Transarterial doxorubicin-eluting beads embolization for the treatment of desmoid fibromatosis in the pubic region.

Desmoid fibromatosis (DFs) is rare, low-grade neoplasm. Although it poses no risk of metastasis, DFs exhibits a range of clinical manifestations characterized by local infiltrative growth tendencies and a propensity for recurrence. Despite its nonmalignant nature, DFs can be highly debilitating and occasionally life-threatening, causing severe pain and functional limitations. Traditionally, surgery served as the conventional primary treatment approach; nevertheless, a recent shift in paradigm towards a more conservative management has emerged, accompanied by efforts to standardize the strategy among clinicians. Systemic doxorubicin has been demonstrated to be effective in treating DFs; however, it carries potential risks of adverse effects on the cardiovascular, digestive, and hematologic systems. The novel intravascular intervention employing drug-eluting beads loaded with doxorubicin represents an effective treatment for DFs, optimizing drug delivery to the target lesion and reducing systemic toxicity. In this article, we present a rare case of DFs in the right pubic region treated with transarterial doxorubicin-eluting beads embolization.

Social, behavioral and clinical risk factors are associated with clonal hematopoiesis.

BACKGROUND: Risk factors including smoking, alcohol intake, physical activity (PA), and sleep patterns have been associated with cancer risk. Clonal hematopoiesis (CH), including mosaic chromosomal alterations (mCAs) and clonal hematopoiesis of indeterminate potential (CHIP), is linked to increased hematopoietic cancer risk, and could be used as common pre-clinical intermediates for better understanding associations of risk factors with rare hematologic malignancies. METHODS: We analyzed cross-sectional data from 478,513 UK Biobank participants without hematologic malignancies using multivariable adjusted analyses to assess the associations between lifestyle factors and CH types. RESULTS: Smoking was reinforced as a potent modifiable risk factor for multiple CH types, with dose-dependent relationships persisting post-cessation. Males in socially deprived areas of England had lower risk of mosaic loss of chromosome Y (mLOY), females with moderate/high alcohol consumption (2-3 drinks/day) had increased mLOX risk (OR=1.17, 95%CI:[1.09-1.25], p=8.31×10-6) compared to light drinkers, active males (moderate-high PA) had elevated risks of mLOY (PA Category 3: OR=1.06, 95%CI:[1.03-1.08], p=7.57×10-6) and men with high BMI (≥40) had reduced risk of mLOY (OR=0.57, 95%CI:[0.51-0.65], p=3.30×10-20). Sensitivity analyses with BMI adjustment attenuated the effect in the mLOY-PA associations (IPAQ2: OR=1.03, 95%CI:[1.00-1.06], p=2.13×10-2 and IPAQ3: OR=1.03, 95%CI:[1.01-1.06], p=7.77×10-3). CONCLUSIONS: Our study reveals associations between social deprivation, smoking, alcohol consumption, and CH risk, suggesting these exposures could contribute to common types of CH and potentially rare hematologic cancers. IMPACT: This study underscores the impact of lifestyle factors on CH frequency, emphasizing social, behavioral, and clinical influences and the importance of socio-behavioral contexts when investigating CH risk factors.

Amine-bearing hydrocarbon cross-links: Tailoring helix stability, hydrophilicity, and synthetic adaptability in peptides.

This study comprehensively explored the helix-stabilizing effects of amine-bearing hydrocarbon cross-links (ABXs), revealing their context-dependent nature influenced by various structural parameters. Notably, we identified a 9-atom ABX as a robust helix stabilizer, showcasing versatile synthetic adaptability while preserving peptide water solubility. Future investigations are imperative to fully exploit this system's potential and enrich our chemical toolkit for designing innovative peptide-based biomolecules.

Innovative Semi-Nested Realtime PCR Assay with Extendable Blocking Probe for Enhanced Analysis of SEPT9 Methylation in Colorectal Cancer.

(1) Background: The detection of methylated SEPT9 (mSEPT9) in plasma is a promising approach to non-invasive colorectal cancer (CRC) screening. Traditional approaches have limitations in sensitivity and cost-effectiveness, particularly in resource-limited settings. (2) Methods: We developed a semi-nested realtime PCR assay utilizing extendable blocking probes (ExBP) to enhance the detection of low-level mSEPT9 based on DNA melting. This assay allows for the discrimination of mSEPT9 in the presence of high concentrations of non-methylated SEPT9 (up to 100,000 times higher). (3) Results: The assay demonstrated a sensitivity of 73.91% and specificity of 80%, showcasing its ability to detect very low levels of methylated DNA effectively. The innovative use of ExBP without costly modified probes simplifies the assay setup and reduces the overall costs, enhancing its applicability in diverse clinical settings. (4) Conclusions: This novel assay significantly improves the detection of mSEPT9, offering a potential advance in CRC screening and monitoring. Its cost-efficiency and high sensitivity make it particularly suitable for the early detection and management of CRC, especially in settings with limited resources. Future studies are encouraged to validate this assay in larger populations to establish its clinical benefits and practical utility.

Who Do We Fail to Rescue after Pancreatoduodenectomy? Outcomes Among >4000 Procedures Expose Windows of Opportunity.

OBJECTIVE: Our investigation on in-hospital mortality after 4474 pancreatoduodenectomies aimed to identify time-dependent risks as well as windows of opportunity to rescue patients from complications. BACKGROUND: Pancreatoduodenectomy is generally considered a safe procedure with a 1-10% perioperative mortality based on complexity and surgical volume. Yet, patients are susceptible for life-threatening complications particularly with extended resections. Recognition of distinct vulnerabilities over time while patients recover is required to permit focused monitoring, sophisticated resource allocation, and greatest surgical safety. METHODS: Patients who deceased in-hospital after pancreatoduodenectomy between 2003-2021 were retrieved from the institutional pancreatectomy registry and analyzed in detail with respect to their postoperative course. RESULTS: Among 4474 pancreatoduodenectomies, 156 patients deceased in-hospital (3.5%). When assessing root causes of mortality, we observed 3 different clusters of complications which were postpancreatectomy-specific (47.4%), visceral vasculature-associated (25.6%), or cardiopulmonary in origin (23.7%). The median times of root cause onset in the 3 categories were postoperative day (POD) 9, POD 4.5 ( P =0.008) and POD 3 ( P <0.001), and medians of in-hospital mortality were POD 31, POD 18 ( P =0.009) and POD 8 ( P <0.001), respectively. Intervals between root cause onset and mortality varied with medians of 23 days, 11 days ( P =0.017), and 1 days ( P <0.001). The 3 categories were similarly distributed between different types of surgical complexity. CONCLUSION: Postpancreatectomy-specific complications prompt almost half of in-hospital mortalities after pancreatoduodenectomy, with rather long intervals for interventions to prevent failure to rescue. In contrast, visceral vasculature-related events and cardiopulmonary complications dominate early in-hospital mortalities with short intervals until mortality, demanding rigorous management of such events or preoperative conditioning. These data externally validate a previous high-volume initiative and highlight distinct windows of opportunity to optimize perioperative safety.

Interferons and interferon-related pathways in heart disease.

Interferons (IFNs) and IFN-related pathways play key roles in the defence against microbial infection. However, these processes may also be activated during the pathogenesis of non-infectious diseases, where they may contribute to organ injury, or function in a compensatory manner. In this review, we explore the roles of IFNs and IFN-related pathways in heart disease. We consider the cardiac effects of type I IFNs and IFN-stimulated genes (ISGs); the emerging role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; the seemingly paradoxical effects of the type II IFN, IFN-γ; and the varied actions of the interferon regulatory factor (IRF) family of transcription factors. Recombinant IFNs and small molecule inhibitors of mediators of IFN receptor signaling are already employed in the clinic for the treatment of some autoimmune diseases, infections, and cancers. There has also been renewed interest in IFNs and IFN-related pathways because of their involvement in SARS-CoV-2 infection, and because of the relatively recent emergence of cGAS-STING as a pattern recognition receptor-activated pathway. Whether these advances will ultimately result in improvements in the care of those experiencing heart disease remains to be determined.

Streptomyces tagetis sp. nov., a chromomycin producing bacteria isolated from the roots of Tagetes patula.

A novel halotolerant actinobacterium, designated as RG38T, capable of producing black extracellular melanin pigment on SP2 agar, was isolated from the roots of Tagetes patula. Comparative analysis of the 16S rRNA gene sequence revealed the highest similarity to Streptomyces collinus NBRC 12759T (99.3%). Phylogenetic analysis showed that strain RG38T clustered within the genus Streptomyces forming a monophyletic cluster with its close relatives. The average nucleotide identity (ANI), digital DNA-DNA hybridization (dDDH), and amino-acid identity (AAI) values between strain RG38T and related species within the genus Streptomyces were below the standard threshold for prokaryotic species delineation. The DNA G + C content of the strain RG38T was determined to be 73.3%. The genome size measured 7,150,598 bp comprising 17 contigs and encompassed 6,053 protein coding genes. AntiSMASH analysis of the whole genome revealed 35 putative biosynthetic gene clusters (BGCs) responsible for various secondary metabolites. Among these clusters, two gene clusters exhibited 100% similarity to the chromomycin A3, albaflavenone, and anthracimycin, respectively. These compounds were reported to possess significant anticancer and antibacterial activities. LC-MS-based analysis, coupled with further isolation studies, confirmed the production of chromomycins A2 (1), A3 (2), and their derivatives, along with their antibiotic activities. These findings underscore the potential of this novel strain as a novel resource for the discovery of diverse antimicrobial compounds. This study is the first to report an antimicrobial compound producing Streptomyces species isolated from medicinal plant T. patula. Based on a polyphasic study, the strain RG38T isolated from an unexplored habitat with a high potential for new natural products represents a novel species within the genus Streptomyces. Accordingly, we propose the name Streptomyces tagetis sp. nov. for this novel species, with the type strain is RG38T (=KCTC 49624T = TBRC 15113T).

Plasma Proteomic Signature Predicts Myeloid Neoplasm Risk.

PURPOSE: Clonal hematopoiesis (CH) is thought to be the origin of myeloid neoplasms (MN). Yet, our understanding of the mechanisms driving CH progression to MN and clinical risk prediction of MN remains limited. The human proteome reflects complex interactions between genetic and epigenetic regulation of biological systems. We hypothesized that the plasma proteome might predict MN risk and inform our understanding of the mechanisms promoting MN development. EXPERIMENTAL DESIGN: We jointly characterized CH and plasma proteomic profiles of 46,237 individuals in the UK Biobank at baseline study entry. During 500,036 person-years of follow-up, 115 individuals developed MN. Cox proportional hazard regression was used to test for an association between plasma protein levels and MN risk. RESULTS: We identified 115 proteins associated with MN risk, of which 30% (N = 34) were also associated with CH. These were enriched for known regulators of the innate and adaptive immune system. Plasma proteomics improved the prediction of MN risk (AUC = 0.85; P = 5×10-9) beyond clinical factors and CH (AUC = 0.80). In an independent group (N = 381,485), we used inherited polygenic risk scores (PRS) for plasma protein levels to validate the relevance of these proteins toMNdevelopment. PRS analyses suggest that most MN-associated proteins we identified are not directly causally linked toMN risk, but rather represent downstream markers of pathways regulating the progression of CH to MN. CONCLUSIONS: These data highlight the role of immune cell regulation in the progression of CH to MN and the promise of leveraging multi-omic characterization of CH to improveMN risk stratification. See related commentary by Bhalgat and Taylor, p. 3095.

ArCH: improving the performance of clonal hematopoiesis variant calling and interpretation.

MOTIVATION: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH. RESULTS: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches. AVAILABILITY AND IMPLEMENTATION: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH.

The antimicrobial activity and essential oil constituents of the leaves and trunks of Aquilaria banaensis P.H.Hô (Thymelaeceae) from Vietnam.

The aim of the present paper was to report the chemical constituents and antimicrobial activity of essential hydrodistilled from the leaves and trunk of Aquilaria banaensis P.H.Hô (Thymelaeceae) from Vietnam. The essential oils were analysed comprehensively for their constituents by using Gas chromatography coupled with Mass spectrometry (GC/MS). The antimicrobial activity was determined by agar well diffusion and broth microdilution methods. The leaf essential oil comprised mainly of sesquiterpenes while fatty acids constitutes the bulk of the trunk essential oil. The main constituents of the leaf essential oil were ß-caryophyllene (17.11%), α-selinene (10.99%), α-humulene (8.98%), ß-selinene (8.01%), ß-guaiol (6.69%) and ß-elemene (5.65%). However, hexadecanoic acid (48.46%), oleic acid (19.80%) and tetradecanoic acid (5.32%) were the major compounds identified in the trunk essential oil. The trunk essential oil displayed antimicrobial activity against Staphylococcus aureus, with the minimum inhibitory concentration (MIC) value of about 256.0 µg/mL.

Pancreaticoduodenectomy with superior mesenteric artery first-approach combined total meso-pancreas excision for periampullary malignancies: A high-volume single-center experience with short-term outcomes.

Backgrounds/Aims: Pancreaticoduodenectomy (PD) is the only radical treatment for periampullary malignancies. Superior mesenteric artery (SMA) first approach combined with total meso-pancreas (MP) excision was conducted to improve the oncological results. There has not been any previous research of a technique that combines the SMA first approach and total MP excision with a detailed description of the MP macroscopical shape. Methods: We prospectively assessed 77 patients with periampullary malignancies between October 2020 and March 2022 (18 months). All patients had undergone PD with SMA first approach combined total MP excision. The perioperative indications, clinical data, intra-operative index, R0 resection rate of postoperative pathological specimens (especially mesopancreatic margin), postoperative complications, and follow-up results were evaluated. Results: The median operative time was 289.6 min (178-540 min), the median intraoperative blood loss was 209 mL (30-1,600 mL). Microscopically, there were 19 (24.7%) cases with metastatic MP, and five cases (6.5%) with R1-resection of the MP. The number of lymph nodes (LNs) harvested and metastatic LNs were 27.2 (maximum was 74) and 1.8 (maximum was 16), respectively. Some (46.8%) patients had pancreatic fistula, but mostly in grade A, with 7 patients (9.1%) who required re-operations. Some 18.2% of cases developed postoperative refractory diarrhea. The rate of in-hospital mortality was 1.3%. Conclusions: The PD with SMA first approach combined TMpE for periampullary malignancies was effective in achieving superior oncological statistics (rate of MP R0-resection and number of total resected LNs) with non-inferior short-term outcomes. It is necessary to evaluate survival outcomes with long-term follow-up.

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization.

Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published assays to date demanded a very high-depth sequencing, resulting in an elevated price of test. Herein, we developed a multimodal assay called SPOT-MAS (screening for the presence of tumor by methylation and size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing (~0.55×) of cell-free DNA. We applied SPOT-MAS to 738 non-metastatic patients with breast, colorectal, gastric, lung, and liver cancer, and 1550 healthy controls. We then employed machine learning to extract multiple cancer and tissue-specific signatures for detecting and locating cancer. SPOT-MAS successfully detected the five cancer types with a sensitivity of 72.4% at 97.0% specificity. The sensitivities for detecting early-stage cancers were 73.9% and 62.3% for stages I and II, respectively, increasing to 88.3% for non-metastatic stage IIIA. For tumor-of-origin, our assay achieved an accuracy of 0.7. Our study demonstrates comparable performance to other ctDNA-based assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening.

Improvement in neoantigen prediction via integration of RNA sequencing data for variant calling.

Introduction: Neoantigen-based immunotherapy has emerged as a promising strategy for improving the life expectancy of cancer patients. This therapeutic approach heavily relies on accurate identification of cancer mutations using DNA sequencing (DNAseq) data. However, current workflows tend to provide a large number of neoantigen candidates, of which only a limited number elicit efficient and immunogenic T-cell responses suitable for downstream clinical evaluation. To overcome this limitation and increase the number of high-quality immunogenic neoantigens, we propose integrating RNA sequencing (RNAseq) data into the mutation identification step in the neoantigen prediction workflow. Methods: In this study, we characterize the mutation profiles identified from DNAseq and/or RNAseq data in tumor tissues of 25 patients with colorectal cancer (CRC). Immunogenicity was then validated by ELISpot assay using long synthesis peptides (sLP). Results: We detected only 22.4% of variants shared between the two methods. In contrast, RNAseq-derived variants displayed unique features of affinity and immunogenicity. We further established that neoantigen candidates identified by RNAseq data significantly increased the number of highly immunogenic neoantigens (confirmed by ELISpot) that would otherwise be overlooked if relying solely on DNAseq data. Discussion: This integrative approach holds great potential for improving the selection of neoantigens for personalized cancer immunotherapy, ultimately leading to enhanced treatment outcomes and improved survival rates for cancer patients.

Myocarditis Following Inactivated SARS-CoV-2 Vaccine (Vero Cell) in an Adult Female in Vietnam: A Case Report.

During the Coronavirus disease 2019 (COVID-19) pandemic, vaccination against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has proven to be an important measure to help control disease spread and improve patient outcome. There are four distinct vaccine categories: inactivated viral vaccines, messenger RNA (mRNA) vaccines, adenovirus vector-based vaccines, and adjuvanted protein vaccines. In 2021, increased cases of myocarditis and pericarditis were reported after mRNA and adenovirus vector-based COVID-19 vaccination. A similar reporting pattern has not been observed after receipt of inactivated virus vaccines. Here, we present a case of clinically suspected acute myocarditis in a 26-year-old female, occurring 11 days after the administration of Sinopharm Vero Cell, an inactivated virus COVID-19 vaccine. This event led to acute heart failure, with marked clinical resolution observed within 34 days.

Prevalence and genetic spectrum associated with hereditary colorectal cancer syndromes, the need to improve cancer risk awareness, and family cascade testing in Vietnam.

In Vietnam, colorectal cancer is one of the top diagnosed cancers, with 5-10% originating from inherited mutations. This study aims to define the mutation spectrum associated with hereditary colorectal cancer syndromes (HCCS) in Vietnam, evaluate the influence of genetic testing on carriers' awareness, and also investigate the barriers in familial testing. Genetic test reports were collected to identify HCCS cases, then cases underwent a survey investigating self-risk and familial-risk awareness, proactive cancer screening, and familial testing barriers. Participant characteristics, mutation prevalence, and results from the survey were descriptively analyzed and reported. Of all genetic test results, 3% (49/1632) were identified with mutations related to HCCS. Over 77% of them belonged to Lynch syndrome. PMS2 appeared to be the gene with the highest mutation frequency, while MLH1 was the lowest. 44% of cases further undertook cancer screening tests, and 48% of cases' families had uptake genetic testing. The biggest barrier of familial members for not taking genetic test was psychological reasons (fear, not being interested, or not feeling necessary). This study provided new evidence for HCCS mutation spectrum in Vietnamese population and the success in promoting cascade test in high-risk family members through financial and technical support. Also, study has suggested the needs of an innovative genetic testing process focusing on the quality of pre-and post-test consultancy, an increase in follow-ups, and the change in policy for permission of contacting relatives directly to improve the rate of cascade testing and proactive cancer screening.

Pancreaticoduodenectomy combined gastroduodenal collateral reconstruction and preservation due to median arcuate ligament syndrome: technical notes with two surgical cases report (with video).

INTRODUCTION: Pancreaticoduodenectomy in patients with CA stenosis due to median arcuate ligament often required carefully collateral pathways management to avoid hepatic ischemic complications. CASES PRESENTATION: Case 1: A 63-year-old man was referred to our department because of jaundice with distal common bile duct tumor. Pancreaticoduodenectomy with left posterior SMA first approach and circumferential lymphadenectomy was performed. Case 2: A 48-year-old man was referred to our department because of right-upper-quadrant abdominal pain with Vater tumor. Laparoscopic pancreaticoduodenectomy with left posterior SMA first approach and circumferential lymphadenectomy was performed. Postoperatively, in all two cases, three-dimensional reconstruction images showed developed collateral pathways around the pancreatic head, and the CA was stenosis in 75% and 70% due to MAL, respectively. Intraoperatively, in all two cases, we confirmed poor blood flow in the common hepatic artery (CHA) by palpation and observation. So that in the first case, we have decided to proceed a no-touch technique of GDA segmental resection en bloc with the tumor and reconstructed with an end-to-end GDA anastomosis; in the second cases, we have decided to proceed gastroduodenal collateral preservation. When preserving these collateral pathways, we confirmed that the PHA flow remained pulsatile as an indicator that the blood flow was adequate. CONCLUSION: Celiac axis stenosis was a rare but difficult-to-managed condition associated with pancreaticoduodenectomy. Collateral pathways management depends on variety of collateral pathways.

Fabrication of Antibacterial Ag/Graphene-Integrated Non-woven Polypropylene Textile for Air Pollutant Filtering.

Air pollution and infectious diseases (such as the COVID-19 pandemic) have attracted considerable attention from governments and scientists worldwide to find the best solutions to address these issues. In this study, a new simultaneous antibacterial and particulate matter (PM) filtering Ag/graphene-integrated non-woven polypropylene textile was fabricated by simply immersing the textile into a Ag/graphene-containing solution. The Ag/graphene nanocomposite was prepared by reducing Ag ions on the surface of graphene nanoplatelets (GNPs) using the leaf extract. The prepared Ag/graphene textile was characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), Energy Dispersive X-ray (EDX), and contact angle measurements. The results showed excellent integration of the Ag/GNP nanocomposite into the non-woven polypropylene textile matrix. The prepared textile exhibited superhydrophobicity with a contact angle of 152°. The maximum PM removal percentage of the Ag/GNP-integrated textile was determined to be 98.5% at an Ag/GNP content of 1.5% w/w and a silicon adhesive of 1% w/w. The Ag/GNP textile exhibited high antibacterial activity toward Escherichia coli with no sign of bacteria on the surface. Remarkably, the as-prepared Ag/GNP textile was highly durable and stable and could be reused many times after washing.

Single cell G-protein coupled receptor profiling of activated kidney fibroblasts expressing transcription factor 21.

BACKGROUND AND PURPOSE: Activated fibroblasts deposit fibrotic matrix in chronic kidney disease (CKD) and G-protein coupled receptors (GPCRs) are the most druggable therapeutic targets. Here, we set out to establish a transcriptional profile that identifies activated kidney fibroblasts and the GPCRs that they express. EXPERIMENTAL APPROACH: RNA sequencing and single cell qRT-PCR were performed on mouse kidneys after unilateral ureteral obstruction (UUO). Candidate expression was evaluated in mice with UUO or diabetes or injected with adriamycin or folic acid. Intervention studies were conducted in mice with diabetes or UUO. Correlative histology was performed in human kidney tissue. KEY RESULTS: Transcription factor 21 (Tcf21)+ cells that expressed 2 or 3 of Postn, Acta2 and Pdgfra were highly enriched for fibrogenic genes and were defined as activated kidney fibroblasts. Tcf21+ α-smooth muscle actin (α-SMA)+ interstitial cells accumulated in kidneys of mice with UUO or diabetes or injected with adriamycin or folic acid, whereas renin-angiotensin system blockade attenuated increases in Tcf21 in diabetic mice. Fifty-six GPCRs were up-regulated in single Tcf21+ kidney fibroblasts, the most up-regulated being Adgra2 and S1pr3. Adenosine receptors, Adora2a/2b, were up-regulated in Tcf21+ fibroblasts and the adenosine receptor antagonist, caffeine decreased Tcf21 upregulation and kidney fibrosis in UUO mice. TCF21, ADGRA2, S1PR3 and ADORA2A/2B were each detectable in α-SMA+ interstitial cells in human kidney samples. CONCLUSION AND IMPLICATIONS: Tcf21 is a marker of kidney fibroblasts that are enriched for fibrogenic genes in CKD. Further analysis of the GPCRs expressed by these cells may identify new targets for treating CKD. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.

Comparative validation of machine learning algorithms for surgical workflow and skill analysis with the HeiChole benchmark.

PURPOSE: Surgical workflow and skill analysis are key technologies for the next generation of cognitive surgical assistance systems. These systems could increase the safety of the operation through context-sensitive warnings and semi-autonomous robotic assistance or improve training of surgeons via data-driven feedback. In surgical workflow analysis up to 91% average precision has been reported for phase recognition on an open data single-center video dataset. In this work we investigated the generalizability of phase recognition algorithms in a multicenter setting including more difficult recognition tasks such as surgical action and surgical skill. METHODS: To achieve this goal, a dataset with 33 laparoscopic cholecystectomy videos from three surgical centers with a total operation time of 22 h was created. Labels included framewise annotation of seven surgical phases with 250 phase transitions, 5514 occurences of four surgical actions, 6980 occurences of 21 surgical instruments from seven instrument categories and 495 skill classifications in five skill dimensions. The dataset was used in the 2019 international Endoscopic Vision challenge, sub-challenge for surgical workflow and skill analysis. Here, 12 research teams trained and submitted their machine learning algorithms for recognition of phase, action, instrument and/or skill assessment. RESULTS: F1-scores were achieved for phase recognition between 23.9% and 67.7% (n = 9 teams), for instrument presence detection between 38.5% and 63.8% (n = 8 teams), but for action recognition only between 21.8% and 23.3% (n = 5 teams). The average absolute error for skill assessment was 0.78 (n = 1 team). CONCLUSION: Surgical workflow and skill analysis are promising technologies to support the surgical team, but there is still room for improvement, as shown by our comparison of machine learning algorithms. This novel HeiChole benchmark can be used for comparable evaluation and validation of future work. In future studies, it is of utmost importance to create more open, high-quality datasets in order to allow the development of artificial intelligence and cognitive robotics in surgery.

Mouse genomic associations with in vitro sensitivity to simulated space radiation.

Exposure to ionizing radiation is considered by NASA to be a major health hazard for deep space exploration missions. Ionizing radiation sensitivity is modulated by both genomic and environmental factors. Understanding their contributions is crucial for designing experiments in model organisms, evaluating the risk of deep space (i.e. high-linear energy transfer, or LET, particle) radiation exposure in astronauts, and also selecting therapeutic irradiation regimes for cancer patients. We identified single nucleotide polymorphisms in 15 strains of mice, including 10 collaborative cross model strains and 5 founder strains, associated with spontaneous and ionizing radiation-induced in vitro DNA damage quantified based on immunofluorescent tumor protein p53 binding protein (53BP1) positive nuclear foci. Statistical analysis suggested an association with pathways primarily related to cellular signaling, metabolism, tumorigenesis and nervous system damage. We observed different genomic associations in early (4 and 8 h) responses to different LET radiation, while later (24 hour) DNA damage responses showed a stronger overlap across all LETs. Furthermore, a subset of pathways was associated with spontaneous DNA damage, suggesting 53BP1 positive foci as a potential biomarker for DNA integrity in mouse models. Our results suggest several mouse strains as new models to further study the impact of ionizing radiation and validate the identified genetic loci. We also highlight the importance of future human in vitro studies to refine the association of genes and pathways with the DNA damage response to ionizing radiation and identify targets for space travel countermeasures.