Fecal miRNA profiles in colorectal cancers with mucinous morphology.

Diagnostic performance of molecular markers in surrogate tissues like stool may be affected by colorectal cancer (CRC) morphological heterogeneity. The mucinous histotype represents a subgroup of CRC with a peculiar molecular program and unfavorable disease progression. However, the percentage of mucinous morphology necessary to define this subtype is still a matter of debate. In this study, we investigated whether stool miRNA profiles of CRC patients differ in patients with mucinous histopathological subtypes compared to non-mucinous cancers. In this respect, we also explored how the stool miRNA signature reported in our previous multicentric study (Pardini et al., Gastroenterology 2023) behave in this histotype. Small-RNA sequencing was performed in fecal and tissue samples of an Italian cohort (n=172), including 27 CRC with mucinous morphology (mucinous cancers with >50% mucinous morphology and those with mucinous component >5% but <50%), 58 non-mucinous CRC, and 87 colonoscopy-negative controls. Results were compared with fecal miRNA profiles of a cohort from the Czech Republic (n=98). Most of the differentially expressed (DE) stool miRNAs (n=324) were in common between CRC with mucinous morphology and non-mucinous histopathological subtypes in comparison with healthy controls. Interestingly, the altered levels of 25 fecal miRNAs previously identified distinguishing CRC cases from controls in both cohorts were also confirmed after stratification for mucinous morphology. Forty-nine miRNAs were DE exclusively in CRC with mucinous morphology and 61 in non-mucinous CRC. Mucinous cancers and those with mucinous component showed fairly similar profiles that were comparable in the Czech cohort. Among the stool DE miRNAs observed in CRC with mucinous morphology, 20 were also altered in the comparison between tumor and adjacent mucosa tissue. This study highlights miRNAs specifically altered in CRC with mucinous morphology. Nevertheless, the performance of our stool miRNA signature in accurately distinguishing CRC cases from controls was not significantly affected by this histological subtype. This aspect further supports the use of stool miRNAs for noninvasive diagnosis and screening strategies.

Early Detection and Monitoring of Anastomotic Leaks via Naked Eye-Readable, Non-Electronic Macromolecular Network Sensors.

Anastomotic leakage (AL) is the leaking of non-sterile gastrointestinal contents into a patient's abdominal cavity. AL is one of the most dreaded complications following gastrointestinal surgery, with mortality rates reaching up to 27%. The current diagnostic methods for anastomotic leaks are limited in sensitivity and specificity. Since the timing of detection directly impacts patient outcomes, developing new, fast, and simple methods for early leak detection is crucial. Here, a naked eye-readable, electronic-free macromolecular network drain fluid sensor is introduced for continuous monitoring and early detection of AL at the patient's bedside. The sensor array comprises three different macromolecular network sensing elements, each tailored for selectivity toward the three major digestive enzymes found in the drainage fluid during a developing AL. Upon digestion of the macromolecular network structure by the respective digestive enzymes, the sensor produces an optical shift discernible to the naked eye. The diagnostic efficacy and clinical applicability of these sensors are demonstrated using clinical samples from 32 patients, yielding a Receiver Operating Characteristic Area Under the Curve (ROC AUC) of 1.0. This work has the potential to significantly contribute to improved patient outcomes through continuous monitoring and early, low-cost, and reliable AL detection.

Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4.

There is a lack of systematic research exploring cross-species variation in liver lobular geometry and zonation patterns of critical drug-metabolizing enzymes, a knowledge gap essential for translational studies. This study investigated the critical interplay between lobular geometry and key cytochrome P450 (CYP) zonation in four species: mouse, rat, pig, and human. We developed an automated pipeline based on whole slide images (WSI) of hematoxylin-eosin-stained liver sections and immunohistochemistry. This pipeline allows accurate quantification of both lobular geometry and zonation patterns of essential CYP proteins. Our analysis of CYP zonal expression shows that all CYP enzymes (besides CYP2D6 with panlobular expression) were observed in the pericentral region in all species, but with distinct differences. Comparison of normalized gradient intensity shows a high similarity between mice and humans, followed by rats. Specifically, CYP1A2 was expressed throughout the pericentral region in mice and humans, whereas it was restricted to a narrow pericentral rim in rats and showed a panlobular pattern in pigs. Similarly, CYP3A4 is present in the pericentral region, but its extent varies considerably in rats and appears panlobular in pigs. CYP2D6 zonal expression consistently shows a panlobular pattern in all species, although the intensity varies. CYP2E1 zonal expression covered the entire pericentral region with extension into the midzone in all four species, suggesting its potential for further cross-species analysis. Analysis of lobular geometry revealed an increase in lobular size with increasing species size, whereas lobular compactness was similar. Based on our results, zonated CYP expression in mice is most similar to humans. Therefore, mice appear to be the most appropriate species for drug metabolism studies unless larger species are required for other purposes, e.g., surgical reasons. CYP selection should be based on species, with CYP2E1 and CYP2D6 being the most preferable to compare four species. CYP1A2 could be considered as an additional CYP for rodent versus human comparisons, and CYP3A4 for mouse/human comparisons. In conclusion, our image analysis pipeline together with suggestions for species and CYP selection can serve to improve future cross-species and translational drug metabolism studies.

Emerging role of circulating cell-free RNA as a non-invasive biomarker for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a severe neoplastic disease associated with high morbidity and mortality rates. HCC is often detected at advanced stages leading to ineffective curative treatments. Recently, liquid biopsy has emerged as a non-invasive method to identify highly specific HCC biomarkers in bodily fluids such as blood, serum, urine, and saliva. Circulating cell-free nucleic acids (cfNAs), particularly cell-free DNA (cfDNA) and cell-free RNA (cfRNA), have become promising candidates for biomarkers in liquid biopsy applications. While cfDNA presented significant challenges, researchers have turned their attention to cfRNA, which can be efficiently identified through various methods and is considered a potential biomarker for cancer diagnosis and prognosis. This review primarily focuses on studies related to detecting various cfRNA in body fluids as biomarkers. The aim is to provide a summary of available information to assist researchers in their investigations and the development of new diagnostic and prognostic tools.

Mast Cells in the Microenvironment of Hepatocellular Carcinoma Confer Favorable Prognosis: A Retrospective Study using QuPath Image Analysis Software.

The insights provided by in-situ detection of immune cells within hepatocellular carcinoma (HCC) might present information on patient outcomes. Studies investigating the expression and localization of immune cells within tumor tissues are associated with several challenges, including a lack of precise annotation for tumor regions and random selection of microscopic fields of view. QuPath is an open-source, user-friendly software that could meet the growing need for digital pathology in whole-slide image (WSI) analysis. The infiltration of HCC and adjacent tissues by CD1a+ immature dendritic cells (iDCs), CD117+ mast cells, and NKp46+ natural killer cells (NKs) cells was assessed immunohistochemically in representative specimens of 67 patients with HCC who underwent curative resection. The area fraction (AF) of positively stained cells was assessed automatically in WSIs using QuPath in the tumor center (TC), inner margin (IM), outer margin (OM), and peritumor (PT) area. The prognostic significance of immune cells was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). The AF of mast cells was significantly greater than the AF of NKs, and the AF of iDCs was significantly lower compared to NKs in each region of interest. High AFs of mast cells in the IM and PT areas were associated with longer DFS. In addition, high AF of mast cells in IM was associated with longer OS. Computer-assisted analysis using this software is a suitable tool for obtaining prognostic information for tumor-infiltrating immune cells (iDCs, mast cells, and NKs) in different regions of HCC after resection. Mast cells displayed the greatest AF in all regions of interest (ROIs). Mast cells in the peritumor region and IM showed a positive prognostic significance.

Major improvement in thyroid cancer survival of elderly patients in the Nordic countries.

OBJECTIVES: We describe age-specific survival in thyroid cancer (TC) from Denmark, Finland, Norway, and Sweden over a 50-year period. DESIGN: Population-based survival study. METHODS: Relative 5-year survival data were obtained from the NORDCAN database for the years 1972-2021. RESULTS: In the first period 1972-1976, 5-year survival in TC in Finland, Norway, and Sweden was 90% or higher, but a strong negative step-wise age gradient was observed, which was worse for men than women. Over time, survival increased, and in the final period, 2017-2021, survival for all women and Danish men up to age 69 years was about 90% or higher and, for men from the other countries, only marginally lower. Even for older women survival reached 80%, for older men somewhat less. CONCLUSIONS: Age disadvantage in TC survival was for the most part corrected over the 50-year period, and the remaining task is to boost survival for the oldest patients.

Reversible Mechanical Contraception and Endometriosis Treatment Using Stimuli-Responsive Hydrogels.

Female sterilization via fallopian tube ligation is a common procedure; However, after the operation, over 10% of women seek re-fertilization, which is frequently unsuccessful. In addition, there is evidence that fallopian tubes contribute to the spread of endometriotic tissue as they serve as channels for proinflammatory media entering the abdominal cavity via retrograde menstruation. Here, stimuli-degradable hydrogel implants are presented for the functional, biocompatible, and reversible occlusion of fallopian tubes. The hydrogel implants, designed with customized swelling properties, mechanically occlude fallopian tubes in a high-performance manner with burst pressures reaching 255-558 mmHg, exceeding normal abdominal pressures (95 mmHg). Their damage-free removal can be achieved within 30 min using near-visible UV light or a glutathione solution, employing a method akin to standard fallopian tube perfusion diagnostics. Ultrasound-guided implant placement is demonstrated using a clinical hysteroscope in a human-scale uterus model and biocompatibility in a porcine in vivo model. Importantly, the prevention of live sperm as well as endometrial cell passage through blocked fallopian tubes is demonstrated. Overall, a multifunctional system is presented that constitutes a possible means of on-demand, reversible contraception along with the first-ever mechanical approach to abdominal endometriosis prevention and treatment.

Prognostic role of macrophages and mast cells in the microenvironment of hepatocellular carcinoma after resection.

BACKGROUND: The prognostic significance of mast cells and different phenotypes of macrophages in the microenvironment of hepatocellular carcinoma (HCC) following resection is unclear. We aimed in this study to assess the local distribution of infiltrating macrophages and mast cells of specific phenotypes in tissues of HCC and to evaluate their prognostic values for survival of post-surgical patients. METHODS: The clinicopathological and follow-up data of 70 patients with HCC, who underwent curative resection of tumor from 1997 to 2019, were collected. The infiltration of CD68+ and CD163+ macrophages and CD117+ mast cells was assessed immunohistochemically in representative resected specimens of HCC and adjacent tissues. The area fraction (AF) of positively stained cells was estimated automatically using QuPath image analysis software in several regions, such as tumor center (TC), inner margin (IM), outer margin (OM), and peritumor (PT) area. The prognostic significance of immune cells, individually and in associations, for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: High AF of CD68+ macrophages in TC and IM and high AF of mast cells in IM and PT area were associated with a longer DFS. High AF of CD163+ macrophages in PT area correlated with a shorter DFS. Patients from CD163TChigh & CD68TClow group had a shorter DFS compared to all the rest of the groups, and cases with CD163IMlow & CD68IMhigh demonstrated significantly longer DFS compared to low AF of both markers. Patients from CD68IMhigh & CD163PTlow group, CD117IMhigh & CD163PTlow group, and CD117PThigh & CD163PTlow group had a significantly longer DFS compared to all other combinations of respective cells. CONCLUSIONS: The individual prognostic impact of CD68+ and CD163+ macrophages and mast cells in the microenvironment of HCC after resection depends on their abundance and location, whereas the cumulative impact is built upon combination of different cell phenotypes within and between regions.

Concomitant antihypertensive medication and outcome of patients with metastatic castration-resistant prostate cancer receiving enzalutamide or abiraterone acetate.

BACKGROUND: The introduction of novel hormonal therapies represented by enzalutamide (ENZ) and abiraterone acetate (ABI) has reached a great progress in the treatment of metastatic castration-resistant prostate cancer (mCRPC). The majority of mCRPC patients are elderly suffering from chronic co-morbidities requiring use of various concomitant medications. In the present study, we focused on impact of concomitant antihypertensive medication on the outcomes of mCRPC patients treated with ENZ or ABI. METHODS: In total, 300 patients were included and their clinical data were retrospectively analyzed. RESULTS: Angiotensin-converting enzyme inhibitors (ACEIs) represented the only concomitant medication significantly associated with survival. The median radiographic progression-free survival (rPFS) and overall survival (OS) for patients using ACEIs were 15.5 and 32.3 months compared to 10.7 and 24.0 months for those not using ACEIs (p = 0.0053 and p = 0.0238, respectively). Cox multivariable analysis revealed the use of ACEIs a significant predictive factor for both rPFS (HR = 0.704, p = 0.0364) and OS (HR = 0.592, p = 0.0185). CONCLUSION: The findings of this study suggest an association between the concomitant use of ACEIs and longer survival of mCRPC patients receiving ENZ or ABI therapy.

miRNA and lncRNA as potential tissue biomarkers in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is primary liver cancer, frequently diagnosed at advanced stages with limited therapeutic options. MicroRNAs (miRNAs) regulate target gene expression and through inhibitory competitive binding of miRNA influence cellular processes including carcinogenesis. Extensive evidence proved that certain miRNA's are specifically expressed in neoplastic tissues of HCC patients and are confirmed as important factors that can participate in the regulation of key signalling pathways in cancer cells. As such, miRNAs have a great potential in the clinical diagnosis and treatment of HCC and can improve the limitations of standard diagnosis and treatment. Long non-coding RNAs (lncRNAs) have a critical role in the development and progression of HCC. HCC-related lncRNAs have been demonstrated to exhibit abnormal expression and contribute to transformation process (such as proliferation, apoptosis, accelerated vascular formation, and gain of invasive potential) through their interaction with DNA, RNA, or proteins. LncRNAs can bind mRNAs to release their target mRNA and enable its translation. These lncRNA-miRNA networks regulate cancer cell expression and so its proliferation, apoptosis, invasion, metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and autophagy. In this narrative review, we focus on miRNA and lncRNA in HCC tumor tissue and their interaction as current tools, and biomarkers and therapeutic targets unravelled in recent years.

Large-Scale Development of Antibacterial Scaffolds: Gentamicin Sulfate-Loaded Biodegradable Nanofibers for Gastrointestinal Applications.

The ever-increasing demands of modern medicine drive the development of novel drug delivery materials. In particular, nanofibers are promising for such materials due to their favorable properties. However, most development is still carried out through laboratory techniques that do not allow extensive and reproducible characterization of materials, which slows medical research. In this work, we focus on the large-scale fabrication and testing of specific antibacterial nanofibrous materials to prevent the postoperative complications associated with the occurrence of bacterial infection. Poly-ε-caprolactone with gentamicin sulfate (antibiotic) in different concentrations was electrospun via a needleless device. The amount of antibiotics was proven by elemental analysis, UV spectrophotometry, and HPLC. The cytocompatibility of the materials was verified in vitro according to ISO 10993-5. The cell adhesion and proliferation were assessed after 2, 7, 14, and 21 days using the CCK-8 metabolic assay, fluorescence, and scanning electron microscopy. The tested nanofiber materials supported cell growth. Antibacterial tests were performed to confirm the release of gentamicin sulfate, and its antibacterial properties were proven toward Staphylococcus gallinarum and Escherichia coli bacteria. The effect of ethylene oxide sterilization was also studied. The sterilized nanofibrous layers are cytocompatible while antibacterial and therefore suitable for medical applications.

Prognostic potential of whole exome sequencing in the clinical management of metachronous colorectal cancer liver metastases.

BACKGROUND: Colorectal cancer is a highly prevalent and deadly. The most common metastatic site is the liver. We performed a whole exome sequencing analysis of a series of metachronous colorectal cancer liver metastases (mCLM) and matched non-malignant liver tissues to investigate the genomic profile of mCLM and explore associations with the patients' prognosis and therapeutic modalities. METHODS: DNA samples from mCLM and non-malignant liver tissue pairs (n = 41) were sequenced using whole exome target enrichment and their germline and somatic genetic variability, copy number variations, and mutational signatures were assessed for associations with relapse-free (RFS) and overall survival (OS). RESULTS: Our genetic analysis could stratify all patients into existing targeted therapeutic regimens. The most commonly mutated genes in mCLM were TP53, APC, and KRAS together with PIK3CA and several passenger genes like ABCA13, FAT4, PCLO, and UNC80. Patients with somatic alterations in genes from homologous recombination repair, Notch, and Hedgehog pathways had significantly prolonged RFS, while those with altered MYC pathway genes had poor RFS. Additionally, alterations in the JAK-STAT pathway were prognostic of longer OS. Patients bearing somatic variants in VIPR2 had significantly shorter OS and those with alterations in MUC16 prolonged OS. Carriage of the KRAS-12D variant was associated with shortened survival in our and external datasets. On the other hand, tumor mutation burden, mismatch repair deficiency, microsatellite instability, mutational signatures, or copy number variation in mCLM had no prognostic value. CONCLUSIONS: The results encourage further molecular profiling for personalized treatment of colorectal cancer liver metastases discerning metachronous from synchronous scenarios.

Evaluation of human papillomavirus DNA in colorectal cancer and adjacent mucosal tissue samples.

BACKGROUND: Although the role of viral agents, such as human papillomavirus (e.g. HPV16, HPV18) in colorectal cancer (CRC) has been previously investigated, results remain inconclusive. METHODS: To further evaluate the involvement of oncogenic HPV types in CRC, 40 frozen neoplastic and 40 adjacent colonic tissues collected from Italian patients were analyzed by Luminex-based assays that detect a broad spectrum of HPV types, i.e. Alpha (n = 21), Beta (n = 46) and Gamma HPVs (n = 52). In addition, 125 frozen CRC samples and 70 surrounding mucosal tissues were collected from Czech patients and analyzed by broad spectrum PCR protocols: (i) FAP59/64, (ii) FAPM1 and (iii) CUT combined with Next Generation Sequencing (NGS). RESULTS: Using Luminex-basedassays, DNA from HPV16 was detected in 5% (2/40) CRC tissues from Italian patients. One HPV16 DNA-positive CRC case was subsequently confirmed positive for E6*I mRNA. Cutaneous beta HPV types were detected in 10% (4/40) adjacent tissues only, namely HPV111 (n = 3) and HPV120 (n = 1), while gamma HPV168 (n = 1) and HPV199 (n = 1) types were detected in adjacent and in tumor tissues, respectively. The NGS analysis of the CRC Czech samples identified HPV sequences from mucosal alpha-3 (HPV89), alpha-7 (HPV18, 39, 68 and 70) and alpha-10 species (HPV11), as well as cutaneous beta-1 (HPV20, 24, 93, 98, 105,124) beta-2 (HPV23), beta-3 (HPV49) and gamma-1 species (HPV205). CONCLUSIONS: Our findings indicate that HPV types belonging to the mucosal alpha, and the 'cutaneous' beta and gamma genera can be detected in the colonic mucosal samples with a low prevalence rate and a low number of HPV reads by Luminex and NGS, respectively. However, additional studies are required to corroborate these findings.

Protein expression and localization of ABC transporters in pancreatic adenocarcinoma: Prognostic role of ABCC8.

BACKGROUND: ATP-binding cassette (ABC) transporters translocate various substances across cellular membranes. Their deregulation may cause cancer drug resistance or perturbations in the supply of building blocks for cancer cells and modify patients' prognosis. This study investigated protein expression and cellular localization of the previously suggested putative prognostic biomarkers - ABCB2/TAP1, ABCC7/CFTR, ABCC8/SUR1, and ABCD4 in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Protein expression and localization were assessed by immunohistochemistry in formalin-fixed paraffin-embedded primary tumor tissue blocks of 61 PDAC patients and associated with clinical data and the survival of patients. RESULTS: No CFTR protein expression was observed in PDAC, while TAP1 and ABCC8 were expressed predominantly in the cytoplasm of tumor cells. Most samples (81 %) had detectable both membranous and cytoplasmic ABCD4 staining and 42 % had ABCD4 expressed in the apical orientation. Negative membranous ABCD4 staining was significantly more frequent in advanced stage III or IV tumors (p = 0.022). Small or medium counts of individual ABCC8-positive cells in the stroma surrounding tumor tubules were also more often found in stage III or IV (p = 0.044). Patients with moderate or strong ABCC8 cytoplasmic staining intensity in tumor cells had a 3.5-fold higher risk of disease progression than those with weak staining (p = 0.002). CONCLUSIONS: The study shows for the first time that the cytoplasmic ABCC8 protein expression has prognostic value in PDAC.

Periphery of porcine hepatic lobes has the smallest length density of hepatic sinusoids and bile canaliculi: A stereological histological study with implications for liver biopsies.

BACKGROUND: Porcine liver is widely used in hepatologic research as a large animal model with many anatomical and physiological similarities with humans. However, only limited information on porcine liver spatial microstructure has been published, especially regarding the hepatic sinusoids and bile canaliculi. The aim of our study was to quantify the sinusoidal and bile canalicular network in healthy male and female porcine livers and to map the variability of these structures with heterogenous distribution to improve the evaluability of liver biopsy samples. METHODS: Livers from 12 healthy piglets (6 females and 6 neutered males) were sampled into 36 tissue samples per organ, representing six hepatic lobes and three different regions related to the hepatic vasculature (peripheral, paracaval and paraportal region). Histological sections were processed with a random orientation of the cutting plane. The endothelium and the bile canaliculi were stained using Ricinus communis agglutinin I lectin histochemistry. The length densities of hepatic sinusoids LV(sinusoids,liver), of bile canaliculi LV(bile canaliculi,liver) and volume fraction VV(sinusoids,liver) and surface density SV(sinusoids,liver) of sinusoids were estimated using stereological methods. The newly acquired morphometric data were compared with previously published data on density of porcine hepatocytes and fractions of connective tissue. RESULTS: The peripheral region had smallest LV(sinusoids,liver), smallest LV(bile canaliculi,liver) and greatest VV(sinusoids,liver). The six hepatic lobes had statistically comparable length densities of both sinusoids and bile canaliculi, but the left lateral lobe had smallest VV(sinusoids,liver). Regions with greater LV(sinusoids,liver) had also greater LV(bile canaliculi,liver) and SV(sinusoids,liver) and were accompanied by greater density of smaller hepatocytes. Regions with smaller LV(sinusoids,liver) and LV(bile canaliculi,liver) contained a greater fraction of interlobular connective tissue. CONCLUSIONS: The length density of hepatic sinusoids is smaller in the peripheral regions of the porcine liver than in other regions related to the hepatic vasculature - paracaval and paraportal regions, and smaller in castrated males than in females. Greater length density of liver sinusoids was linked with greater local density of bile canaliculi, with local increase in the density of smaller hepatocytes and, simultaneously, with smaller fractions of hepatic connective tissue. The intrahepatic and inter-sexual variability of the porcine liver morphology needs to be taken into account when designing and interpreting experiments involving the histological quantification of the microvascular network. The complete primary morphometric data describing the distribution of morphometric parameters within porcine liver were made available in a form facilitating the power analysis to justify the minimal number of tissue samples or animals required when designing further histological evaluation studies. The macroscopic map of microvessels and bile canaliculi variability facilitates their assessment in liver biopsies in the pig.

Nanothermometry-Enabled Intelligent Laser Tissue Soldering.

While often life-saving, surgical resectioning of diseased tissues puts patients at risk for post-operative complications. Sutures and staples are well-accepted and routinely used to reconnect tissues, however, their mechanical mismatch with biological soft tissue and invasiveness contribute to wound healing complications, infections, and post-operative fluid leakage. In principle, laser tissue soldering offers an attractive, minimally-invasive alternative for seamless soft tissue fusion. However, despite encouraging experimental observations, including accelerated healing and lowered infection risk, critical issues related to temperature monitoring and control during soldering and associated complications have prevented their clinical exploitation to date. Here, intelligent laser tissue soldering (iSoldering) with integrated nanothermometry is introduced as a promising yet unexplored approach to overcome the critical shortcomings of laser tissue soldering. It demonstrates that adding thermoplasmonic and nanothermometry nanoparticles to proteinaceous solders enables heat confinement and non-invasive temperature monitoring and control, offering a route to high-performance, leak-tight tissue sealing even at deep tissue sites. The resulting tissue seals exhibit excellent mechanical properties and resistance to chemically-aggressive digestive fluids, including gastrointestinal juice. The iSolder can be readily cut and shaped by surgeons to optimally fit the tissue defect and can even be applied using infrared light from a medically approved light source, hence fulfilling key prerequisites for application in the operating theatre. Overall, iSoldering enables reproducible and well-controlled high-performance tissue sealing, offering new prospects for its clinical exploitation in diverse fields ranging from cardiovascular to visceral and plastic surgery.

Surgical Sealant with Integrated Shape-Morphing Dual Modality Ultrasound and Computed Tomography Sensors for Gastric Leak Detection.

Postoperative anastomotic leaks are the most feared complications after gastric surgery. For diagnostics clinicians mostly rely on clinical symptoms such as fever and tachycardia, often developing as a result of an already fully developed, i.e., symptomatic, surgical leak. A gastric fluid responsive, dual modality, electronic-free, leak sensor system integrable into surgical adhesive suture support materials is introduced. Leak sensors contain high atomic number carbonates embedded in a polyacrylamide matrix, that upon exposure to gastric fluid convert into gaseous carbon dioxide (CO2 ). CO2 bubbles remain entrapped in the hydrogel matrix, leading to a distinctly increased echogenic contrast detectable by a low-cost and portable ultrasound transducer, while the dissolution of the carbonate species and the resulting diffusion of the cation produces a markedly reduced contrast in computed tomography imaging. The sensing elements can be patterned into a variety of characteristic shapes and can be combined with nonreactive tantalum oxide reference elements, allowing the design of shape-morphing sensing elements visible to the naked eye as well as artificial intelligence-assisted automated detection. In summary, shape-morphing dual modality sensors for the early and robust detection of postoperative complications at deep tissue sites, opening new routes for postoperative patient surveillance using existing hospital infrastructure is reported.

A Fecal MicroRNA Signature by Small RNA Sequencing Accurately Distinguishes Colorectal Cancers: Results From a Multicenter Study.

BACKGROUND & AIMS: Fecal tests currently used for colorectal cancer (CRC) screening show limited accuracy in detecting early tumors or precancerous lesions. In this respect, we comprehensively evaluated stool microRNA (miRNA) profiles as biomarkers for noninvasive CRC diagnosis. METHODS: A total of 1273 small RNA sequencing experiments were performed in multiple biospecimens. In a cross-sectional study, miRNA profiles were investigated in fecal samples from an Italian and a Czech cohort (155 CRCs, 87 adenomas, 96 other intestinal diseases, 141 colonoscopy-negative controls). A predictive miRNA signature for cancer detection was defined by a machine learning strategy and tested in additional fecal samples from 141 CRC patients and 80 healthy volunteers. miRNA profiles were compared with those of 132 tumors/adenomas paired with adjacent mucosa, 210 plasma extracellular vesicle samples, and 185 fecal immunochemical test leftover samples. RESULTS: Twenty-five miRNAs showed altered levels in the stool of CRC patients in both cohorts (adjusted P < .05). A 5-miRNA signature, including miR-149-3p, miR-607-5p, miR-1246, miR-4488, and miR-6777-5p, distinguished patients from control individuals (area under the curve [AUC], 0.86; 95% confidence interval [CI], 0.79-0.94) and was validated in an independent cohort (AUC, 0.96; 95% CI, 0.92-1.00). The signature classified control individuals from patients with low-/high-stage tumors and advanced adenomas (AUC, 0.82; 95% CI, 0.71-0.97). Tissue miRNA profiles mirrored those of stool samples, and fecal profiles of different gastrointestinal diseases highlighted miRNAs specifically dysregulated in CRC. miRNA profiles in fecal immunochemical test leftover samples showed good correlation with those of stool collected in preservative buffer, and their alterations could be detected in adenoma or CRC patients. CONCLUSIONS: Our comprehensive fecal miRNome analysis identified a signature accurately discriminating cancer aimed at improving noninvasive diagnosis and screening strategies.

Interleukin-22 promotes the proliferation and migration of hepatocellular carcinoma cells via the phosphoinositide 3-kinase (PI3K/AKT) signaling pathway.

BACKGROUND: Interleukin-22 (IL-22) is a pro-inflammatory cytokine released during the immune response in chronic liver injury. Although IL-22 mediates tissue regeneration, its uncontrolled production may generate a carcinogenic environment resulting in hepatocellular carcinoma (HCC). This study aims to identify the effect of IL-22 on anti-apoptotic and metastatic genes and the molecular pathways responsible for IL-22-mediated hepatic carcinogenesis. METHODS AND RESULTS: Three cancerous liver lines, HepG2, SNU-387, Huh7, and one normal liver line, THLE2, were treated with IL-22. RT-qPCR analysis was conducted to study the role of IL-22 in altering the expression levels of anti-apoptotic genes, MCL-1 and BCL-2, and metastatic genes, MMP-7 and MMP-9. A significant increase in expression levels of these genes was observed after IL-22 treatment. Furthermore, to explore the major pathways involved in IL-22-mediated upregulation of anti-apoptotic and metastatic genes, cells were treated with inhibitors of JAK/STAT and PI3K/AKT pathways along with IL-22. Resultantly, a significant decrease in expression levels of target genes was observed, indicating the involvement of JAK/STAT and PI3K/AKT signaling cascades in IL-22-mediated oncogenesis. Finally, Cell Scratch assay was performed to check the effect of IL-22 and inhibitors of JAK/STAT and PI3K/AKT on the metastatic potential of liver cells. While migration was observed in Huh7 and THLE2 cells treated with IL-22, no migration was observed in cells treated with IL-22 along with JAK/STAT and PI3K/AKT inhibitors. Results indicate that IL-22 encourages metastasis in HCC cells via the JAK/STAT and PI3K/AKT pathways. CONCLUSION: Results showed that IL-22 upregulates anti-apoptotic and metastatic genes in HCC through JAK/STAT and PI3K/AKT signaling pathways.