Tracking single-cell evolution using clock-like chromatin accessibility loci.

Single-cell chromatin accessibility sequencing (scATAC-seq) reconstructs developmental trajectory by phenotypic similarity. However, inferring the exact developmental trajectory is challenging. Previous studies showed age-associated DNA methylation (DNAm) changes in specific genomic regions, termed clock-like differential methylation loci (ClockDML). Age-associated DNAm could either result from or result in chromatin accessibility changes at ClockDML. As cells undergo mitosis, the heterogeneity of chromatin accessibility on clock-like loci is reduced, providing a measure of mitotic age. In this study, we developed a method, called EpiTrace, that counts the fraction of opened clock-like loci from scATAC-seq data to determine cell age and perform lineage tracing in various cell lineages and animal species. It shows concordance with known developmental hierarchies, correlates well with DNAm-based clocks and is complementary with mutation-based lineage tracing, RNA velocity and stemness predictions. Applying EpiTrace to scATAC-seq data reveals biological insights with clinically relevant implications, ranging from hematopoiesis, organ development, tumor biology and immunity to cortical gyrification.

Disruption of maternal vascular remodeling by a fetal endoretrovirus-derived gene in preeclampsia.

BACKGROUND: Preeclampsia, one of the most lethal pregnancy-related diseases, is associated with the disruption of uterine spiral artery remodeling during placentation. However, the early molecular events leading to preeclampsia remain unknown. RESULTS: By analyzing placentas from preeclampsia, non-preeclampsia, and twin pregnancies with selective intrauterine growth restriction, we show that the pathogenesis of preeclampsia is attributed to immature trophoblast and maldeveloped endothelial cells. Delayed epigenetic reprogramming during early extraembryonic tissue development leads to generation of excessive immature trophoblast cells. We find reduction of de novo DNA methylation in these trophoblast cells results in selective overexpression of maternally imprinted genes, including the endoretrovirus-derived gene PEG10 (paternally expressed gene 10). PEG10 forms virus-like particles, which are transferred from the trophoblast to the closely proximate endothelial cells. In normal pregnancy, only a low amount of PEG10 is transferred to maternal cells; however, in preeclampsia, excessive PEG10 disrupts maternal vascular development by inhibiting TGF-beta signaling. CONCLUSIONS: Our study reveals the intricate epigenetic mechanisms that regulate trans-generational genetic conflict and ultimately ensure proper maternal-fetal interface formation.

Integrative Single Cell Atlas Revealed Intratumoral Heterogeneity Generation from an Adaptive Epigenetic Cell State in Human Bladder Urothelial Carcinoma.

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) contributes to therapy resistance and immune evasion affecting clinical prognosis. The molecular and cellular mechanisms contributing to BLCA ITH generation remain elusive. It is found that a TM4SF1-positive cancer subpopulation (TPCS) can generate ITH in BLCA, evidenced by integrative single cell atlas analysis. Extensive profiling of the epigenome and transcriptome of all stages of BLCA revealed their evolutionary trajectories. Distinct ancestor cells gave rise to low-grade noninvasive and high-grade invasive BLCA. Epigenome reprograming led to transcriptional heterogeneity in BLCA. During early oncogenesis, epithelial-to-mesenchymal transition generated TPCS. TPCS has stem-cell-like properties and exhibited transcriptional plasticity, priming the development of transcriptionally heterogeneous descendent cell lineages. Moreover, TPCS prevalence in tumor is associated with advanced stage cancer and poor prognosis. The results of this study suggested that bladder cancer interacts with its environment by acquiring a stem cell-like epigenomic landscape, which might generate ITH without additional genetic diversification.

Analyses of the electronic structures of FeFe-cofactors compared with those of FeMo- and FeV-cofactors and their P-clusters.

The electronic structures of FeFe-cofactors (FeFe-cos) in resting and turnover states, together with their PN clusters from iron-only nitrogenases, have been calculated using the bond valence method, and their crystallographic data were reported recently and deposited in the Protein Data Bank (PDB codes: 8BOQ and 8OIE). The calculated results have also been compared with those of their homologous Mo- and V-nitrogenases. For FeFe-cos in the resting state, Fe1/2/4/5/6/7/8 atoms are prone to Fe3+, while the Fe3 atom shows different degrees of mixed valences. The results support that the Fe8 atom at the terminal positions of FeFe-cos possesses the same oxidation states as the Mo3+/V3+ atoms of FeMo-/FeV-cos. In the turnover state, the overall oxidation state of FeFe-co is slightly reduced than those in the resting species, and its electronic configuration is rearranged after the substitution of S2B with OH, compatible with those found in CO-bound FeV-co. Moreover, the calculations give the formal oxidation states of 6Fe2+-2Fe3+ for the electronic structures of PN clusters in Fe-nitrogenases. By the comparison of Mo-, V- and Fe-nitrogenases, the overall oxidation levels of 7Fe atoms (Fe1-Fe7) for both FeFe- and FeMo-cos in resting states are found to be higher than that of FeV-co. For the PN clusters in MoFe-, VFe- and FeFe-proteins, they all exhibit a strong reductive character.

USP43 stabilizes c-Myc to promote glycolysis and metastasis in bladder cancer.

A hallmark of tumor cells, including bladder cancer (BLCA) cells, is metabolic reprogramming toward aerobic glycolysis (Warburg effect). The classical oncogene MYC, which is crucial in regulating glycolysis, is amplified and activated in BLCA. However, direct targeting of the c-Myc oncoprotein, which regulates glycolytic metabolism, presents great challenges and necessitates the discovery of a more clarified regulatory mechanism to develop selective targeted therapy. In this study, a siRNA library targeting deubiquitinases identified a candidate enzyme named USP43, which may regulate glycolytic metabolism and c-Myc transcriptional activity. Further investigation using functional assays and molecular studies revealed a USP43/c-Myc positive feedback loop that contributes to the progression of BLCA. Moreover, USP43 stabilizes c-Myc by deubiquitinating c-Myc at K148 and K289 primarily through deubiquitinase activity. Additionally, upregulation of USP43 protein in BLCA increased the chance of interaction with c-Myc and interfered with FBXW7 access and degradation of c-Myc. These findings suggest that USP43 is a potential therapeutic target for indirectly targeting glycolytic metabolism and the c-Myc oncoprotein consequently enhancing the efficacy of bladder cancer treatment.

The efficacy of a device-based approach to microorganism disinfection and protein removal for orthokeratology lenses in varied clinical circumstances.

PURPOSE: RigidCare is an electrolysis-based device that recently obtained approval from the US's FDA to sterilise microorganisms and remove proteins for orthokeratology (O-K) lenses. The study was conducted to investigate the device's performance in varied clinical circumstances. METHODS: Trial lenses and private lenses were employed by O-K lens wearers from five hospitals for an evaluation of disinfection and sterilisation and an assessment of protein removal, respectively. Menicon multipurpose solution and protein remover were selected for use with the control group. Following the instructions, pre-cleaning lens samples, post-cleaning lens samples and residual solution samples of trial lenses of the experimental and control groups were collected for microorganism examinations by an experienced third-party testing organisation. The levels of protein deposition for these two approaches were rated by senior O-K experts. Categorical variables were analysed using statistical tests, such as the chi-squared test and Fisher's exact test. RESULTS: The microbial positive rate detected from the pre-cleaning and post-cleaning lens samples and the residual solution of the trial lenses for the experimental and control group was 4/76 vs 1/74 (P = 0.37), 1/76 vs 0/74 (P = 1.00) and 0/76 vs 8/74 (P = 0.006), respectively. Following protein removal, the experimental group exhibited a significantly higher overall proportion of lenses rated as 'clean' or with a 'mild deposit' (96.4 %, 79/82) compared to the control group (85.7 %, 66/77), with a significant difference (P < 0.05). CONCLUSION: This multi-center study demonstrated that RigidCare exhibited superior efficacy in disinfection, sterilisation and protein removal as compared to Menicon multipurpose solution and protein remover.

Novel Inhibitor of Mixed-Lineage Kinase Domain-Like Protein: The Antifibrotic Effects of a Necroptosis Antagonist.

The pseudokinase mixed-lineage kinase domain-like protein plays a crucial role in programmed cell death via necroptosis. We developed a novel mixed-lineage kinase domain-like inhibitor, P28, which demonstrated potent necroptosis inhibition and antifibrotic effects. P28 treatment directly inhibited mixed-lineage kinase domain-like phosphorylation and oligomerization after necroptosis induction, inhibited immune cell death after necroptosis, and reduced the expression of adhesion molecules. Additionally, P28 treatment reduced the level of activation of hepatic stellate cells and the expression of hepatic fibrosis markers induced by necroptosis stimulation. Unlike the necrosulfonamide treatment, the P28 treatment did not induce cytotoxicity. Finally, the cysteine covalent bonding of P28 was confirmed by liquid chromatography-tandem mass spectrometry.

High myopia control is comparable between multifocal rigid gas-permeable lenses and spectacles.

Purpose: Ocular pathology may be reduced by slowing myopia progression. The purpose of this study was to evaluate the potential of a novel custom-designed rigid gas permeable (RGP) contact lens to control high myopia by comparing the efficacy of multifocal RGP lenses and single-vision spectacles for high myopia control. Methods: The medical records of children fitted with spectacles or multifocal rigid gas-permeable lenses between January 2018 and May 2020 were retrospectively reviewed. Children (5-17 years) with non-cycloplegic spherical equivalent refraction of ≤ -6.00 D or spherical equivalent refraction > - 6.00 D with baseline axial length ≥ 26.5 mm, and astigmatism of ≥ -2.00 D were included. Axial length and refraction were measured at baseline, before fitting the participants with multifocal rigid gas-permeable lenses or spectacles, and at 1- and 2-year follow-up visits. Changes in axial length were compared between the groups. Results: Among the 77 children with 1-year follow-up data, the mean axial elongation was 0.20 ± 0.17 mm and 0.21 ± 0.14 mm in the multifocal rigid gas-permeable and control groups, respectively, without significant differences between groups (F = 0.004, p = 0.835). Among the 41 patients who completed 2 years of follow-up, the mean axial elongation values in the multifocal rigid gas-permeable and control groups were 0.21 ± 0.15 mm and 0.24 ± 0.13 mm, respectively, at the 1-year follow-up, and 0.37 ± 0.27 mm and 0.43 ± 0.23 mm, respectively, at the 2-year follow-up, without significant between-group differences at either time point (p = 0.224). Conclusion: Axial length increased at a similar rate in both the control (spectacles) and multifocal rigid gas-permeable lens groups, suggesting that multifocal rigid gas-permeable lenses have no significant impact on controlling high myopia progression compared with spectacles.

Pectolinarigenin inhibits bladder urothelial carcinoma cell proliferation by regulating DNA damage/autophagy pathways.

Pectolinarigenin (PEC), an active compound isolated from traditional herbal medicine, has shown potential anti-tumor properties against various types of cancer cells. However, its mechanism of action in bladder cancer (BLCA), which is one of the fatal human carcinomas, remains unexplored. In this study, we first revealed that PEC, as a potential DNA topoisomerase II alpha (TOP2A) poison, can target TOP2A and cause significant DNA damage. PEC induced G2/M phase cell cycle arrest via p53 pathway. Simultaneously, PEC can perform its unique function by inhibiting the late autophagic flux. The blocking of autophagy caused proliferation inhibition of BLCA and further enhanced the DNA damage effect of PEC. In addition, we proved that PEC could intensify the cytotoxic effect of gemcitabine (GEM) on BLCA cells in vivo and in vitro. Summarily, we first systematically revealed that PEC had great potential as a novel TOP2A poison and an inhibitor of late autophagic flux in treating BLCA.

Pers reverse angiotensin II -induced vascular smooth muscle cell proliferation by targeting cyclin E expression via inhibition of the MAPK signaling pathway.

The circadian rhythm of blood pressure (BP) is believed to be regulated by the clock system, which is closely linked to levels of angiotensin II (Ang II). This study aimed to investigate whether Ang II mediates the proliferation of vascular smooth muscle cells (VSMCs) through the interaction between the clock system and the mitogen-activated protein kinase (MAPK) signaling pathway. Primary rat aortic VSMCs were treated with Ang II, with or without MAPK inhibitors. VSMC proliferation, expression of clock genes, CYCLIN E, and MAPK pathways were assessed. Ang II treatment resulted in increased VSMC proliferation and rapid upregulation of clock gene Periods (Pers) expression. Compared to the non-diseased control (NC) group, VSMCs incubated with Ang II displayed a noticeable delay in the G1/S phase transition and downregulation of CYCLIN E upon silencing of Per1 and Per2 genes. Importantly, silencing Per1 or Per2 in VSMCs led to decreased expression of key MAPK pathway proteins, including RAS, phosphorylated mitogen-activated protein kinase (P-MEK), and phosphorylated extracellular signal-regulated protein kinase (P-ERK). Moreover, the MEK and ERK inhibitors, U0126 and SCH772986, significantly attenuated the Ang II-induced proliferation of VSMCs, as evidenced by an increased G1/S phase transition and decreased CYCLIN E expression. The MAPK pathway plays a critical role in regulating VSMC proliferation in response to Ang II stimulation. This regulation is controlled by the expression of circadian clock genes involved in the cell cycle. These findings provide novel insights for further research on diseases associated with abnormal VSMC proliferation.

Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor ß type II receptor.

BACKGROUND: The transforming growth factor ß (TGFß) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFß type II receptor (TGFßR2), followed by the recruitment of TGFßR1 finally triggering downstream signaling pathway. AIM: To find drugs targeting TGFßR2 that inhibit TGFßR1/TGFßR2 complex formation, theoretically inhibit TGFß signaling pathway, and thereby ameliorate liver fibrosis. METHODS: Food and Drug Administration-approved drugs were screened for binding affinity with TGFßR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect. RESULTS: We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFß induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFßR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFßR2 disrupted the binding of TGFßR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson's trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver. CONCLUSION: DHE alleviates liver fibrosis by binding to TGFßR2 thereby suppressing TGFß signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC.

To date, most studies on the DNA polymerase, POLD1, have focused on the effect of POLD1 inactivation mutations in tumors. However, the implications of high POLD1 expression in tumorigenesis remains elusive. Here, we determine that POLD1 has a pro-carcinogenic role in bladder cancer (BLCA) and is associated to the malignancy and prognosis of BLCA. Our studies demonstrate that POLD1 promotes the proliferation and metastasis of BLCA via MYC. Mechanistically, POLD1 stabilizes MYC in a manner independent of its' DNA polymerase activity. Instead, POLD1 attenuates FBXW7-mediated ubiquitination degradation of MYC by directly binding to the MYC homology box 1 domain competitively with FBXW7. Moreover, we find that POLD1 forms a complex with MYC to promote the transcriptional activity of MYC. In turn, MYC increases expression of POLD1, forming a POLD1-MYC positive feedback loop to enhance the pro-carcinogenic effect of POLD1-MYC on BLCA. Overall, our study identifies POLD1 as a promotor of BCLA via a MYC driven mechanism and suggest its potential as biomarker for BLCA.

HOXA5 inhibits the proliferation and metastasis of cervical squamous cell carcinoma by suppressing the ß-catenin/Snail signaling.

HOXA5, as a transcription factor, plays an important role in a variety of malignant tumors. Nevertheless, its biological role in cervical squamous cell carcinoma (CSCC) is largely unknown. In our study, we aimed to explore the function of HOXA5 in CSCC and its molecular mechanism. Immunohistochemistry showed that HOXA5 expression was downregulated in human CSCC tissues and HOXA5 staining was negatively correlated with tumor size and histological grade of CSCC. Ectopic expression of HOXA5 inhibited proliferative and metastatic abilities of CSCC cells in vitro and in vivo. Furthermore, overexpression of HOXA5 inhibited the cell cycle by arresting the S/G2 phase by flow cytometry and that was related to the downregulation of Cyclin A. Further study showed that HOXA5 suppressed EMT by inhibiting the ß-catenin/Snail signaling resulting in reduced metastasis of CSCC cells. Altogether, our results suggested that HOXA5 inhibited the proliferation and metastasis via repression of the ß-catenin/Snail pathway, proposing the potential role of HOXA5 in the prevention and treatment of CSCC.

MYBL2 promotes proliferation and metastasis of bladder cancer through transactivation of CDCA3.

The transcription factor MYB proto-oncogene like 2 (MYBL2) is critical in regulating gene expression and tumorigenesis. However, the biological function of MYBL2 in bladder cancer (BLCA) remains to be elucidated. Here, we first revealed that MYBL2 was elevated in BLCA tissues and significantly correlated with clinicopathological parameters and cancer-specific survival in BLCA patients. Phenotypic assays showed that MYBL2 deficiency suppressed the proliferation and migration of BLCA cells in vitro and in vivo, whereas MYBL2 overexpression contributed to the opposite phenotype. Mechanistically, MYBL2 could bind to the promoter of its downstream target gene cell division cycle-associated protein 3 (CDCA3) and transactivate it, which in turn promoted the malignant phenotype of BLCA cells. Further investigations revealed that MYBL2 interacted with forkhead box M1 (FOXM1) to co-regulate the transcription of CDCA3. In addition, MYBL2/FOXM1 and CDCA3 might activate Wnt/ß-catenin signaling, thereby promoting the malignant phenotype of BLCA cells. In conclusion, the current study identifies MYBL2 as an oncogene in BLCA. MYBL2 can accelerate the proliferation and metastasis of BLCA through the transactivation of CDCA3.

Non-invasive diagnosis and surveillance of bladder cancer with driver and passenger DNA methylation in a prospective cohort study.

BACKGROUND: State-of-art non-invasive diagnosis processes for bladder cancer (BLCA) harbour shortcomings such as low sensitivity and specificity, unable to distinguish between high- (HG) and low-grade (LG) tumours, as well as inability to differentiate muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). This study investigates a comprehensive characterization of the entire DNA methylation (DNAm) landscape of BLCA to determine the relevant biomarkers for the non-invasive diagnosis of BLCA. METHODS: A total of 304 samples from 224 donors were enrolled in this multi-centre, prospective cohort study. BLCA-specific DNAm signature discovery was carried out with genome-wide bisulfite sequencing in 32 tumour tissues and 12 normal urine samples. A targeted sequencing assay for BLCA-specific DNAm signatures was developed to categorize tumour tissue against normal urine, or MIBC against NMIBC. Independent validation was performed with targeted sequencing of 259 urine samples in a double-blinded manner to determine the clinical diagnosis and prognosis value of DNAm-based classification models. Functions of genomic region harbouring BLCA-specific DNAm signature were validated with biological assays. Concordances of pathology to urine tumour DNA (circulating tumour DNA [ctDNA]) methylation, genomic mutations or other state-of-the-art diagnosis methods were measured. RESULTS: Genome-wide DNAm profile could accurately classify LG tumour from HG tumour (LG NMIBC vs. HG NMIBC: p = .038; LG NMIBC vs. HG MIBC, p = .00032; HG NMIBC vs. HG MIBC: p = .82; Student's t-test). Overall, the DNAm profile distinguishes MIBC from NMIBC and normal urine. Targeted-sequencing-based DNAm signature classifiers accurately classify LG NMIBC tissues from HG MIBC and could detect tumours in urine at a limit of detection of less than .5%. In tumour tissues, DNAm accurately classifies pathology, thus outperforming genomic mutation or RNA expression profiles. In the independent validation cohort, pre-surgery urine ctDNA methylation outperforms fluorescence in situ hybridization (FISH) assay to detect HG BLCA (n = 54) with 100% sensitivity (95% CI: 82.5%-100%) and LG BLCA (n = 26) with 62% sensitivity (95% CI: 51.3%-72.7%), both at 100% specificity (non-BLCA: n = 72; 95% CI: 84.1%-100%). Pre-surgery urine ctDNA methylation signature correlates with pathology and predicts recurrence and metastasis. Post-surgery urine ctDNA methylation (n = 61) accurately predicts recurrence-free survival within 180 days, with 100% accuracy. CONCLUSION: With the discovery of BLCA-specific DNAm signatures, targeted sequencing of ctDNA methylation outperforms FISH and DNA mutation to detect tumours, predict recurrence and make prognoses.

Post-cardiac arrest PCI is underutilized among cancer patients: Machine learning augmented nationally representative case-control study of 30 million hospitalizations.

BACKGROUND: Cancer patients are less likely to undergo percutaneous coronary intervention (PCI) after cardiac arrest, although they demonstrate improved mortality benefit from the procedure. We produced the largest nationally representative analysis of mortality of cardiac arrest and PCI for patients with cancer versus non-cancer. METHODS: Propensity score adjusted multivariable regression for mortality was performed in this case-control study of the United States' largest all-payer hospitalized dataset, the 2016 National Inpatient Sample. Regression models of mortality and PCI weighted by the complex survey design were fully adjusted for age, race, income, cancer metastases, NIS-calculated mortality risk by Diagnosis Related Group (DRG), acute coronary syndrome, and likelihood of undergoing PCI. RESULTS: Of the 30,195,722 hospitalized adult patients, 15.43% had cancer, and 0.79% of the whole sample presented with cardiac arrest (of whom 20.57% underwent PCI). In fully adjusted regression analysis among patients with cardiac arrest, PCI significantly reduced mortality (OR 0.15, 95 %CI 0.13-0.19; p < 0.001) among patients with cancer greater than those without it (OR 0.21, 95 %CI 0.20-0.23; p < 0.001). CONCLUSIONS: This nationally representative study suggests that post-cardiac arrest PCI is underutilized among patients with cancer despite its significant mortality reduction for such patients (independent of clinical acuity).

Fractional Flow Reserve Cardio-Oncology Effects on Inpatient Mortality, Length of Stay, and Cost Based on Malignancy Type: Machine Learning Supported Nationally Representative Case-Control Study of 30 Million Hospitalizations.

Background and Objectives: There are no nationally representative studies of mortality and cost effectiveness for fractional flow reserve (FFR) guided percutaneous coronary interventions (PCI) in patients with cancer. Our study aims to show how this patient population may benefit from FFR-guided PCI. Materials and Methods: Propensity score matched analysis and backward propagation neural network machine learning supported multivariable regression was performed for inpatient mortality in this case-control study of the 2016 National Inpatient Sample (NIS). Regression results were adjusted for age, race, income, geographic region, metastases, mortality risk, and the likelihood of undergoing FFR versus non-FFR PCI. All analyses were adjusted for the complex survey design to produce nationally representative estimates. Results: Of the 30,195,722 hospitalized patients meeting criteria, 3.37% of the PCIs performed included FFR. In propensity score adjusted multivariable regression, FFR versus non-FFR PCI significantly reduced inpatient mortality (OR 0.47, 95%CI 0.35−0.63; p < 0.001) and length of stay (LOS) (in days; beta −0.23, 95%CI −0.37−−0.09; p = 0.001) while increasing cost (in USD; beta $5708.63, 95%CI, 3042.70−8374.57; p < 0.001), without significantly increasing complications overall. FFR versus non-FFR PCI did not specifically change cancer patients' inpatient mortality, LOS, or cost. However, FFR versus non-FFR PCI significantly increased inpatient mortality for Hodgkin's lymphoma (OR 52.48, 95%CI 7.16−384.53; p < 0.001) and rectal cancer (OR 24.38, 95%CI 2.24−265.73; p = 0.009). Conclusions: FFR-guided PCI may be safely utilized in patients with cancer as it does not significantly increase inpatient mortality, complications, and LOS. These findings support the need for an increased utilization of FFR-guided PCI and further studies to evaluate its long-term impact.

Reclassification of Treatment Strategy with Fractional Flow Reserve in Cancer Patients with Coronary Artery Disease.

Background and Objectives: Cancer and coronary artery disease (CAD) often coexist. Compared to quantitative coronary angiography (QCA), fractional flow reserve (FFR) has emerged as a more reliable method of identifying significant coronary stenoses. We aimed to assess the specific management, safety and outcomes of FFR-guided percutaneous coronary intervention (PCI) in cancer patients with stable CAD. Materials and Methods: FFR was used to assess cancer patients that underwent coronary angiography for stable CAD between September 2008 and May 2016, and were found to have ≥50% stenosis by QCA. Patients with lesions with an FFR > 0.75 received medical therapy alone, while those with FFR ≤ 0.75 were revascularized. Procedure-related complications, all-cause mortality, nonfatal myocardial infarction, or urgent revascularizations were analyzed. Results: Fifty-seven patients with stable CAD underwent FFR on 57 lesions. Out of 31 patients with ≥70% stenosis as measured by QCA, 14 (45.1%) had an FFR ≥ 0.75 and lesions were reclassified as moderate and did not receive PCI nor DAPT. Out of 26 patients with <70% stenosis as measured by QCA, 6 (23%) had an FFR < 0.75 and were reclassified as severe and were treated with PCI and associated DAPT. No periprocedural complications, urgent revascularization, acute coronary syndromes, or cardiovascular deaths were noted. There was a 22.8% mortality at 1 year, all cancer related. Patients who received a stent by FFR assessment showed a significant association with decreased risk of all-cause death (HR: 0.37, 95% CI 0.15−0.90, p = 0.03). Conclusions: Further studies are needed to define the optimal therapeutic approach for cancer patients with CAD. Using an FFR cut-off point of 0.75 to guide PCI translates into fewer interventions and can facilitate cancer care. There was an overall reduction in mortality in patients that received a stent, suggesting increased resilience to cancer therapy and progression.

The Genetic Diversity in Thereuonema tuberculata (Wood, 1862) (Scutigeromorpha: Scutigeridae) and the Phylogenetic Relationship of Scutigeromorpha Using the Mitochondrial Genome.

Based on morphological characteristics to make species identification, the cryptic species of the Scutigeromorpha can be greatly underestimated. The mitochondrial genome provides a desirable tool for the biological identifications and the discovery of the cryptic species. The capacity to acquire mitochondrial genome sequences has substantially improved in recent years using next-generation sequencing (NGS) technology. On the basis of the next-generation sequencing, we obtained four complete mitochondrial genomes of Thereuonema tuberculata (Wood, 1862) from Nanyang, Henan Province (NY), Nanchang, Jiangxi Province (NC), Jinan, Shandong Province (JN), and Dali, Yunnan Province (DL) in China with GenBank numbers OK513221, OL449685, ON058988 and ON058989, respectively. The lengths of the four mitochondrial genomes ranged from 14,903 to 14,909 bp. The composition and order of genes of the four mitochondrial genomes were identical to the published mitochondrial genome of Scutigera coleoptrata (Linnaeus, 1758) (Scutigeromorpha: Scutigerdae). It was the first time that the tandem repeats in the control region were detected in Scutigeromorpha. We also calculated the corrected pairwise genetic distance of four complete mitochondrial genomes of T. tuberculata, ranging from 7.7 to 15.2%. The results showed that the T.tuberculata NC belonged to the typical sample of T. tuberculata, and T. tuberculata DL was hypothesized as a cryptic species of T. tuberculata. Meanwhile, T. tuberculata NY and T. tuberculata JN were hypothesized as potential cryptic species of T. tuberculata in this study. In both BI and ML trees, the monophyly of Scutigeromorpha, Scolopendromorpha, Geophilomorpha, and Lithobiomorpha was forcefully advocated. Moreover, Scutigeromorpha was recovered as the sister clade of (Scolopendromorpha + (Lithobiomorpha + Geophilomorpha)). Four specimens of T. tuberculata were clustered into one clade, which was the sister to the clade of S. coleoptrata.