TCRαß/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis.

ABSTRACT: TCRαß/CD19 cell depletion is a promising graft manipulation technique frequently used in the context of human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (HSCT). We previously reported the results of a phase I-II clinical trial (NCT01810120) to assess the safety and the efficacy of this type of exvivo T-cell depletion in 80 children with acute leukemia, showing promising survival outcomes. We now report an updated analysis on a cohort of 213 children with a longer follow-up (median, 47.6 months for surviving patients). With a 5-year cumulative incidence of nonrelapse mortality of 5.2% (95% confidence interval [CI], 2.8%-8.8%) and a cumulative incidence of relapse of 22.7% (95% CI, 16.9%-29.2%), projected 10-year overall and disease-free survival (DFS) were 75.4% (95% CI, 68.6%-80.9%) and 71.6% (95% CI, 64.4%-77.6%), respectively. Cumulative incidence of both grade II-IV acute and chronic graft-versus-host disease were low (14.7% and 8.1%, respectively). In a multivariable analysis for DFS including type of disease, use of total body irradiation in the conditioning regimen (hazard ratio [HR], 0.5; 95% CI, 0.26-0.98; P = .04), disease status at HSCT (complete remission [CR] ≥3 vs CR 1/2; HR, 2.23; 95% CI, 1.20-4.16; P = .01), and high levels of pre-HSCT minimal residual disease (HR, 2.09; 95% CI, 1.01-4.33; P = .04) were independently associated with outcome. In summary, besides confirming the good outcome results already reported (which are almost superimposable on those of transplant from HLA-matched donors), this clinical update allows the identification of patients at higher risk of treatment failure for whom personalized approaches, aimed at reducing the risk of relapse, are warranted.

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis.

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly(ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, with an IBD patient cohort as well as two mouse colitis models, that is, IBD-mimicking oral dextran sulfate sodium (DSS) exposure and oral Salmonella infection. Parp14 was expressed in the human colon by cells in the lamina propria, but, in particular, by the epithelial cells with a granular staining pattern in the cytosol. The same expression pattern was evidenced in both mouse models. Parp14-deficiency caused increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss, and immune cell infiltration in DSS-exposed mice. The absence of Parp14 did not affect the mouse colon bacterial microbiota. Also, the colon leukocyte populations of Parp14-deficient mice were normal. In contrast, bulk tissue RNA-Seq demonstrated that the colon transcriptomes of Parp14-deficient mice were dominated by abnormalities in inflammation and infection responses both prior and after the DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

Impact of an exercise-based cardiac rehabilitation program on cardiopulmonary test parameters.

INTRODUCTION: The exercise-based cardiac rehabilitation program (CRP) represent a multidisciplinary therapeutic approach tailored to improving cardiorespiratory fitness and overall health-related quality of life, while reducing cardiovascular hospitalizations and mortality. Our aim is to determine changes in exercise capacity and cardiac events according to the left ventricular ejection fraction (LVEF) following a CRP. METHODS: This single-center cohort study of 131 patients who completed a center-based CRP from 2015 to 2022. Cardiopulmonary exercise testing (CPET), transthoracic echocardiography, and laboratory analysis were conducted before and after program completion. RESULTS: Of 232 enrolled patients, 131 were included in our cohort analysis, with 36.6% having a reduced LVEF. These patients exhibited higher rates of atrial fibrillation (p=0.019) and NT-proBNP values (p<0.001). Patients with reduced LVEF had lower peak VO2 (p=0.046), ppVO2 (p<0.001) and VO2 at anaerobic threshold (p=0.015) during baseline CPET. Completion of the CRP lead to comparable improvements in exercise performance between groups, assessed through Δ pVO2 (p=0.990), Δ ppVO2 (p=0.610), and Δ VE/VCO2 slope (p=0.200). In the study population, male gender and hypertension independently predicted variation in VE/VCO2 slope (p=0.017) and oxygen uptake efficiency slope (p=0.048), respectively, post-CRP. During follow-up, 9.2% of all patients had hospital admissions for cardiac events, and 3.8% died, with no group differences. CONCLUSION: Patients with reduced LVEF admitted to our CRP showed lower functional status based on specific CPET parameters. After CRP, both reduced and preserved LVEF groups experienced similar functional improvements. Therefore, strategies to increase participation of patients with reduced LVEF in such programs are warranted.

Human leukocyte antigen evolutionary divergence influences outcomes of paediatric patients and young adults affected by malignant disorders given allogeneic haematopoietic stem cell transplantation from unrelated donors.

High genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9-10/10 HLA-matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, using the locus median to stratify patients with 'high' or 'low' HED. Patients with high HED-B and -DRB1 showed significantly improved disease-free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED-B + -DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non-relapse-mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED-B + -DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA-DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice.

Association between metabolic syndrome components and gingival bleeding is women-specific: a nested cross-sectional study.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of atherosclerotic risk factors that increases cardiovascular risk. MetS has been associated with periodontitis, but the contribution of single MetS components and any possible sexual dimorphism in this relation remain undetermined. METHODS: Using the third National Health and Nutrition Examination Survey (NHANES III), we performed a nested cross-sectional study to test whether individuals aged > 30 years undergoing periodontal evaluation (population) exposed to ≥ 1 MetS component (exposure) were at increased risk of bleeding/non-bleeding periodontal diseases (outcome) compared to nonexposed individuals, propensity score matched for sex, age, race/ethnicity, and income (controls). The association between MetS components combinations and periodontal diseases was explored overall and across subgroups by sex and smoking. Periodontal health status prediction based on MetS components was assessed. RESULTS: In total, 2258 individuals (n. 1129/group) with nested clinical-demographic features were analyzed. Exposure was associated with gingival bleeding (+ 18% risk for every unitary increase in MetS components, and triple risk when all five were combined), but not with stable periodontitis; the association was specific for women, but not for men, irrespective of smoking. The only MetS feature with significant association in men was high BP with periodontitis. CRP levels significantly increased from health to disease only among exposed women. MetS components did not substantially improve the prediction of bleeding/non-bleeding periodontal disease. CONCLUSION: The observed women-specific association of gingival bleeding with single and combined MetS components advances gender and precision periodontology. Further research is needed to validate and expand these findings.

Hypertension and periodontitis: A joint report by the Italian society of hypertension (SIIA) and the Italian society of periodontology and implantology (SIdP).

An accumulating body of evidence supports an independent association between high blood pressure (BP) and periodontitis, possibly mediated by low-grade inflammation. This joint report by the Italian Society of Hypertension (SIIA) and the Italian Society of Periodontology and Implantology (SIdP) working group on Hypertension and Periodontitis (Hy-Per Group) provides a review of the evidence on this topic encompassing epidemiology, biological plausibility, relevance, magnitude, and treatment management. Consensus recommendations are provided for health professionals on how to manage BP in individuals showing signs of poor oral health. In summary, (1) large epidemiological studies highlight that individuals with periodontal diseases have increased risk for high/uncontrolled BP independent of confounders; (2) mechanistically, low-grade inflammation might have a causal role in the association; (3) BP profile and control might benefit from periodontal treatment in pre-hypertensive and hypertensive individuals; (4) oral health status should be evaluated as a potential risk factor for high/uncontrolled BP, and effective oral care should be included as an adjunct lifestyle measure during hypertension management. Further research is needed to optimize BP management in individuals with poor oral health.

Human METTL18 is a histidine-specific methyltransferase that targets RPL3 and affects ribosome biogenesis and function.

Protein methylation occurs primarily on lysine and arginine, but also on some other residues, such as histidine. METTL18 is the last uncharacterized member of a group of human methyltransferases (MTases) that mainly exert lysine methylation, and here we set out to elucidate its function. We found METTL18 to be a nuclear protein that contains a functional nuclear localization signal and accumulates in nucleoli. Recombinant METTL18 methylated a single protein in nuclear extracts and in isolated ribosomes from METTL18 knockout (KO) cells, identified as 60S ribosomal protein L3 (RPL3). We also performed an RPL3 interactomics screen and identified METTL18 as the most significantly enriched MTase. We found that His-245 in RPL3 carries a 3-methylhistidine (3MH; τ-methylhistidine) modification, which was absent in METTL18 KO cells. In addition, both recombinant and endogenous METTL18 were found to be automethylated at His-154, thus further corroborating METTL18 as a histidine-specific MTase. Finally, METTL18 KO cells displayed altered pre-rRNA processing, decreased polysome formation and codon-specific changes in mRNA translation, indicating that METTL18-mediated methylation of RPL3 is important for optimal ribosome biogenesis and function. In conclusion, we have here established METTL18 as the second human histidine-specific protein MTase, and demonstrated its functional relevance.

Home oral hygiene is associated with blood pressure profiles: Results of a nationwide survey in Italian pharmacies.

AIM: Periodontal diseases are associated with cardiovascular risk factors/diseases, and whether home oral hygiene practices are inversely related to the same conditions could carry relevant practical implications. We investigated the association of home oral hygiene habits with hypertension. MATERIALS AND METHODS: During World Hypertension Day 2020, a nationwide cross-sectional survey was conducted on volunteers ≥18 years at 733 Italian pharmacies. Participants underwent standardized blood pressure (BP) measurement and answered a questionnaire on cardiovascular risk factors, oral health status, and home oral hygiene habits (toothbrushing daily frequency and manual/electric toothbrush). The association between home oral care habits and BP was assessed using multivariate logistic regression. Interactions between exposures and outcome were formally tested. RESULTS: Among the 4506 participants (44.8% males, 66.1 ± 37.8 years), 47.6% reported brushing ≥3 times/day and 23.4% declared using the electric toothbrush. Brushing ≥3 versus <3 times/day and use of electric versus manual toothbrush were associated with 19% (odds ratio [OR]: 0.81, 95% confidence interval [CI] 0.70-0.94) and 28% (OR: 0.72, 95% CI 0.61-0.85) lower odds of hypertension, respectively. No significant additive interaction was observed in the association of exposures with the outcome. CONCLUSIONS: Regular daily brushing and electric toothbrushing are associated with a better BP profile in a real-world context. Future interdisciplinary research is warranted to test these findings.

The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA.

RNA methylations are essential both for RNA structure and function, and are introduced by a number of distinct methyltransferases (MTases). In recent years, N6-methyladenosine (m6A) modification of eukaryotic mRNA has been subject to intense studies, and it has been demonstrated that m6A is a reversible modification that regulates several aspects of mRNA function. However, m6A is also found in other RNAs, such as mammalian 18S and 28S ribosomal RNAs (rRNAs), but the responsible MTases have remained elusive. 28S rRNA carries a single m6A modification, found at position A4220 (alternatively referred to as A4190) within a stem-loop structure, and here we show that the MTase ZCCHC4 is the enzyme responsible for introducing this modification. Accordingly, we found that ZCCHC4 localises to nucleoli, the site of ribosome assembly, and that proteins involved in RNA metabolism are overrepresented in the ZCCHC4 interactome. Interestingly, the absence of m6A4220 perturbs codon-specific translation dynamics and shifts gene expression at the translational level. In summary, we establish ZCCHC4 as the enzyme responsible for m6A modification of human 28S rRNA, and demonstrate its functional significance in mRNA translation.

Iron deficiency in heart failure: diagnosis and clinical implications.

Iron deficiency is a widely prevalent finding in patients with heart failure, observed on average in 50% of outpatients and up to 80% of acute patients, regardless of the ejection fraction and the presence of anaemia, being an independent predictor of worst functional capacity and reduced survival. The definition of iron deficiency in heart failure considers the state of chronic inflammation that characterizes the pathology, recognizing a discriminating role for transferrin saturation. The studies conducted so far, which focused on the patient with heart failure with at least moderately reduced ejection fraction, have shown clinical benefit with intravenous supplementation of ferric carboxymaltose in terms of functional capacity, quality of life, laboratory markers of disease and inflammation, and possible reduction of re-hospitalizations, but not in terms of mortality. Based on this evidence, guidelines recommend intravenous ferric carboxymaltose in decompensated and iron-deficient patients, while research is at work to investigate the clinical impact of supplementation in contexts not yet examined, such as that of decompensation in patients with heart failure and preserved ejection fraction.

Multiregional assessment of CIMP in primary colorectal cancers: Phenotype concordance but marker variability.

Intratumor heterogeneity of colorectal cancers (CRCs) is manifested both at the genomic and epigenomic levels. Early genetic aberrations in carcinogenesis are clonal and present throughout the tumors, but less is known about the heterogeneity of the epigenetic CpG island methylator phenotype (CIMP). CIMP characterizes a subgroup of CRCs thought to originate from specific precursor lesions, and it is defined by widespread DNA methylation within promoter regions. In this work, we investigated CIMP in two to four multiregional samples from 30 primary tumors (n = 86 samples) using the consensus Weisenberger gene panel (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1). Twenty-nine of 30 tumors (97%) showed concordant CIMP status in all samples, and percent methylated reference (PMR) values of all five markers had higher intertumor than intratumor variation (P value = 1.5e-09). However, a third of the CIMP+ tumors exhibited discrepancies in methylation status in at least one of the five gene markers. To conclude, CIMP status was consistent within primary CRCs, and it is likely a clonal phenotype. However, spatial discordances of the individual genes suggest that large-scale analysis of multiregional samples could be of interest for identifying CIMP markers that are robust to intratumor heterogeneity.

Periodontal therapy and treatment of hypertension-alternative to the pharmacological approach. A systematic review and meta-analysis.

AIM: Quantitative comparison of the effects of intensive (IPT) or conventional (CPT) periodontal treatment on arterial blood pressure, endothelial function and inflammatory/metabolic biomarkers. MATERIALS AND METHODS: A systematic search was conducted to identify randomized controlled trials (RCT) of IPT (supra and subgingival instrumentation). Eight RCTs were included in the meta-analysis. Difference in change of systolic blood pressure (SBP) and diastolic blood pressure (DBP) before and after IPT or CPT were the primary outcomes. The secondary outcomes included: endothelial function and selected inflammatory/anti-inflammatory (CRP, IL-6, IL-10, IFN-γ) and metabolic biomarkers (HDL, LDL, TGs). RESULTS: The overall effect estimates (pooled Weighted Mean Difference (WMD)) of the primary outcome for SBP and DBP was -4.3 mmHg [95%CI: -9.10-0.48], p = 0.08 and -3.16 mmHg [95%CI: -6.51-0.19], p = 0.06 respectively. These studies were characterized by high heterogeneity. Therefore, random effects model for meta-analysis was performed. Sub-group analyses confirmed statistically significant reduction in SBP [WMD = -11.41 mmHg (95%CI: -13.66, -9.15) P < 0.00001] and DBP [WMD = -8.43 mmHg (95%CI: -10.96,-5.91)P < 0.00001] after IPT vs CPT among prehypertensive/hypertensive patients, while this was not observed in normotensive individuals. The meta-analyses showed significant reductions in CRP and improvement of endothelial function following IPT at all analysed timepoints. CONCLUSIONS: IPT leads to improvement of the cardiovascular health in hypertensive and prehypertensive individuals.

Acute effects of exercise on cardiac autonomic function and arterial stiffness in patients with stable coronary artery disease.

Objectives. To examine the acute effect of a maximal aerobic exercise effort on aortic, peripheral arterial stiffness and cardiovagal modulation of trained and untrained patients with coronary artery disease (CAD). Design. Cross-sectional study. Methods. Eighteen untrained patients with CAD, 18 trained patients with CAD, and 18 apparently healthy trained subjects were sampled and matched for age and body mass index. Aortic and peripheral stiffness were measured by applanation tonometry estimates of carotid-femoral (cfPWV), carotid-radial (crPWV), and carotid-dorsalis pedis pulse wave velocity (cdPWV), respectively. Cardiovagal modulation was assessed by heart-rate variability (HRV) indices including the standard deviation of normal-to-normal RR intervals (SDNN), root-mean-square of successive differences (RMSSD), and the high-frequency power band (HF). cfPWV, crPWV, cdPWV, and HRV indices were measured at rest, 10 and 30 min following a maximal cardiopulmonary exercise test on a cycle ergometer. Results. No differences were observed between groups at rest nor over time in indices of HRV, cfPWV and cdPWV. Still, main effects of time were observed in cfPWV (p < .001; ɳ2 = 0.313) and cdPWV (p = .003, ɳ2 = 0.111), RMSSD (p < .001, ɳ2 = 0.352), HF (p < .001, ɳ2 = 0.265) and LF/HF (p = .001, ɳ2 = 0.239), as cdPWV, RMSSD, and HF were reduced 10 min following exercise, whereas cfPWV and LF/HF were increased. Changes in cPP were associated with changes in HRV from rest to min 10 (HF, r = 0.302), and to min 30 (HF, r = 0.377; SDNN, r = 0.357; RMSSD, r = 0.429). Conclusion. Training level and CAD do not seem to influence arterial stiffness and cardiac autonomic responses to maximal exercise.

Recurrent pericarditis is less scary: the new therapeutic solutions.

Pericarditis is a common inflammatory disease affecting the pericardial sac, resulting from a variety of stimuli that trigger a stereotyped immune response. Generally self-limiting, this condition can be burdened by a significant risk of acute complications and relapses, with recurrence rates affecting up to 30% of patients, especially in the case of diagnostic and therapeutic delay. Therapeutic options in recurrent forms, initially based only on the use of traditional drugs such as colchicine, non-steroidal anti-inflammatory drugs, and corticosteroids, have recently been enriched with new molecules, such as interleukin 1 blockers anakinra and rilonacept, particularly indicated in refractory forms dependent on corticosteroids. Other medically relevant therapeutic possibilities in refractory disease include azathioprine, methotrexate, and intravenous immunoglobulins. This brief review aims to summarize the treatment strategies of recurrent pericarditis in light of the most up-to-date evidence and recommendations.

The effects of 12-months supervised periodized training on health-related physical fitness in coronary artery disease: a randomized controlled trial.

We compared the impact of a one-year periodized exercise training versus a non-periodized exercise training on health-related physical fitness (HRPF) including body composition, cardiorespiratory and muscular fitness in patients with coronary artery disease (CAD). Fifty CAD patients (60.4 ± 9.9 years) were randomized to either a periodized training group (PG) (n = 25) or a non-periodized training group (NPG) (n = 25). Both consisted of a combined training programme, performed 3 days/week for 12 months. Thirty-six CAD patients (PG: n = 18, NPG: n = 18) successfully completed the exercise regimes. In both groups, a favourable main effect for time was evident for peak VO2, peak workload, anaerobic threshold and respiratory compensation point workloads and VO2, whole body skeletal muscle mass and quality index at 12 months.In conclusion, a periodized model is as effective as a non-periodized model in promoting increases in HRPF outcomes following a one-year intervention. These findings indicate that health-professionals can add variation to cardiac rehabilitation workouts without compromising effectiveness.

Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman-Diamond Syndrome Subjects.

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from SDS patients (SDS-OBs), we show that SDS-OBs displayed reduced SBDS gene expression and reduced/undetectable SBDS protein compared to osteoblasts from healthy subjects (H-OBs). SDS-OBs cultured in an osteogenic medium displayed a lower mineralization capacity compared to H-OBs. Whole transcriptome analysis showed significant differences in the gene expression of SDS-OBs vs. H-OBs, particularly in the ossification pathway. SDS-OBs expressed lower levels of the main genes responsible for osteoblastogenesis. Of all downregulated genes, Western blot analyses confirmed lower levels of alkaline phosphatase and collagen type I in SDS-OBs than in H-OBs. Interestingly, SDS-OBs showed higher protein levels of p53, an inhibitor of osteogenesis, compared to H-OBs. Silencing of Tp53 was associated with higher collagen type I and alkaline phosphatase protein levels and an increase in SDS-OB mineralization capacity. In conclusion, our results show that the reduced capacity of SDS-OBs to mineralize is mediated, at least in part, by the high levels of p53 and highlight an important role of SBDS in osteoblast functions.

Human FAM173A is a mitochondrial lysine-specific methyltransferase that targets adenine nucleotide translocase and affects mitochondrial respiration.

Lysine methylation is a common posttranslational modification of nuclear and cytoplasmic proteins but is also present in mitochondria. The human protein denoted "family with sequence similarity 173 member B" (FAM173B) was recently uncovered as a mitochondrial lysine (K)-specific methyltransferase (KMT) targeting the c-subunit of mitochondrial ATP synthase (ATPSc), and was therefore renamed ATPSc-KMT. We here set out to investigate the biochemical function of its yet uncharacterized paralogue FAM173A. We demonstrate that FAM173A localizes to mitochondria, mediated by a noncanonical targeting sequence that is partially retained in the mature protein. Immunoblotting analysis using methyllysine-specific antibodies revealed that FAM173A knock-out (KO) abrogates lysine methylation of a single mitochondrial protein in human cells. Mass spectrometry analysis identified this protein as adenine nucleotide translocase (ANT), represented by two highly similar isoforms ANT2 and ANT3. We found that methylation occurs at Lys-52 of ANT, which was previously reported to be trimethylated. Complementation of KO cells with WT or enzyme-dead FAM173A indicated that the enzymatic activity of FAM173A is required for ANT methylation at Lys-52 to occur. Both in human cells and in rat organs, Lys-52 was exclusively trimethylated, indicating that this modification is constitutive, rather than regulatory and dynamic. Moreover, FAM173A-deficient cells displayed increased mitochondrial respiration compared with FAM173A-proficient cells. In summary, we demonstrate that FAM173A is the long-sought KMT responsible for ANT methylation at Lys-52, and point out the functional significance of Lys-52 methylation in ANT. Based on the established naming nomenclature for KMTs, we propose to rename FAM173A to ANT-KMT (gene name ANTKMT).

Lysine methylation by the mitochondrial methyltransferase FAM173B optimizes the function of mitochondrial ATP synthase.

Lysine methylation is an important post-translational modification that is also present on mitochondrial proteins, but the mitochondrial lysine-specific methyltransferases (KMTs) responsible for modification are in most cases unknown. Here, we set out to determine the function of human family with sequence similarity 173 member B (FAM173B), a mitochondrial methyltransferase (MTase) reported to promote chronic pain. Using bioinformatics analyses and biochemical assays, we found that FAM173B contains an atypical, noncleavable mitochondrial targeting sequence responsible for its localization to mitochondria. Interestingly, CRISPR/Cas9-mediated KO of FAM173B in mammalian cells abrogated trimethylation of Lys-43 in ATP synthase c-subunit (ATPSc), a modification previously reported as ubiquitous among metazoans. ATPSc methylation was restored by complementing the KO cells with enzymatically active human FAM173B or with a putative FAM173B orthologue from the nematode Caenorhabditis elegans Interestingly, lack of Lys-43 methylation caused aberrant incorporation of ATPSc into the ATP synthase complex and resulted in decreased ATP-generating ability of the complex, as well as decreased mitochondrial respiration. In summary, we have identified FAM173B as the long-sought KMT responsible for methylation of ATPSc, a key protein in cellular ATP production, and have demonstrated functional significance of ATPSc methylation. We suggest renaming FAM173B to ATPSc-KMT (gene name ATPSCKMT).

A panel of intestinal differentiation markers (CDX2, GPA33, and LI-cadherin) identifies gastric cancer patients with favourable prognosis.

BACKGROUND: Gastric cancer is the fifth most common cancer and the third cause of global cancer mortality. CDX2 is an intestinal differentiation marker with prognostic value in gastric cancer and transcriptionally regulates the expression of glycoprotein A33 (GPA33) and liver intestine cadherin (LI-cadherin). METHODS: This study evaluated the clinical significance of the combined expression of CDX2 and its targets GPA33 and LI-cadherin in gastric cancer by fluorescence-based multiplex immunohistochemistry together with digital image analysis and chromogenic immunohistochemistry in 329 gastric cancer samples arranged in tissue microarrays. Additionally, publicly available RNA-seq expression data from 354 gastric cancer samples from the TCGA database were used to validate the immunohistochemistry results. RESULTS: Expression of the three markers (CDX2, GPA33, and LI-cadherin) was strongly correlated, defining an intestinal differentiation panel. Low or negative protein expression of the intestinal differentiation panel identified patients with particularly poor overall survival, irrespective of the methodology used, and was validated in the independent series at the RNA-seq level. CONCLUSIONS: Expression of the intestinal differentiation panel (CDX2, GPA33, and LI-cadherin) defines a set of biomarkers with a strong biological rationale and favourable impact for prognostication of gastric cancer patients.

Association between periodontal inflammation and hypertension using periodontal inflamed surface area and bleeding on probing.

AIM: Periodontitis is a relapsing-remitting disease. Compared with bleeding on probing (BoP), expression of disease activity, periodontal inflamed surface area (PISA), incorporates chronic disease parameters. We tested the association of PISA and BoP with blood pressure (BP) in NHANES III. MATERIALS AND METHODS: A total of 8,614 subjects (≥30 years) with complete periodontal and BP examinations were enrolled. PISA was derived from periodontal probing depth and BoP. The association of PISA and BoP with high/uncontrolled BP was examined by multiple-adjusted models. Inflammatory markers were tested as possible mediators. A machine learning (ML) approach was used to define the relative importance of PISA and BoP and estimate the power of BP status prediction. RESULTS: Compared to no inflammation, severe PISA and BoP were associated with 43% (p < .001) and 32% (p = .006) higher odds of high/uncontrolled BP (≥130/80 mmHg), and with higher systolic BP by ≈4 (p < .001) and 5 (p < .001) mmHg, respectively. Inflammatory markers appeared to mediate this association with various extents, without threshold effect. BoP predicted high/uncontrolled BP more efficiently than PISA using ML. CONCLUSION: PISA and BoP describe the association of periodontal inflammation and hypertension with subtle differences. The contribution of local inflammation to the global inflammatory burden might explain the observed findings.