Predictors of Poor Outcome of Anti-MDA5-Associated Rapidly Progressive Interstitial Lung Disease in a Chinese Cohort with Dermatomyositis

Objective. Antimelanoma differentiation-associated protein 5 (anti-MDA5) autoantibody has been reported in dermatomyositis (DM) to be associated with rapidly progressive interstitial lung disease (RP-ILD). Our study is aimed at determining the clinical characteristics and prognostic factors underpinning anti-MDA5-associated RP-ILD. Methods. Patients with anti-MDA5-associated DM (aMDA5-DM) were identified at the Peking University People’s Hospital. The presence of anti-MDA5 antibody was determined by immunoblotting. Kaplan-Meier, chi-square test, univariate, and multivariate data analyses were used. Results. Out of 213 patients with DM and clinically amyopathic dermatomyositis (CADM), 20.7% (44/213) of patients were identified as aMDA5-DM. Amongst the aMDA5-DM patients, 63.6% (28/44) were identified as having anti-MDA5-associated RP-ILD. During the follow-up, 32.1% (9/28) of patients with anti-MDA5-associated RP-ILD died of respiratory failure. We identified older age and periungual erythema as two independent risk factors for RP-ILD mortality. Age ≥ 57 years at disease onset was significantly associated with poor survival ( P = 0.02 ) in patients with anti-MDA5-associated RP-ILD, while patients with periungual erythema had a better survival rate than those without periungual erythema ( P < 0.05 ). Conclusions. Anti-MDA5-associated RP-ILD is significantly associated with poor survival rates in DM/CADM patients. More effective intervention should be administered to anti-MDA5-associated RP-ILD patients, especially to senior patients and those without periungual erythema.

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Comparison of Clinical Features and Prognostic Factors of Polymyositis/Dermatomyositis Associated Interstitial Lung Disease According to Autoantibodies: Anti-Aminoacyl tRNA Synthetase Antibodies Versus Anti-Melanoma Differentiation-Associated Gene 5 Antibody.

10.21203/rs.3.rs-27714/v1 ◽

2020 ◽

Author(s):

Yujuan Gao ◽

Yan Li ◽

Xin Yan ◽

Miaomiao Xie ◽

Hui Li ◽

...

Keyword(s):

Prognostic Factors ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Clinical Features ◽

Disease Onset ◽

Trna Synthetase ◽

Acute Disease ◽

Chi Square ◽

Kaplan Meier ◽

Drum Tower Hospital

Abstract Objective: The serum myositis-specific autoantibodies has been considered to be relatively specific and be useful for diagnosis of polymyositis/dermatomyositis associated interstitial lung disease (PM/DM-ILD). The goal of our retrospective study was to identify clinical features and prognostic factors for PM/DM-ILD based on serological phenotypes.Methods: PM/DM-ILD patients were diagnosed in the Department of Respiratory Medicine, Nanjing Drum Tower Hospital. MSAs were measured by anti-myositis antibody profile IgG detection kit. Based on the results of MSAs, the patients were divided into three groups: anti-MDA5 group, anti-Jo-1 group and other anti-ARS group. Kaplan-Meier, log rank, Kruskal-Wallis test and chi-square tests were used for analysis.Results: We identified 30 patients (22.0%) with positive anti-MDA5, 42 patients (31.0%) with positive anti-Jo-1 and 64 patients(47.0%) with other anti-ARS. acute disease onset was more frequently observed in the anti-MDA5 group (P = 0.005). The highest mortality rate was in the anti-MDA5 group (66.7%, P < 0.001). The overall survival of patients with anti-Jo-1 was significantly better than that of patients with anti-MDA5 (P < 0.001) and similar to that of patients with other anti-ARS. The acute disease onset (P = 0.002), DAD pattern for HRCT imaging (P < 0.001), current smokers (P = 0.02), presence of Anti-MDA5 (P < 0.001), fever (P < 0.001) were significantly associated with the mortality of the study population. Interestingly, in the subgroup survival analysis for anti-MDA5 group, age was a risk factor for death of patients with anti-MDA5 (P = 0.02), and the treatment with PSL pulse and IVIG were markedly correlated with high mortality (P < 0.001 and P = 0.001, respectively).Conclusion: Anti–MDA5 antibody is significantly associated with associated with worse prognosis in PM/DM-ILD patients. The application of PSL pulse and IVIG are not necessarily an effective treatment for positive anti-MDA5 patients.

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Epidemiology and survival analyses of 333 adult glioma patients from Eastern Algeria (2008-2016)

African Health Sciences ◽

10.4314/ahs.v20i3.29 ◽

2020 ◽

Vol 20 (3) ◽

pp. 1250-1258

Author(s):

Sabrina Touati ◽

Rachid Djekkoun ◽

Mohamed El-Hadef El-Okki ◽

Dalila Satta

Keyword(s):

Cox Model ◽

Survival Rates ◽

University Hospital ◽

Prognosis Factors ◽

Chi Square ◽

Oncological Treatment ◽

Kaplan Meier ◽

Chi Square Test ◽

The Mean ◽

Eastern Algeria

Background: Gliomas are a relatively rare group of tumors with a poor prognosis. We aimed to describe and analyze the clinical characteristics and survival of patients with glioma tumors of Eastern Algeria. Methods: A retrospective study was conducted at the University Hospital of Constantine. Medical records of patients enrolled between January 2008 and October 2016 were consulted. Demographic characteristics, clinical data, treatment strategy and dates of last follow-up or death were collected. Chi-square test was used for checking associations, Kaplan- Meier methodology for estimating the survival, and the cox model for identifying prognosis factors. Results: A total of 333 patients composed our cohort. The mean age was 48.07 years, and men were 1.87 times more frequent than women. High grade tumors were mainly observed among adults and old adults and in supra-tentorial locations. More than half of the patients had a large resection and a curative protocol of oncological treatment (50.7% and 57%, re- spectively). The mean overall survival was 45.4 months, the median was 21.7 months, and survival rates at 1-, 2-, and 5-years were: 62.8%, 48.5% and 32.9% respectively. Age, histology, grade of malignancy and oncological treatment were the major prognosis factors. Conclusion: Our sample was relatively young with a higher survival compared to others. Keywords: Glioma; epidemiology; Algeria.

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AB0458 SURVIVAL OF SCLERODERMA PATIENTS WITH INTERSTITIAL LUNG DISEASE: OBSERVATION DATA FROM A MALAYSIAN TERTIARY CENTRE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3830 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1256.1-1256

Author(s):

J. Raja ◽

S. Muthusamy ◽

C. M. Ng

Keyword(s):

Survival Rate ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Median Survival ◽

Respir Crit ◽

Demographic Data ◽

Disease Onset ◽

Observation Data ◽

Tertiary Centre ◽

Kaplan Meier

Background:Interstitial lung disease (ILD) is the leading cause of death in scleroderma (SSc) with decline in FVC as a predictor of mortality in patients with SSc-ILD, especially in the early course of the disease.Objectives:The aim of this study is to determine the survival rate of SSc-ILD in a Malaysian cohort of patients from University Malaya Medical Centre (UMMC).Methods:61 patients clinically diagnosed with SSc-ILD were identified and prospectively recruited. Baseline demographic data were collected. Kaplan-Meier analysis was used to estimate the survival.Results:Females were predominant (56, 91.8%). 39 (64%) had limited cutaneous SSc. Majority were ethnicity Chinese 30 (49.2%), followed by Malays 20 (32.8%), Indians 7 (11.4%) and others 4 (6.6%). Mean age was 56.25 (SD ± 12.5) years while mean duration of disease (non-Raynaud’s disease onset) was 10.5 years (SD ± 9.2) (range of 1 year to 44 years) years. 29 (47.5%) patients were positive for anti-ScL-70, whereas 6 (9.8%) patients were anti-centromere positive. There were 16 (26.2%) deaths. Median survival was 24 years. Patients had a sharper drop in survival probability for the first 10 years compared to the next 20 years (Figure 1). Median survival in limited subset was 24 years whereas in diffuse subset was 11 years. Patients from the limited subset appeared to have higher chance of surviving for 10 years and above, compared to those in the diffuse subset (Figure 2).Conclusion:The results demonstrate the poor survival in SSc-ILD patients. The survival rate tends to be worse in the first 10 years of SSc disease duration. Survival rate was poorer in patients with diffuse cutaneous subset.References:[1]Parelas A et al. Lancet Resp Med 2020[2]Goh NS et al. Am J Respir Crit Care Med 2008Disclosure of Interests:JASMIN RAJA Speakers bureau: For Boehringer Ingelheim for topic on Scleroderma-ILD, Grant/research support from: From Boehringer Ingelheim for scleroderma research, Shantini Muthusamy: None declared., CHOUNG MIN NG: None declared.

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Abnormal platelet count correlates with poor survival in hepatocellular carcinoma

Infection International ◽

10.1515/ii-2017-0160 ◽

2018 ◽

Vol 6 (3) ◽

pp. 93-102

Author(s):

Lei Gu ◽

Wen Wen ◽

ZhiXian Wu ◽

Kai Bai ◽

Wei Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Resection ◽

Vital Role ◽

Poor Survival ◽

Chi Square ◽

Normal Platelet ◽

Kaplan Meier ◽

Chi Square Test ◽

Prognostic Importance ◽

Automated Hematology Analyzer

AbstractBackgroundNormal platelet (PLT) plays a vital role in thrombosis, the inflammatory response, and liver regeneration. The effect of abnormal PLT counts has been seldom explored in hepatocellular carcinoma (HCC); hence, this investigation was conducted to evaluate the prognostic importance of preoperative abnormal PLT count in HCC patients after liver resection retrospectively.MethodologyThe PLT counts were determined using Sysmex XT-1800i automated hematology analyzer and its matching reagents. Patients were divided into two groups: a normal PLT group and an abnormal PLT group. Chi-square test, Kaplan–Meier method, and Cox univariable and multivariable regressions were utilized to analyze the data.ResultsA total of 391 HCC patients who underwent liver resection were included in this study. The overall survival (OS) rates were 59% and 31%, and the median survival time was 69 months and 31 months in the normal and abnormal PLT groups, respectively. The PLT level was associated with OS in univariate and multivariate analyses (hazard ratio [HR], 1.991 [95% confidence interval {CI}, 1.412–2.808] and HR, 2.217 [95% CI, 1.556–3.159], respectively).ConclusionsPatients with normal PLT had a better outcome in terms of OS. The results suggested that abnormal PLT count is an independent prognostic factor for HCC patients after liver resection.

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Estimates of epidemiology, mortality and disease burden associated with progressive fibrosing interstitial lung disease in France (the PROGRESS study)

Respiratory Research ◽

10.1186/s12931-021-01749-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Mouhamad Nasser ◽

Sophie Larrieu ◽

Loic Boussel ◽

Salim Si-Mohamed ◽

Fabienne Bazin ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Healthcare Resource ◽

Pulmonary Function Tests ◽

Healthcare Services ◽

Resource Utilisation ◽

High Resolution Computed Tomography ◽

Healthcare Database ◽

Healthcare Resource Utilisation ◽

Kaplan Meier

Abstract Background There is a paucity of data on the epidemiology, survival estimates and healthcare resource utilisation and associated costs of patients with progressive fibrosing interstitial lung disease (PF-ILD) in France. An algorithm for extracting claims data was developed to indirectly identify and describe patients with PF-ILD in the French national administrative healthcare database. Methods The French healthcare database, the Système National des Données de Santé (SNDS), includes data related to ambulatory care, hospitalisations and death for 98.8% of the population. In this study, algorithms based on age, diagnosis and healthcare consumption were created to identify adult patients with PF-ILD other than idiopathic pulmonary fibrosis between 2010 and 2017. Incidence, prevalence, survival estimates, clinical features and healthcare resource usage and costs were described among patients with PF-ILD. Results We identified a total of 14,413 patients with PF-ILD. Almost half of them (48.1%) were female and the mean (± standard deviation) age was 68.4 (± 15.0) years. Between 2010 and 2017, the estimated incidence of PF-ILD ranged from 4.0 to 4.7/100,000 person-years and the estimated prevalence from 6.6 to 19.4/100,000 persons. The main diagnostic categories represented were exposure-related ILD other than hypersensitivity pneumonitis (n = 3486; 24.2%), idiopathic interstitial pneumonia (n = 3113; 21.6%) and rheumatoid arthritis-associated ILD (n = 2521; 17.5%). Median overall survival using Kaplan–Meier estimation was 3.7 years from the start of progression. During the study, 95.2% of patients had ≥ 1 hospitalisation for respiratory care and 34.3% were hospitalised in an intensive care unit. The median (interquartile range) total specific cost per patient during the follow-up period was €25,613 (10,622–54,287) and the median annual cost per patient was €18,362 (6856–52,026), of which €11,784 (3003–42,097) was related to hospitalisations. Limitations included the retrospective design and identification of cases through an algorithm in the absence of chest high-resolution computed tomography scans and pulmonary function tests. Conclusions This large, real-world, longitudinal study provides important insights into the characteristics, epidemiology and healthcare resource utilisation and costs associated with PF-ILD in France using a comprehensive and exhaustive database, and provides vital evidence that PF-ILD represents a high burden on both patients and healthcare services. Trial registration ClinicalTrials.gov, NCT03858842. ISRCTN, ISRCTN12345678. Registered 3 January 2019—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03858842

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The myositis clinical phenotype associated with anti-Zo autoantibodies: a case series of nine UK patients

Rheumatology ◽

10.1093/rheumatology/kez504 ◽

2019 ◽

Vol 59 (7) ◽

pp. 1626-1631 ◽

Cited By ~ 1

Author(s):

Sarah L Tansley ◽

Zoe Betteridge ◽

Hui Lu ◽

Emma Davies ◽

Simon Rothwell ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Interstitial Pneumonia ◽

Clinical Phenotype ◽

Disease Onset ◽

Usual Interstitial Pneumonia ◽

Trna Synthetase ◽

Muscle Disease ◽

Ancestral Haplotype ◽

Common Finding

Abstract Objectives It has been over 10 years since the first report of autoantibodies directed against phenylalanyl tRNA synthetase (anti-Zo) in a patient with features of the anti-synthetase syndrome. In that time no further cases have been published. Here we aim to characterize more fully the clinical phenotype of anti-Zo–associated myositis by describing the clinical features of nine patients. Methods Anti-Zo was identified by protein-immunoprecipitation in patients referred for extended spectrum myositis autoantibody testing at our laboratory. Results were confirmed by immunodepletion using a reference serum. Medical records were retrospectively reviewed to provide detailed information of the associated clinical phenotype for all identified patients. Where possible, HLA genotype was imputed using Illumina protocols. Results Nine patients with anti-Zo were identified. The median age at disease onset was 51 years, and six patients were female. Seven patients had evidence of inflammatory muscle disease, seven of interstitial lung disease and six of arthritis. The reported pattern of interstitial lung disease varied with usual interstitial pneumonia, non-specific interstitial pneumonia and organizing pneumonia all described. Other features of the anti-synthetase syndrome such as RP and mechanics hands were common. HLA data was available for three patients, all of whom had at least one copy of the HLA 8.1 ancestral haplotype. Conclusion Patients with anti-Zo presenting with features of the anti-synthetase syndrome and interstitial lung disease is a common finding. Like other myositis autoantibodies, there is likely to be a genetic association with the HLA 8.1 ancestral haplotype.

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Evaluation of poor prognostic factors of respiratory related death in microscopic polyangiitis complicated by interstitial lung disease

Scientific Reports ◽

10.1038/s41598-021-81311-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shogo Matsuda ◽

Takuya Kotani ◽

Takayasu Suzuka ◽

Takao Kiboshi ◽

Keisuke Fukui ◽

...

Keyword(s):

Prognostic Factors ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Clinical Laboratory ◽

Microscopic Polyangiitis ◽

Survival Rates ◽

Lower Lobe ◽

Left Lower Lobe ◽

Fibrosis Score ◽

High Resolution Computed Tomography

AbstractThe prognosis of microscopic polyangiitis (MPA) with interstitial lung disease (ILD) is significantly worse than that of MPA without ILD. However, the clinical characteristics in MPA-ILD, especially poor prognostic factors, are not elucidated. We evaluated demographic, clinical, laboratory, and radiological findings, treatments, and outcomes of 80 patients with MPA, and investigated prognostic factors of respiratory-related death in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) positive MPA-ILD. Ground-glass opacity and fibrosis were evaluated as scores on high-resolution computed tomography (HRCT). The presence of ILD was consistent with a high risk of respiratory-related death (hazard ratio, 4.8; P = 0.04). Multivariable logistic regression analyses using propensity scoring showed right or left lower lobe fibrosis score to be significantly associated with respiratory-related death (P = 0.0005 and 0.0045, respectively). A right or left lower lobe fibrosis score ≥ 2, indicating the presence of honeycombing at 1 cm above the diaphragm, was determined to be the best cut-off value indicating a poor prognosis. The 5-year survival rate was significantly lower in patients with right or left lower lobe fibrosis score ≥ 2 (survival rates: 37% and 19%, respectively) than those with a score < 2 (71% and 68%, respectively) (P = 0.002 and 0.0007, respectively). These findings suggest that the presence of honeycomb lesions in bilateral lower lobes on chest HRCT was associated with respiratory-related death in patients with MPO-ANCA positive MPA-ILD.

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Abstract 1805: Chromosome 9p21.3 Genetic Variation is Associated with Angiographic CAD but not with CAD Disease Burden

Circulation ◽

10.1161/circ.118.suppl_18.s_389-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Chrissa P Mower ◽

Jeffrey L Anderson ◽

Benjamin D Horne ◽

James J Park ◽

Jesse L Coleman ◽

...

Keyword(s):

Genetic Variation ◽

Disease Burden ◽

Disease Onset ◽

Cardiac Risk ◽

Wild Type ◽

Chi Square ◽

High Risk Disease ◽

Chi Square Test ◽

Male Frequency ◽

Cad Risk

Genetic variation at the 9p21.3 locus rs2383206 is associated with coronary heart disease (CHD) phenotypes. In a comparison of patients with and without angiographically confirmed CHD, the G allele of rs2383206 was present more frequently in diseased vs controls (normal angiograms). However, the pathophysiologic impact, whether it affects initiation, severity, or triggers an event, of the 9p21.3 locus remains unknown. We sought to determine whether 9p21.3 variation affects disease severity (promotion) by assessing its association with CAD burden. Methods: Genotyping for rs2383206 using 5′exonuclease chemistry (Taqman) was performed on 1759 subjects. Subjects were grouped as homozygous wild-type (low risk), heterozygous (intermediate risk) or homozygous risk-associated genotype (high risk). Disease burden was assessed by 1, 2, or 3 vessels; ≥70% stenosis and the validated Duke CAD Index (DCI). Comparison used a chi-square test (single vs multivessel disease) and analysis of variance (ANOVA) for the DCI comparison. Results: Average age 51.1± 7.4 years, 64.0% male. Frequency of the CAD risk allele did not differ among groups with 1, 2, or 3 vessel disease. There was no difference among groups with respect to the DCI. After adjustment for standard cardiac risk factors, the rs2383206 genotype was associated with CAD compared to controls (OR (CI)=1.73(1.26–1.85), p=0.001). Conclusion: The rs2383206 polymorphism was not associated with CAD disease burden. Findings suggest the rs2383206 polymorphism, although associated with disease onset is not likely involved in its progression. These findings will aid in refining the application of 9p21.3 for risk assessment and developing novel preventive and therapeutic strategies.

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Treatment of Pulmonary Hypertension in Patients with Connective Tissue Disease and Interstitial Lung Disease

Canadian Respiratory Journal ◽

10.1155/2010/686098 ◽

2010 ◽

Vol 17 (6) ◽

pp. 282-286 ◽

Cited By ~ 13

Author(s):

Shikha Mittoo ◽

Thomas Jacob ◽

Andrea Craig ◽

Zoheir Bshouty

Keyword(s):

Pulmonary Hypertension ◽

Interstitial Lung Disease ◽

Connective Tissue ◽

Lung Disease ◽

Connective Tissue Disease ◽

Term Treatment ◽

Kaplan Meier ◽

Long Term Treatment ◽

Survival Differences

BACKGROUND: Pulmonary hypertension (PH) in patients with connective tissue disease (CTD) can occur in isolation or concomitantly with interstitial lung disease (ILD). Targeted therapies for PH can mitigate clinical deterioration in CTD patients with isolated PH; however, the effect of these therapies in CTD patients with PH and ILD (CTD-PH-ILD) are poorly characterized.OBJECTIVE: To investigate outcomes following long-term treatment of PH in patients with CTD-PH-ILD.METHODS: A retrospective evaluation of 13 CTD-PH-ILD patients who were treated with bosentan, sildenafil or bosentan plus sildenafil, was conducted. Immunosuppressants were prescribed as indicated. Patients underwent pulmonary function testing and assessment of 6 min walk distance at the time of treatment initiation and during follow-up. Patients were followed until time of death, lung transplantation or the end of the study. Kaplan-Meier estimates of survival were calculated and log-rank testing was used to analyze survival differences according to CTD subtype.RESULTS: Thirteen patients (seven with systemic sclerosis [SSc], four with overlap syndrome, and two with rheumatoid arthritis) were followed for a mean (± SD) duration of 33.8±21.7 months. The survival estimate at a median duration of 34 months was 85%; two patients with SSc died. Mortality rates were greater among patients with SSc versus other CTD subtypes (P=0.04). No changes from baseline to follow-up in mean forced vital capacity or exercise capacity, and no treatment-related toxicity, were observed.CONCLUSION: Treatment using PH-specific therapies in patients with CTD, PH and ILD was well tolerated. Further studies to investigate the efficacy of PH-specific therapies in CTD-PH-ILD patients are warranted.

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The role of phosphoprotein phosphatases catalytic subunit genes in pancreatic cancer

Bioscience Reports ◽

10.1042/bsr20203282 ◽

2021 ◽

Vol 41 (1) ◽

Author(s):

Junjie Hang ◽

Steven Yuk-Fai Lau ◽

Ruohan Yin ◽

Lina Zhu ◽

Siyuan Zhou ◽

...

Keyword(s):

Pancreatic Cancer ◽

Prognostic Value ◽

Chi Square ◽

Catalytic Subunits ◽

Beneficial Effects ◽

Phosphoprotein Phosphatases ◽

Kaplan Meier ◽

Chi Square Test ◽

Independent Cohort

Abstract Compelling evidence suggests that phosphoprotein phosphatases (PPPs) are involved in a large spectrum of physiological and pathological processes, but little is known about their roles in pancreatic cancer. We investigated the expression level, prognostic value, and potential function of PPPs with data from Oncomine, GEPIA, THPA, and TCGA databases and an independent cohort of patients with pancreatic cancer. Among all the PPP catalytic subunits (PPPcs), the transcription levels of PPP1CA, PPP1CB, PPP3CA, PPP3CB, and PPP4C were higher in pancreatic cancer than in normal pancreas (P<0.01, fold change > 2). Kaplan–Meier analysis showed that high transcription levels of PPP1CA, PPP1CB, PPP2CA, PPP2CB, PPP3CA, and PPP4C correlated with poorer survival. In contrast, patients with high levels of PPP3CB, PPP3CC, PPP5C, PPP6C, and PPEF2 had much better prognoses. Data from THPA and patients with pancreatic cancer enrolled in our hospital also confirmed the prognostic value of PPP1CA, PPP1CB, PPP2CA, PPP2CB, PPP3CA, PPP3CB, and PPP6C at the protein level. In addition, the Pearson Chi-square test showed that PPP3CB level was significantly correlated with T and N stages. GO and KEGG analyses showed that the genes and pathways related to the pathogenesis and progression of pancreatic cancer were greatly affected by alterations in PPPcs. Results of the present study suggest that PPP1CA, PPP1CB, PPP2CA, PPP2CB, and PPP3CA have deleterious effects but PPP3CB, PPP5C, and PPP6C have beneficial effects on pancreatic cancer.

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