together, this study demonstrates that the anti-PD role of GM1 ganglioside resulted from activation of autophagy-dependent α-Syn clearance.

This review summarizes experimental evidence indicating that purinergic mechanisms are causally involved in acupuncture (AP)-induced analgesia. Electroacupuncture (EAP) and manual AP release at pain-relevant acupoints ATP which may activate purinergic P2X receptors (Rs) especially of the P2X3 type situated at local sensory nerve endings (peripheral terminals of dorsal root ganglion [DRG] neurons); the central processes of these neurons are thought to inhibit via collaterals of ascending dorsal horn spinal cord neurons, pain-relevant pathways projecting to higher centers of the brain. In addition, during AP/EAP non-neuronal P2X4 and/or P2X7Rs localized at microglial cells of the CNS become activated at the spinal or supraspinal levels. In consequence, these microglia secrete bioactive compounds such as growth factors, cytokines, chemokines, reactive oxygen, and nitrogen species, which modulate the ascending neuronal pathways conducting painful stimuli. Alternatively, ATP released at acupoints by AP/EAP may be enzymatically degraded to adenosine, stimulating in loco presynaptic A1Rs exerting an inhibitory influence on the primary afferent fibers (the above mentioned pain-sensing peripheral terminals of DRG neurons) which thereby fail to conduct action potentials to the spinal cord dorsal horn. The net effect of the stimulation of P2X3, P2X4, P2X7, and A1Rs by the AP/EAP-induced release of ATP/adenosine at certain acupoints will be analgesia.

Multifunctional nanoparticles for imaging and treatment in cancer are getting more and more attentions recently. Herein, halloysite nanotubes (HNTs), natural clay nanotubes, are designed as multifu...

Hb Bronovo [α103(G10)His→Leu, HBA2: c.311A>T] is an α-globin variant that interferes with and decreases binding efficiency to α hemoglobin (Hb) stabilizing protein (AHSP), a chaperone molecule. The...

The role of long non‐coding RNAs (lncRNAs) in kidney diseases has been gradually discovered in recent years. LINC00963, as an lncRNA, was found to be involved in chronic renal failure. However, the role and molecular mechanisms of LINC00963 engaged in acute kidney injury (AKI) were still unclear. In this study, we established rat AKI models by ischaemia and reperfusion (I/R) treatment. Urea and creatinine levels were determined, and histological features of kidney tissues were examined following HE staining. CCK8 assay was chosen to assess the viability of hypoxia‐induced HK‐2 cells. Dual‐luciferase reporter gene assays were performed to verify the target relationship between LINC00963 and microRNA. The mRNA and protein levels were assayed by RT‐qPCR and Western blot, respectively. Annexin V‐FITC/PI and TUNEL staining were used to evaluate apoptosis. LINC00963 was highly expressed in the cell and rat models, and miR‐128‐3p was predicted and then verified as a target gene of LINC00963. Knockdown of LINC00963 reduced acute renal injury both in vitro and in vivo. LINC00963 activated the JAK2/STAT1 pathway to aggravate renal I/R injury. LINC00963 could target miR‐128‐3p to reduce G1 arrest and apoptosis through JAK2/STAT1 pathway to promote the progression of AKI.