Diagnostic challenges and proposed classification of myeloid neoplasms with overlapping features of thrombocytosis, ring sideroblasts and concurrent del(5q) and SF3B1 mutations.

Not available.

A specific inflammatory suppression fibroblast subpopulation characterized by MHCII expression in human dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a significant cause of heart failure that requires heart transplantation. Fibroblasts play a central role in the fibro-inflammatory microenvironment of DCM. However, their cellular heterogeneity and interaction with immune cells have not been well identified. An integrative analysis was conducted on single-cell RNA sequencing (ScRNA-Seq) data from human left ventricle tissues, which comprised 4 hearts from healthy donors and 6 hearts with DCM. The specific antigen-presenting fibroblast (apFB) was explored as a subtype of fibroblasts characterized by expressing MHCII genes, the existence of which was confirmed by immunofluorescence staining of 3 cardiac tissues from DCM patients with severe heart failure. apFB highly expressed the genes that response to IFN-γ, and it also have a high activity of the JAK-STAT pathway and the transcription factor RFX5. In addition, the analysis of intercellular communication between apFBs and CD4+T cells revealed that the anti-inflammatory ligand-receptor pairs TGFB-TGFR, CLEC2B-KLRB1, and CD46-JAG1 were upregulated in DCM. The apFB signature exhibited a positive correlation with immunosuppression and demonstrated diagnostic and prognostic value when evaluated using a bulk RNA dataset comprising 166 donors and 166 DCM samples. In conclusion, the present study identified a novel subpopulation of fibroblasts that specifically expresses MHCII-encoding genes. This specific apFBs can suppress the inflammation occurring in DCM. Our findings further elucidate the composition of the fibro-inflammatory microenvironment in DCM, and provide a novel therapeutic target.

Effects of hypoxia in cardiac metabolic remodeling and heart failure.

Aerobic cellular respiration requires oxygen, which is an essential part of cardiomyocyte metabolism. Thus, oxygen is required for the physiologic metabolic activities and development of adult hearts. However, the activities of metabolic pathways associated with hypoxia in cardiomyocytes (CMs) have not been conclusively described. In this review, we discuss the role of hypoxia in the development of the hearts metabolic system, and the metabolic remodeling associated with the hypoxic adult heart. Hypoxia-inducible factors (HIFs), the signature transcription factors in hypoxic environments, is also investigated for their potential to modulate hypoxia-induced metabolic changes. Metabolic remodeling existing in hypoxic hearts have also been shown to occur in chronic failing hearts, implying that novel therapeutic options for heart failure (HF) may exist from the hypoxic perspective. The pressure overload-induced HF and diabetes-induced HF are also discussed to demonstrate the effects of HIF factor-related pathways to control the metabolic remodeling of failing hearts.

Universal window size-dependent transition of correlations in complex systems.

Correlation analysis serves as an easy-to-implement estimation approach for the quantification of the interaction or connectivity between different units. Often, pairwise correlations estimated by sliding windows are time-varying (on different window segments) and window size-dependent (on different window sizes). Still, how to choose an appropriate window size remains unclear. This paper offers a framework for studying this fundamental question by observing a critical transition from a chaotic-like state to a nonchaotic state. Specifically, given two time series and a fixed window size, we create a correlation-based series based on nonlinear correlation measurement and sliding windows as an approximation of the time-varying correlations between the original time series. We find that the varying correlations yield a state transition from a chaotic-like state to a nonchaotic state with increasing window size. This window size-dependent transition is analyzed as a universal phenomenon in both model and real-world systems (e.g., climate, financial, and neural systems). More importantly, the transition point provides a quantitative rule for the selection of window sizes. That is, the nonchaotic correlation better allows for many regression-based predictions.

Construction of in vitro 3-D model for lung cancer-cell metastasis study.

BACKGROUND: Cancer metastasis is the main cause of mortality in cancer patients. However, the drugs targeting metastasis processes are still lacking, which is partially due to the short of effective in vitro model for cell invasion studies. The traditional 2-D culture method cannot reveal the interaction between cells and the surrounding extracellular matrix during invasion process, while the animal models usually are too complex to explain mechanisms in detail. Therefore, a precise and efficient 3-D in vitro model is highly desirable for cell invasion studies and drug screening tests. METHODS: Precise micro-fabrication techniques are developed and integrated with soft hydrogels for constructing of 3-D lung-cancer micro-environment, mimicking the pulmonary gland or alveoli as in vivo. RESULTS: A 3-D in vitro model for cancer cell culture and metastasis studies is developed with advanced micro-fabrication technique, combining microfluidic system with soft hydrogel. The constructed microfluidic platform can provide nutrition and bio-chemical factors in a continuous transportation mode and has the potential to form stable chemical gradient for cancer invasion research. Hundreds of micro-chamber arrays are constructed within the collagen gel, ensuring that all surrounding substrates for tumor cells are composed of natural collagen hydrogel, like the in vivo micro-environment. The 3-D in vitro model can also provide a fully transparent platform for the visual observation of the cell morphology, proliferation, invasion, cell-assembly, and even the protein expression by immune-fluorescent tests if needed. The lung-cancer cells A549 and normal lung epithelial cells (HPAEpiCs) have been seeded into the 3-D system. It is found out that cells can normally proliferate in the microwells for a long period. Moreover, although the cancer cells A549 and alveolar epithelial cells HPAEpiCs have the similar morphology on 2-D solid substrate, in the 3-D system the cancer cells A549 distributed sparsely as single round cells on the extracellular matrix (ECM) when they attached to the substrate, while the normal lung epithelial cells can form cell aggregates, like the structure of normal tissue. Importantly, cancer cells cultured in the 3-D in vitro model can exhibit the interaction between cells and extracellular matrix. As shown in the confocal microscope images, the A549 cells present round and isolated morphology without much invasion into ECM, while starting from around Day 5, cells changed their shape to be spindle-like, as in mesenchymal morphology, and then started to destroy the surrounding ECM and invade out of the micro-chambers. CONCLUSIONS: A 3-D in vitro model is constructed for cancer cell invasion studies, combining the microfluidic system and micro-chamber structures within hydrogel. To show the invasion process of lung cancer cells, the cell morphology, proliferation, and invasion process are all analyzed. The results confirmed that the micro-environment in the 3-D model is vital for revealing the lung cancer cell invasion as in vivo.

Two MicroRNAs, miR-34a and miR-125a, Are Implicated in Bicuspid Aortopathy by Modulating Metalloproteinase 2.

It has been recognized that wall shear stress plays an important role in the development of Bicuspid Aortopathy (BA), but the intrinsic mechanism is not well elucidated. This study aims to explore the underlying relationship between hemodynamical forces and pathological phenomenon. Total RNA was prepared from aortic wall tissues collected from 20 BA patients. RNA sequencing, bioinformatic analysis and quantitative reverse-transcription PCR validation identified nine miRNAs that were up-regulated in the aortic part exposed to high wall shear stress compared to the low wall shear stress control, and six miRNAs that were down-regulated. Among these candidates, miR-34a and miR-125a, both down-regulated in the high wall shear stress parts, were shown to be potential inhibitors of the metalloproteinase 2 gene. Luciferase reporter assays confirmed that both miRNAs could inhibit the expression of metalloproteinase 2 mRNA in CRL1999 by complementing with its 3' untranslated region. Conversely, immunofluorescence assays showed that inhibition of miR-34a or miR-125a could lead to increased metalloproteinase 2 protein level. On the other hand, both miR-34a and miR-125a were shown to alleviate stretch-induced stimulation of metalloproteinase 2 expression in CRL1999 cells. The results suggested that miR-34a and miR-125a might be implicated in wall shear stress induced aortic pathogenesis due to their apparent regulatory roles in metalloproteinase 2 expression and extracellular matrix remodeling, which are key events in the weakening of aortic walls among BA patients.

Dissecting transcriptional heterogeneity in primary gastric adenocarcinoma by single cell RNA sequencing.

OBJECTIVE: Tumour heterogeneity represents a major obstacle to accurate diagnosis and treatment in gastric adenocarcinoma (GA). Here, we report a systematic transcriptional atlas to delineate molecular and cellular heterogeneity in GA using single-cell RNA sequencing (scRNA-seq). DESIGN: We performed unbiased transcriptome-wide scRNA-seq analysis on 27 677 cells from 9 tumour and 3 non-tumour samples. Analysis results were validated using large-scale histological assays and bulk transcriptomic datasets. RESULTS: Our integrative analysis of tumour cells identified five cell subgroups with distinct expression profiles. A panel of differentiation-related genes reveals a high diversity of differentiation degrees within and between tumours. Low differentiation degrees can predict poor prognosis in GA. Among them, three subgroups exhibited different differentiation grade which corresponded well to histopathological features of Lauren's subtypes. Interestingly, the other two subgroups displayed unique transcriptome features. One subgroup expressing chief-cell markers (eg, LIPF and PGC) and RNF43 with Wnt/ß-catenin signalling pathway activated is consistent with the previously described entity fundic gland-type GA (chief cell-predominant, GA-FG-CCP). We further confirmed the presence of GA-FG-CCP in two public bulk datasets using transcriptomic profiles and histological images. The other subgroup specifically expressed immune-related signature genes (eg, LY6K and major histocompatibility complex class II) with the infection of Epstein-Barr virus. In addition, we also analysed non-malignant epithelium and provided molecular evidences for potential transition from gastric chief cells into MUC6+TFF2+ spasmolytic polypeptide expressing metaplasia. CONCLUSION: Altogether, our study offers valuable resource for deciphering gastric tumour heterogeneity, which will provide assistance for precision diagnosis and prognosis.

Novel controlled and targeted releasing hydrogen sulfide system exerts combinational cerebral and myocardial protection after cardiac arrest.

BACKGROUND: Cardiac arrest (CA) is a leading cause of death worldwide. Even after successful cardiopulmonary resuscitation (CPR), the majorities of survivals are companied with permanent myocardial and cerebral injury. Hydrogen sulfide (H2S) has been recognized as a novel gasotransmitter exerting multiple organ protection; however, the lacks of ideal H2S donors which can controlled release H2S to targeted organs such as heart and brain limits its application. RESULTS: This work utilized mesoporous iron oxide nanoparticle (MION) as the carriers of diallyl trisulfide (DATS), with polyethylene glycol (PEG) and lactoferrin (LF) modified to MIONs to acquire the prolonged circulation time and brain-targeting effects, and a novel targeted H2S releasing system was constructed (DATS@MION-PEG-LF), which exhibited excellent biocompatibility, controlled-releasing H2S pattern, heart and brain targeting features, and the ability to be non-invasive traced by magnetic resonance imaging. DATS@MION-PEG-LF presented potent protective effects against cerebral and cardiac ischemic injury after CA in both in vitro hypoxia/reoxygenation models and in vivo CA/CPR models, which mainly involves anti-apoptosis, anti-inflammatory and anti-oxidant mechanisms. Accordingly, the cardiac and cerebral functions were obviously improved after CA/CPR, with potentially improved survival. CONCLUSIONS: The present work provides a unique platform for targeted controlled release of H2S based on MIONs, and offers a new method for combinational myocardial and cerebral protection from ischemic injury, bringing considerable benefits for CA patients.

Myocardial injury in severe and critical coronavirus disease 2019 patients.

BACKGROUND AND AIM OF THE STUDY: To investigate the effect of myocardial injury on the prognosis of patients with severe or critical coronavirus disease 2019 (COVID-19). METHODS: Between February 10, 2020 and March 31, 2020, data of severe and critical COVID-19 patients were collected and retrospectively analyzed. Admission data included age, heart rates, mean arterial pressure, and myocardial injury markers including creatine kinase isoenzyme-MB (CK-MB), myoglobin, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and interleukin-6. The endpoints included mortality, the incidence of malignant arrhythmia, and mechanical ventilation time. Univariate regression analysis, multivariate linear regression analysis, and binary logistic analysis were performed to develop the risk predictors in myocardial injury to the prognosis of severe and critical COVID-19 patients. RESULTS: Seventy-four COVID-19 patients were included (mean age of 67.2 ± 14.6 years, male of 66.2%), including 42 severe and 32 critical cases. The mortality was 62.2% (n = 46). CK-MB (odds ratio = 5.895, p < .001, 95% confidence interval: 3.097-8.692) and interleukin-6 (odds ratio = 0.379; p = .005; 95% confidence interval: 1.051-1.769) were independent risk factors of increased mechanical ventilation time; myoglobin (odds ratio = 7.710; p = .045; 95% confidence interval: 1.051-56.571) were the independent predictor of incidence of malignant arrhythmia; age (odds ratio = 1.077; p = .009; 95% confidence interval: 1.019-1.139), myoglobin (odds ratio = 9.480; p = .032; 95% confidence interval: 1.211-78.188), and NT-proBNP (odds ratio = 4.852; p = .047; 95% confidence interval: 0.956-24.627) were the independent predictors of mortality. CONCLUSIONS: In severe and critical COVID-19 patients, the obvious myocardial injury was observed. Increases of CK-MB, myoglobin, NT-proBNP, interleukin-6, and age were independently associated with poor prognosis including increased ventilation duration, the incidence of malignant arrhythmia, and mortality.

Feasibility of off-pump coronary artery grafting for patients with impaired left ventricular ejection fraction: A retrospective cohort study from a single institutional database.

OBJECTIVE: Despite substantial advances in surgical practice, the management of patients with impaired left ventricular ejection fraction (LVEF) remains challenging. Furthermore, evidence on the outcomes of off-pump coronary artery bypass (OPCAB) surgery in this population is inconsistent. We conducted the present study to compare the short- and long-term outcomes of OPCAB in patients with different ejection fractions. METHODS: This retrospective cohort study used data from the Hua-Shan Cardiac Surgery and included consecutive patients aged ≥ 18 years who underwent OPCAB procedures during 2016-2019. The patients included in the study were followed up until death or the end of data collection. Patients with different ejection fractions were matched 1:2 using propensity score matching. Factors associated with short-term outcomes were determined using logistic regression, and Kaplan-Meier survival analyses for the differences in all-cause death were generated. RESULTS: The two propensity score matched groups consisted of 40 left ventricular dysfunction (LVD) and 80 normal left ventricular function (NLVF) patients. No significant intergroup differences were observed in the postoperative outcomes for the occurrence of left heart failure (22.5% in LVD vs. 5.0% in NLVF, p = .009). Age (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) but not the preoperative LVEF was shown to be a strong predictor of short-term events in logistic regression analyses. Kaplan-Meier curves displayed similar freedom from all-cause death (p = .119) or cardio-death (p = .092) between groups. CONCLUSION: The immediate postoperative outcomes and long-term outcomes were similar between the groups, indicating that OPCAB is a safe and effective choice for patients with LVD.

Feasibility of radical gastrointestinal tumor resection with simultaneous off-pump coronary artery bypass surgery for patients with severe heart problems: A retrospective cohort study from a single institutional database.

PURPOSE: Clinical treatment of gastrointestinal neoplasms in patients with severe coronary stenosis is difficult, and it remains controversial to perform staged or simultaneous surgeries. The purpose of this study was to retrospectively analyze the feasibility and indications for simultaneous gastrointestinal tumor resection and off-pump coronary artery bypass (OPCAB) graft surgery. METHODS: Data collected from a total of five patients, including three patients with gastric cancer and two patients with colorectal cancer, who underwent simultaneous radical cancer resection and OPCAB between September 2010 and October 2019, were retrospectively analyzed. Among these patients, one had an incomplete colonic obstruction. All patients had severe coronary stenosis, and one experienced acute heart failure before surgery. OPCAB was performed first, followed by the radical cancer resection. RESULTS: All five patients were discharged from hospital without perioperative death, major cardiovascular events or anastomotic leakage. The mean postoperative hospital stay was 9.4 days. One patient experienced slight gastrointestinal bleeding after surgery, which improved with conservative treatment. After a mean follow-up of 39 months, two patients with gastric cancer died from tumor metastasis at 28 months and 37 months, while the remaining three patients did not have tumor recurrence or metastasis. None of the patients experienced myocardial ischemia. CONCLUSION: It is safe and feasible to perform simultaneous OPCAB and gastrointestinal surgeries on the premise of strictly controlling the indications for patients with gastrointestinal tumors complicated with severe coronary artery stenosis.

Loganetin and 5-fluorouracil synergistically inhibit the carcinogenesis of gastric cancer cells via down-regulation of the Wnt/ß-catenin pathway.

Although most gastrointestinal tumours are sensitive to 5-fluorouracil (5FU), drug resistance is commonly occurred after 5FU therapy in gastric cancer (GC). Loganetin is the primary active compound in Cornus officinali. However, the synergetic effects of loganetin and 5FU on GC remain unknown. Here, we investigated the synergetic effects and the underlying mechanism of loganetin and 5FU on proliferation, stem-like properties, migration, and invasion of GC both in vitro and in vivo. We found that loganetin alone inhibited the proliferation, stem-like properties, migration and invasion of GC cells in vitro. Importantly, the loganetin remarkably enhanced the anti-cancer effect of 5FU on GC cells and the Wnt/ß-catenin pathway might be involved in this process. Animal experiments further confirmed the synergistic effects of 5FU and loganetin on inhibiting cell growth and metastasis of GC. These results suggested that loganetin could synergistically increase the effect of 5FU against GC, which sheds light on effective combinational drug strategies for GC treatment.

Gate-tunable high magnetoresistance in monolayer Fe3GeTe2 spin valves.

Ferromagnetic order in two-dimensional (2D) van der Waals crystals has been attracting much attention recently. Remarkably, room temperature metallic ferromagnetism is realized in 2D Fe3GeTe2. Here we design a monolayer (ML) Fe3GeTe2 spin-valve device by attaching two ends to ferromagnetic electrodes and applying a magnetic field to these ferromagnetic electrodes. We investigate the spin-involved transport characteristics of such a spin valve by using ab initio quantum transport simulation. A high magnetoresistance of ∼390% is obtained and significantly increased to 450-510% after the gates are introduced. The magnetoresistance of the ML Fe3GeTe2 spin valve is insensitive to the strain modulation. Our study provides a potential option for magnetic storage applications and will motivate further studies in spintronics based on this class of materials.

First-principles simulation of monolayer hydrogen passivated Bi2O2S2-metal interfaces.

Monolayer (ML) MoS2 is one of the most extensively studied two-dimensional (2D) semiconductors. However, it suffers from low carrier mobility and pervasive Schottky contact with metal electrodes. 2D semiconductor Bi2O2S, a sulfur analogue of 2D Bi2O2Se, has been prepared recently. ML fully hydrogen-passivated Bi2O2S2 (Bi2O2S2H2) posseses a comparable band gap (1.92 eV) with ML MoS2 (1.8 eV), but probably has a better device performance than ML MoS2. Based on the density functional theory, the electron and hole mobilities of ML Bi2O2S2H2 at 300 K are calculated to be 16 447-26 699 and 264-968 cm2 V-1 s-1, respectively. Then we firstly characterize the contact properties of ML half hydrogen-passivated Bi2O2S2 (Bi2O2S2H) with four bulk metal electrodes (Ti, Sc, Pd, and Pt) based on ab initio quantum transport simulation. In the lateral direction, a p-type Schottky contact is found in Pd and Pt electrodes, and the corresponding hole Schottky barrier heights (SBHs) are 0.54 and 0.99 eV, respectively. Remarkably, a coveted n-type Ohmic contact appears in Sc and Ti electrodes. Finally, the current on-off ratio of the ML hydrogen-passivated Bi2O2S2 field effect transistor with a Ti electrode reaches 105. Hence, the good intrinsic properties, contact properties, and large switching ability put ML hydrogen-passivated Bi2O2S2 in the rank of potential channel candidates for post-silicon era field effect transistors.

Overexpression of microRNA-23a-5p induces myocardial infarction by promoting cardiomyocyte apoptosis through inhibited of PI3K/AKT signalling pathway.

Myocardial infarction (MI) leads to cardiac remodelling and heart failure. Cardiomyocyte apoptosis is considered a critical pathological phenomenon accompanying MI, but the pathogenesis mechanism remains to be explored. MicroRNAs (miRs), with the identity of negative regulator of gene expression, exist as an important contributor to apoptosis. During the experiment of this study, MI mice models were successfully established and sequencing data showed that the expression of miR-23a-5p was significantly enhanced during MI progression. Further steps were taken and it showed that apoptosis of cardiac cells weakened as miR-23a-5p was downregulated and on the contrary that apoptosis strengthened with the overexpression of miR-23a-5p. To explore its working mechanisms, bioinformatics analysis was conducted by referring to multi-databases to predict the targets of miR-23a-5p. Further analysis suggested that those downstream genes enriched in several pathways, especially in the PI3K/Akt singling pathway. Furthermore, it demonstrated that miR-23a-5p was negatively related to the phosphorylation of PI3K/Akt, which plays a critical role in triggering cell apoptosis during MI. Recilisib-activated PI3K/Akt singling pathway could restrain apoptosis from inducing miR-23a-5p overexpression, and Miltefosine-blocked PI3K/Akt singling pathway could restrict apoptosis from inhibiting miR-23a-5p reduction. In conclusion, these findings revealed the pivotal role of miR-23a-5p-PI3K/Akt axis in regulating apoptosis during MI, introducing this novel axis as a potential indicator to detect ischemic heart disease and it could be used for therapeutic intervention.

miR-130 aggravates acute myocardial infarction-induced myocardial injury by targeting PPAR-γ.

Cardiac remodeling is a common pathophysiological change associated with acute myocardial infarction (AMI). Recent evidence indicates that microRNAs are strong posttranscriptional regulators which play an important role in regulating the microenvironment of myocardial tissue after AMI. In this study, we sought to explore the potential role and underlying mechanism of miR-130 in AMI. H9c2 cells were cultured under hypoxic conditions to simulate myocardial infarction. The influence of aberrantly expressed miR-130 on H9c2 cells under hypoxia was also estimated with RT-PCR, western blot and enzyme-linked immunosorbent assay. Using bioinformatics methods, of miR-130 target genes were verified with luciferase reporter assay. Then, the effects of miR-130 on AMI were identified in an induced myocardial injury model in rats. The results show that miR-130 downregulation remarkably decreased hypoxia-induced inflammation and fibrosis related protein expression in H9c2 cells and reversed hypoxia-induced peroxisome proliferator-activated receptor γ (PPAR-γ) inhibition. A bifluorescein reporter assay further confirmed that PPAR-γ was a target gene of miR-130. This study verified that PPAR-γ has a cardioprotective effect by inhibiting NFκB-mediated inflammation and TGF-ß1-mediated fibrosis. In vivo experiments confirmed that downregulation of miR-130 expression promotes PPAR-γ-mediated cardioprotective effects by suppressing inflammation and myocardial fibrosis. Taken together, these findings suggest that miR-130 knockdown alleviates infarction-induced myocardial injury by promoting PPAR-γ expression.

Donor heart preservation with a novel long-term and slow-releasing hydrogen sulfide system.

Cardiac transplantation has been limited by the inability to long preserve donor hearts safely. Hydrogen sulfide (H2S) has been recognized as an important gasotransmitter exerting potent cardioprotection from ischemia/reperfusion injury (I/R). Herein we investigated the cardioprotective effects of a novel long-term and slow-releasing H2S system, namely DATS-MSN, in heart preservation solution using a heart transplantation models. The release of H2S from DATS-MSN was slow and continuous in the University of Wisconsin solution (UW), correspondingly, DATS-MSN application demonstrated superior cardioprotective effects over the control and traditional H2S donors after 6 h heart preservation and 1 h reperfusion, associated with greater allograft performance including left ventricular developed pressure (LVDP) and dP/dt max, reduced plasmic CK-MB and troponin I levels, inhibited myocardial inflammation, increased antioxidant enzyme activities, preserved mitochondria structure and function, and decreased cardiomyocyte apoptosis index. Also, DATS-MSN application presented significant superiority in long-term allografts survival and function after 8 weeks of transplantation. In the in vitro experiments, cardiomyocytes injury from hypoxia was found to be relived with the treatment of DATS-MSN by anti-inflammatory effects via TLR4/NLRP3 pathway. The present work provides a long-term releasing H2S donor compatibly applied in the donor heart preservation, and preliminary explores its underlying mechanisms.

Transcatheter aortic valve-in-valve implantation for early failure of sutureless aortic bioprosthesis.

We report a case of early failure of a Perceval sutureless aortic bioprosthesis (LivaNova, London, UK) which was treated with a transcatheter valve-in-valve implantation with an Edwards 3 bioprosthesis (Edwards Lifesciences, Irvine, CA).

No significant enrichment of rare functionally defective CPA1 variants in a large Chinese idiopathic chronic pancreatitis cohort.

Rare functionally defective carboxypeptidase A1 (CPA1) variants have been reported to predispose to nonalcoholic chronic pancreatitis, mainly the idiopathic subtype. However, independent replication has so far been lacking, particularly in Asian cohorts where initial studies employed small sample sizes. Herein we performed targeted next-generation sequencing of the CPA1 gene in 1,112 Han Chinese idiopathic chronic pancreatitis (ICP) patients-the largest ICP cohort so far analyzed in a single population-and 1,580 controls. Sanger sequencing was used to validate called variants, and the CPA1 activity and secretion of all newly found variants were measured. A total of 18 rare CPA1 variants were characterized, 11 of which have not been previously described. However, no significant association was noted with ICP irrespective of whether all rare variants [20 out of 1,112 (1.8%) in patients vs. 24 out of 1,580 (1.52%) in controls; P = 0.57] or functionally impaired variants [three out of 1,112 (0.27%) in patients vs. two out of 1,580 (0.13%) in controls; P = 0.68] were considered.

No Association Between CEL-HYB Hybrid Allele and Chronic Pancreatitis in Asian Populations.

A hybrid allele between the carboxyl ester lipase gene (CEL) and its pseudogene, CELP (called CEL-HYB), generated by nonallelic homologous recombination between CEL intron 10 and CELP intron 10', was found to increase susceptibility to chronic pancreatitis in a case-control study of patients of European ancestry. We attempted to replicate this finding in 3 independent cohorts from China, Japan, and India, but failed to detect the CEL-HYB allele in any of these populations. The CEL-HYB allele might therefore be an ethnic-specific risk factor for chronic pancreatitis. An alternative hybrid allele (CEL-HYB2) was identified in all 3 Asian populations (1.7% combined carrier frequency), but was not associated with chronic pancreatitis.