Microbiota Metabolites in Health and Disease.

Metabolism is one of the strongest drivers of interkingdom interactions-including those between microorganisms and their multicellular hosts. Traditionally thought to fuel energy requirements and provide building blocks for biosynthetic pathways, metabolism is now appreciated for its role in providing metabolites, small-molecule intermediates generated from metabolic processes, to perform various regulatory functions to mediate symbiotic relationships between microbes and their hosts. Here, we review recent advances in our mechanistic understanding of how microbiota-derived metabolites orchestrate and support physiological responses in the host, including immunity, inflammation, defense against infections, and metabolism. Understanding how microbes metabolically communicate with their hosts will provide us an opportunity to better describe how a host interacts with all microbes-beneficial, pathogenic, and commensal-and an opportunity to discover new ways to treat microbial-driven diseases.

Cold storage and cryopreservation methods for spermatozoa of the sea urchins Lytechinus pictus and Strongylocentrotus purpuratus.

BACKGROUND: Sea urchins have contributed greatly to knowledge of fertilization, embryogenesis, and cell biology. However, until now, they have not been genetic model organisms because of their long generation times and lack of tools for husbandry and gene manipulation. We recently established the sea urchin Lytechinus pictus, as a multigenerational model Echinoderm, because of its relatively short generation time of 4-6 months and ease of laboratory culture. To take full advantage of this new multigenerational species, methods are needed to biobank and share genetically modified L. pictus sperm. RESULTS: Here, we describe a method, based on sperm ion physiology that maintains L. pictus and Strongylocentrotus purpuratus sperm fertilizable for at least 5-10 weeks when stored at 0°C. We also describe a new method to cryopreserve sperm of both species. Sperm of both species can be frozen and thawed at least twice and still give rise to larvae that undergo metamorphosis. CONCLUSIONS: The simple methods we describe work well for both species, achieving >90% embryo development and producing larvae that undergo metamorphosis to juvenile adults. We hope that these methods will be useful to others working on marine invertebrate sperm.

Relevance of the calculation of the diffusion coefficient in a capillary electrophoresis experiment.

This paper analyzes the role of the diffusion coefficient in the movement of analytes that can reversibly react with a selector given a product in the presence of drift. The problem mimics the movement of enantiomers in a capillary electrophoresis experiment. As is well known, the signal in the capillary must be sharp enough to make a good determination of the effective mobility of the analytes being analyzed. The essence of the technique is based on fast interconversion rates. Therefore, the effective diffusion coefficient must be negligible during the experiment. In the present work, an exact expression for both the apparent mobility and the diffusion coefficient is obtained. This is done by writing the rate equations governing the process and solving them using the generating function technique. The effective mobility coincides with the Wren and Rowe equation, whereas the diffusion coefficient allows us to determine the values of the parameters to be taken into account so that this quantity is minimal or close to zero. On the other hand, the numerical solution of the kinetic equations and Monte Carlo simulations allow us to follow the signal in the capillary and to determine its space-time evolution.

Prognostic value of Mandard score and nodal status for recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma.

BACKGROUND: This study evaluated the association of pathological tumour response (tumour regression grade, TRG) and a novel scoring system, combining both TRG and nodal status (TRG-ypN score; TRG1-ypN0, TRG>1-ypN0, TRG1-ypN+ and TRG>1-ypN+), with recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma. METHODS: This Dutch nationwide cohort study included patients treated with neoadjuvant chemoradiotherapy followed by oesophagectomy for distal oesophageal or gastro-oesophageal junctional adenocarcinoma between 2007 and 2016. The primary endpoint was the association of Mandard score and TRG-ypN score with recurrence patterns (rate, location, and time to recurrence). The secondary endpoint was overall survival. RESULTS: Among 2746 inclusions, recurrence rates increased with higher Mandard scores (TRG1 30.6%, TRG2 44.9%, TRG3 52.9%, TRG4 61.4%, TRG5 58.2%; P < 0.001). Among patients with recurrent disease, the distribution (locoregional versus distant) was the same for the different TRG groups. Patients with TRG1 developed more brain recurrences (17.7 versus 9.8%; P = 0.001) and had a longer mean overall survival (44 versus 35 months; P < 0.001) than those with TRG>1. The TRG>1-ypN+ group had the highest recurrence rate (64.9%) and worst overall survival (mean 27 months). Compared with the TRG>1-ypN0 group, patients with TRG1-ypN+ had a higher risk of recurrence (51.9 versus 39.6%; P < 0.001) and worse mean overall survival (33 versus 41 months; P < 0.001). CONCLUSION: Improved tumour response to neoadjuvant therapy was associated with lower recurrence rates and higher overall survival rates. Among patients with recurrent disease, TRG1 was associated with a higher incidence of brain recurrence than TRG>1. Residual nodal disease influenced prognosis more negatively than residual disease at the primary tumour site.

Fabrication of Micropatterns of Aligned Collagen Fibrils.

Many tissues in vivo contain aligned structures such as filaments, fibrils, and fibers, which expose cells to anisotropic structural and topographical cues that range from the nanometer to micrometer scales. Understanding how cell behavior is regulated by these cues during physiological and pathological processes (e.g., wound healing, cancer invasion) requires substrates that can expose cells to anisotropic cues over several length scales. In this study, we developed a novel method of fabricating micropatterns of aligned collagen fibrils of different geometry onto PDMS-coated glass coverslips that allowed us to investigate the roles of topography and confinement on corneal cell behavior. When corneal cells were cultured on micropatterns of aligned collagen fibrils in the absence of confinement, the degree of cell alignment increased from 40 ± 14 to 82 ± 5% as the size of the micropattern width decreased from 750 to 50 µm. Although the cell area (∼2500 µm2), cell length (∼160 µm), and projected nuclear area (∼175 µm2) were relatively constant on the different micropattern widths, cells displayed an increased aspect ratio as the width of the aligned collagen fibril micropatterns decreased. We also observed that the morphology of cells adhering to the surrounding uncoated PDMS was dependent upon both the size of the aligned collagen fibril micropattern and the distance from the micropatterns. When corneal cells were confined to the micropatterns of aligned collagen fibrils by a Pluronic coating to passivate the surrounding area, a similar trend in increasing cell alignment was observed (35 ± 10 to 89 ± 2%). However, the projected nuclear area decreased significantly (∼210 to 130 µm2) as the micropattern width decreased from 750 to 50 µm. The development of this method allows for the deposition of aligned collagen fibril micropatterns of different geometries on a transparent and elastic substrate and provides an excellent model system to investigate the role of anisotropic cues in cell behavior.

What are the short- and long-term abdominal consequences of an omentectomy? A systematic review.

This review provides an overview regarding the abdominal effects of an omentectomy, with or without extra-peritoneal reconstructions. In general, reported complication rates were low. Short-term complications involved ileus, bowel stenosis, abdominal abscess and sepsis (range 0.0%-23%). Donor-site hernia was mainly reported as long-term complication (up to 32%) and negligible gastrointestinal complications were observed. However, the level of evidence and methodological quality are quite low with a maximum of 8.5 years follow-up.

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster. METHODS: Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3. RESULTS: Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3. CONCLUSIONS: During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis.

Sensor system for analysis of biofilm sensitivity to ampicillin.

The resistance of biofilms to antibiotics is a key factor that makes bacterial infections unsusceptible to antimicrobial therapy. The results of classical tests of cell sensitivity to antibiotics cannot be used to predict therapeutic success in infections associated with biofilm formation. We describe a simple and rapid method for the real-time evaluation of bacterial biofilm sensitivity to antibiotics, with Pseudomonas putida and ampicillin as examples. The method uses an electric biosensor to detect the difference between changes in the biofilm electric polarizability, thereby evaluating antibiotic sensitivity. The electric signals showed that P. putida biofilms were susceptible to ampicillin and that at high antibiotic concentrations, the biofilms differed markedly in their susceptibility (dose-dependent effect). The sensor also detected differences between biofilms before and after ampicillin treatment. The electric-signal changes enabled us to describe the physical picture of the processes occurring in bacterial biofilms in the presence of ampicillin. The approach used in this study is promising for evaluating the activity of various compounds against biofilms, because it permits a conclusion about the antibiotic sensitivity of biofilm bacteria to be made in real time and in a short period (analysis time, not longer than 20 min). An added strong point is that analysis can be done directly in liquid, without preliminary sample preparation. KEY POINTS: • Sensor system to analyze biofilm antimicrobial susceptibility is described. • The signal change depended on the ampicillin concentration (dose-dependent effect). • The sensor allows real-time determination of the antibiofilm effect of ampicillin.

Survivorship After Neurocritical Care: A Scoping Review of Outcomes Beyond Physical Status.

Following intensive care unit hospitalization, survivors of acute neurological injury often experience debilitating short-term and long-term impairments. Although the physical/motor impairments experienced by survivors of acute neurological injury have been described extensively, fewer studies have examined cognitive, mental health, health-related quality of life (HRQoL), and employment outcomes. This scoping review describes the publication landscape beyond physical and/or motor sequelae in neurocritical care survivors. Databases were searched for terms related to critical illness, intensive care, and outcomes from January 1970 to March 2022. English-language studies of critically ill adults with a primary neurological diagnosis were included if they reported on at least one outcome of interest: cognition, mental health, HRQoL or employment. Data extraction was performed in duplicate for prespecified variables related to study outcomes. Of 16,036 abstracts screened, 74 citations were identified for inclusion. The studies encompassed seven worldwide regions and eight neurocritical diagnosis categories. Publications reporting outcomes of interest increased from 3 before the year 2000 to 71 after. Follow-up time points included ≤ 1 (n = 15 [20%] citations), 3 (n = 28 [38%]), 6 (n = 28 [38%]), and 12 (n = 21 [28%]) months and 1 to 5 (n = 19 [26%]) and > 5 years (n = 8 [11%]), with 28 (38%) citations evaluating outcomes at multiple time points. Sixty-six assessment tools were used to evaluate the four outcomes of interest: 22 evaluating HRQoL (56 [76%] citations), 21 evaluating cognition (20 [27%] citations), 21 evaluating mental health (18 [24%] citations), and 2 evaluating employment (9 [12%] citations). This scoping review aimed to better understand the literature landscape regarding nonphysical outcomes in survivors of neurocritical care. Although a rising number of publications highlight growing awareness, future efforts are needed to improve study consistency and comparability and characterize outcomes in a disease-specific manner, including outlining of a minimum core outcomes set and associated assessment tools.

Determining Factors in the Success of Direct Pulp Capping: A Systematic Review.

AIM: To elucidate the factors that determine the success of direct pulp capping (DPC) in permanent teeth with pulp exposure due to dental caries. MATERIALS AND METHODS: A comprehensive electronic search from 1980 to 2023 across PubMed, Scopus, and ISI Web databases was conducted using specific keywords and MeSH terms in Q1 or Q2 journals. Only prospective/retrospective clinical studies in English on 15 or more human permanent teeth with carious pulpal exposure treated with DPC agents-mineral trioxide aggregate (MTA), Biodentine, or calcium hydroxide with a rubber dam and minimum 1-year follow-up, were considered. The factors retrieved and analyzed were based on study design, patient age, sample size, type of cavity, exposure size and location, pulp diagnosis, solutions to achieve hemostasis, hemostasis time, capping material, restoration type, follow-up period, methods of evaluation, and overall success. REVIEW RESULTS: Out of 680 articles, only 16 articles were selected for the present systematic review on application of the selection criteria. A wide age range of patients from 6 to 88 years were considered among these studies with sample sizes ranging from 15 to 245 teeth with reversible pulpitis being the predominant diagnosis of the cases. Mineral trioxide aggregate as a capping material was evaluated in 4 studies as a lone agent, while compared with other capping agents such as biodentine or calcium hydroxide in 7 studies. The follow-up period ranged from 9 days to nearly 80 months. While both clinical and radiographic evaluation was carried out in all studies, cold testing dominated the clinical tests while IOPR was the common radiograph considered. Mineral trioxide aggregate success rate was higher and similar to biodentine than calcium hydroxide. CONCLUSION: Direct pulp capping has a high and predictable success rate in permanent teeth with carious exposure to reversible and irreversible pulpitis. Currently, mineral trioxide aggregate and biodentine have better long-term results in DPC than calcium hydroxide, hence, they should be used as an alternative to calcium hydroxide. Definitive restoration within a short period improves long-term prognosis. CLINICAL SIGNIFICANCE: The significance of this review lies in its provision of evidence-based information on the effectiveness of DPC and the factors that influence its success. By considering these factors, clinicians can optimize treatment outcomes and improve the long-term prognosis of the treated teeth. This systematic review serves as a valuable resource for clinicians and researchers in the field of endodontics. How to cite this article: Gomez-Sosa JF, Granone-Ricella M, Rosciano-Alvarez M, et al. Determining Factors in the Success of Direct Pulp Capping: A Systematic Review. J Contemp Dent Pract 2024;25(4):392-401.

Participant retention in follow-up studies of intensive care unit survivors - A scoping review.

OBJECTIVE: To synthesize participant retention data and related reporting in studies evaluating post-hospital outcomes of survivors of critical illness after an intensive care unit (ICU) stay. REVIEW METHOD USED: A synthesis of literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. DATA SOURCES: PubMed, EMBASE, PsycINFO, Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Controlled Trials Registry. Hand searched reference lists and personal files of relevant narrative and systematic review articles. REVIEW METHODS: Articles were screened by pairs of independent reviewers. Similarly, data were abstracted by pairs of data collectors, with conflicts resolved by consensus or by a third reviewer. RESULTS: We included 243 publications, from 225 unique studies of 87,602 participants. Participant retention could not be calculated for any time-points in 13% of studies nor in 22% of all follow-up time-points. Retention ranged from 18-100%. When compared to follow-up before 1-month, retention at each later timepoint was not significantly different. Age and sex were not associated with retention and more recent studies had decreased retention (odds ratio: 0.94 [95% confidence interval: 0.92-0.96; p < 0.001]). Reporting of retention-related study methodology was inconsistent. CONCLUSION: Retention rate could not be calculated for 22% of study follow-up time-points, with retention at the remaining time-points generally being high (≥85%), but with high variability (18% - 100%). ICU survivorship research could be improved via: (i) more detailed guidance on reporting participant retention, and (ii) use of existing resources and best practices to facilitate better study design and to improve participant retention to preserve statistical power and reduce selection bias.

Prescription of potentially inappropriate medications after an intensive care unit stay for acute respiratory failure.

BACKGROUND: Among survivors of critical illness, prescription of potentially inappropriate medications (PIM) at hospital discharge is thought to be an important, modifiable patient safety concern. To date, there are little empirical data evaluating this issue. RESEARCH QUESTION: The objective of this study was to determine the frequency of PIM prescribed to survivors of acute respiratory failure (ARF) at hospital discharge and explore their association with readmissions or death within 90 days of hospital discharge. STUDY DESIGN AND METHODS: Prospective multicenter cohort study of ARF survivors admitted to ICUs and discharged home. Prospective of new PIMs with a high-adverse-effect profile ("high impact") at discharge was the primary exposure. Potential inappropriateness was determined by a structured consensus process using Screening Tool of Older Persons' Prescriptions-Screening Tool to Alert to Right Treatment, Beers' criteria, and clinical context of prescriptions by a multidisciplinary team. Covariate balancing propensity score was used for the primary analysis. RESULTS: Of the 195 Addressing Post Intensive Care Syndrome-01 (APICS-01) patients, 169 (87%) had ≥1 new medications prescribed at discharge, with 154 (91.1%) prescribed with one or more high-impact (HI) medications. Patients were prescribed a median of 5 [3-7] medications, of which 3 [1-4] were HI. Twenty percent of HI medications were potentially inappropriate. Medications with significant central nervous system side-effects were most prescribed potentially inappropriately. Forty-six (30%) patients experienced readmission or death within 90 days of hospital discharge. After adjusting for prespecified covariates, the association between prescription of potentially inappropriate HI medications and the composite primary outcome did not meet the prespecified threshold for statistical significance (risk ratio: 0.54; 0.26-1.13; p = 0.095) or with the constituent endpoints: readmission (risk ratio: 0.57, 0.27-1.11) or death (0.7, 0.05-9.32). CONCLUSION: At hospital discharge, most ARF survivors are prescribed medications with a high-adverse-effect profile and approximately one-fifth are potentially inappropriate. Although prescription of such medications was not associated with 90-day readmissions and mortality, these results highlight an area for additional investigation.

Trends in Distal Esophageal and Gastroesophageal Junction Cancer Care: The Dutch Nationwide Ivory Study.

OBJECTIVE: This study evaluated the nationwide trends in care and accompanied postoperative outcomes for patients with distal esophageal and gastro-esophageal junction cancer. SUMMARY OF BACKGROUND DATA: The introduction of transthoracic esophagectomy, minimally invasive surgery, and neo-adjuvant chemo(radio)therapy changed care for patients with esophageal cancer. METHODS: Patients after elective transthoracic and transhiatal esophagectomy for distal esophageal or gastroesophageal junction carcinoma in the Netherlands between 2007-2016 were included. The primary aim was to evaluate trends in both care and postoperative outcomes for the included patients. Additionally, postoperative outcomes after transthoracic and tran-shiatal esophagectomy were compared, stratified by time periods. RESULTS: Among 4712 patients included, 74% had distal esophageal tumors and 87% had adenocarcinomas. Between 2007 and 2016, the proportion of transthoracic esophagectomy increased from 41% to 81%, and neo-adjuvant treatment and minimally invasive esophagectomy increased from 31% to 96%, and from 7% to 80%, respectively. Over this 10-year period, postoperative outcomes improved: postoperative morbidity decreased from 66.6% to 61.8% ( P = 0.001), R0 resection rate increased from 90.0% to 96.5% (P <0.001), median lymph node harvest increased from 15 to 19 ( P <0.001), and median survival increased from 35 to 41 months ( P = 0.027). CONCLUSION: In this nationwide cohort, a transition towards more neo-adju-vant treatment, transthoracic esophagectomy and minimally invasive surgery was observed over a 10-year period, accompanied by decreased postoperative morbidity, improved surgical radicality and lymph node harvest, and improved survival.

Association Between Unmet Nonmedication Needs After Hospital Discharge and Readmission or Death Among Acute Respiratory Failure Survivors: A Multicenter Prospective Cohort Study.

OBJECTIVES: To characterize early unmet nonmedication discharge needs (UDNs), classified as durable medical equipment (DME), home health services (HHS), and follow-up medical appointments (FUAs) and explore their association with 90-day readmission and mortality among survivors of acute respiratory failure (ARF) who were discharged home. DESIGN: Prospective multicenter cohort study. SETTING: Six academic medical centers across United States. PARTICIPANTS: Adult survivors of ARF who required an ICU stay and were discharged home from hospital. INTERVENTIONS: None. Exposure of interest was the proportion of UDN for the following categories: DME, HHS, and FUA ascertained within 7-28 days after hospital discharge. MEASUREMENTS AND MAIN RESULTS: Two hundred eligible patients were recruited between January 2019 and August 2020. One-hundred ninety-five patients were included in the analytic cohort: 118 were prescribed DME, 134 were prescribed HHS, and 189 needed at least one FUA according to discharge plans. 98.4% (192/195) had at least one identified nonmedication need at hospital discharge. Median (interquartile range) proportion of unmet needs across three categories were 0 (0-15%) for DME, 0 (0-50%) for HHS, and 0 (0-25%) for FUA, and overall was 0 (0-20%). Fifty-six patients (29%) had 90-day death or readmission. After adjusting for prespecified covariates, having greater than the median level of unmet needs was not associated with an increased risk of readmission or death within 90 days of discharge (risk ratio, 0.89; 0.51-1.57; p = 0.690). Age, hospital length of stay, Acute Physiology and Chronic Health Evaluation II severity of illness score, and Multidimensional Scale Perceived Social Support score were associated with UDN. CONCLUSIONS: UDN were common among survivors of ARF but not significantly associated a composite outcome of 90-day readmission or death. Our results highlight the substantial magnitude of UDN and identifies areas especially vulnerable to lapses in healthcare coordination.

Prioritizing a research agenda on built environments and physical activity: a twin panel Delphi consensus process with researchers and knowledge users.

BACKGROUND: The growth of urban dwelling populations globally has led to rapid increases of research and policy initiatives addressing associations between the built environment and physical activity (PA). Given this rapid proliferation, it is important to identify priority areas and research questions for moving the field forward. The objective of this study was to identify and compare research priorities on the built environment and PA among researchers and knowledge users (e.g., policy makers, practitioners). METHODS: Between September 2022 and April 2023, a three-round, modified Delphi survey was conducted among two independent panels of international researchers (n = 38) and knowledge users (n = 23) to identify similarities and differences in perceived research priorities on the built environment and PA and generate twin 'top 10' lists of the most important research needs. RESULTS: From a broad range of self-identified issues, both panels ranked in common the most pressing research priorities including stronger study designs such as natural experiments, research that examines inequalities and inequities, establishing the cost effectiveness of interventions, safety and injuries related to engagement in active transportation (AT), and considerations for climate change and climate adaptation. Additional priorities identified by researchers included: implementation science, research that incorporates Indigenous perspectives, land-use policies, built environments that support active aging, and participatory research. Additional priorities identified by knowledge users included: built environments and PA among people living with disabilities and a need for national data on trip chaining, multi-modal travel, and non-work or school-related AT. CONCLUSIONS: Five common research priorities between the two groups emerged, including (1) to better understand causality, (2) interactions with the natural environment, (3) economic evaluations, (4) social disparities, and (5) preventable AT-related injuries. The findings may help set directions for future research, interdisciplinary and intersectoral collaborations, and funding opportunities.

Ancient engineering of fish capture and storage in southwest Florida.

In the 16th century, the Calusa, a fisher-gatherer-hunter society, were the most politically complex polity in Florida, and the archaeological site of Mound Key was their capital. Based on historic documents, the ruling elite at Mound Key controlled surplus production and distribution. The question remains exactly how such surplus pooling occurred and when such traditions were elaborated on and reflected in the built environment. Our work focuses on the "watercourts" and associated areas at Mound Key. These subrectangular constructions of shell and other sediments around centralized inundated areas have been variously interpreted. Here, we detail when these enclosures were constructed and their engineering and function. We argue that these structures were for large surplus capture and storage of aquatic resources that were controlled and managed by corporate groups.

An ErbB2 splice variant lacking exon 16 drives lung carcinoma.

Lung cancer causes more deaths annually than any other malignancy. A subset of non-small cell lung cancer (NSCLC) is driven by amplification and overexpression or activating mutation of the receptor tyrosine kinase (RTK) ERBB2 In some contexts, notably breast cancer, alternative splicing of ERBB2 causes skipping of exon 16, leading to the expression of an oncogenic ERBB2 isoform (ERBB2ΔEx16) that forms constitutively active homodimers. However, the broader implications of ERBB2 alternative splicing in human cancers have not been explored. Here, we have used genomic and transcriptomic analysis to identify elevated ERBB2ΔEx16 expression in a subset of NSCLC cases, as well as splicing site mutations facilitating exon 16 skipping and deletions of exon 16 in a subset of these lung tumors and in a number of other carcinomas. Supporting the potential of ERBB2ΔEx16 as a lung cancer driver, its expression transformed immortalized lung epithelial cells while a transgenic model featuring inducible ERBB2ΔEx16 specifically in the lung epithelium rapidly developed lung adenocarcinomas following transgene induction. Collectively, these observations indicate that ERBB2ΔEx16 is a lung cancer oncogene with potential clinical importance for a proportion of patients.

Liquid Biopsy in Lung Cancer: Biomarkers for the Management of Recurrence and Metastasis.

Liquid biopsies have emerged as a promising tool for the detection of metastases as well as local and regional recurrence in lung cancer. Liquid biopsy tests involve analyzing a patient's blood, urine, or other body fluids for the detection of biomarkers, including circulating tumor cells or tumor-derived DNA/RNA that have been shed into the bloodstream. Studies have shown that liquid biopsies can detect lung cancer metastases with high accuracy and sensitivity, even before they are visible on imaging scans. Such tests are valuable for early intervention and personalized treatment, aiming to improve patient outcomes. Liquid biopsies are also minimally invasive compared to traditional tissue biopsies, which require the removal of a sample of the tumor for further analysis. This makes liquid biopsies a more convenient and less risky option for patients, particularly those who are not good candidates for invasive procedures due to other medical conditions. While liquid biopsies for lung cancer metastases and relapse are still being developed and validated, they hold great promise for improving the detection and treatment of this deadly disease. Herein, we summarize available and novel approaches to liquid biopsy tests for lung cancer metastases and recurrence detection and describe their applications in clinical practice.

Mechanically Stimulated Solid-State Interaction of Platinum Tetrachloride with Sodium ß-Diketonates.

A new mechanically stimulated solid-state reaction of PtCl4 with sodium ß-diketonates has been discovered. Platinum (II) ß-diketonates were obtained by grinding excess sodium trifluoroacetylacetonate Na(tfac) or hexafluoroacetylacetonate Na(hfac) in a vibration ball mill, followed by subsequent heating of the resulting mixture. The reactions occur under much milder conditions (at about 170 °C) compared to similar reactions of PtCl2 or K2PtCl6 (at about 240 °C). Excess diketonate salt plays the role of a reducing agent in the conversion of Pt (IV) salt to Pt (II) compounds. The effect of grinding on properties of the ground mixtures was studied by XRD, IR, and thermal analysis methods. The difference in the course of the interaction of PtCl4 with Na(hfac) or Na(tfac) indicates the dependence of the reaction on the ligand properties. The probable reaction mechanisms were discussed. This method of synthesis of platinum (II) ß-diketonates makes it possible to substantially reduce the variety of reagents used, the number of reaction steps, the reaction time, the use of solvents, and waste generation compared to conventional solution-based methods.

A dual cohesin-dockerin complex binding mode in Bacteroides cellulosolvens contributes to the size and complexity of its cellulosome.

The Cellulosome is an intricate macromolecular protein complex that centralizes the cellulolytic efforts of many anaerobic microorganisms through the promotion of enzyme synergy and protein stability. The assembly of numerous carbohydrate processing enzymes into a macromolecular multiprotein structure results from the interaction of enzyme-borne dockerin modules with repeated cohesin modules present in noncatalytic scaffold proteins, termed scaffoldins. Cohesin-dockerin (Coh-Doc) modules are typically classified into different types, depending on structural conformation and cellulosome role. Thus, type I Coh-Doc complexes are usually responsible for enzyme integration into the cellulosome, while type II Coh-Doc complexes tether the cellulosome to the bacterial wall. In contrast to other known cellulosomes, cohesin types from Bacteroides cellulosolvens, a cellulosome-producing bacterium capable of utilizing cellulose and cellobiose as carbon sources, are reversed for all scaffoldins, i.e., the type II cohesins are located on the enzyme-integrating primary scaffoldin, whereas the type I cohesins are located on the anchoring scaffoldins. It has been previously shown that type I B. cellulosolvens interactions possess a dual-binding mode that adds flexibility to scaffoldin assembly. Herein, we report the structural mechanism of enzyme recruitment into B. cellulosolvens cellulosome and the identification of the molecular determinants of its type II cohesin-dockerin interactions. The results indicate that, unlike other type II complexes, these possess a dual-binding mode of interaction, akin to type I complexes. Therefore, the plasticity of dual-binding mode interactions seems to play a pivotal role in the assembly of B. cellulosolvens cellulosome, which is consistent with its unmatched complexity and size.