A fibroblast-centric network drives cold fibrosis in the tumor microenvironment of lung squamous cell carcinoma.

The tumor microenvironment (TME) of chronic inflammation-associated cancers (CIACs) is shaped by cycles of injury and maladaptive repair, yet the principles organizing fibrotic stroma in these tumors remain unclear. Here, we applied the concept of hot versus cold fibrosis, originally credentialed in non-cancerous fibrosis of heart and kidney, to lung squamous cell carcinoma (LUSC), a prototypical CIAC. Single-cell transcriptomics of matched tumor and adjacent-normal tissue from 16 treatment-naive LUSC patients identified a cold fibrotic architecture in the LUSC TME: cancer-associated fibroblasts (CAFs) expanded and adopted myofibroblast and stress-response states, while macrophages were depleted.

Concerted changes in Epithelium and Stroma: a multi-scale, multi-omics analysis of progression from Barrett's Esophagus to adenocarcinoma.

Esophageal adenocarcinoma arises from Barrett's esophagus, a metaplastic condition. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue mechanics and spatial proteomics of the paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, in 107 samples from 26 patients in two independent cohorts, defined shared and patient-specific progression characteristics. Metaplastic replacement of epithelial cell composition and architecture was paralleled by changes in stromal cells, extracellular matrix (ECM) and tissue stiffness.

A Fibroblast State Choreographs an Epithelial YAP-dependent Regenerative Program Essential to (Pre)malignancy via ECM-mediated Mechanotransduction.

Unlabelled: Chronic lung injury generates metaplasia which occasionally, but ominously, progresses to squamous dysplasia and squamous lung cancer. To identify mechanisms through which disrupted tissue homeostasis contributes to malignant initiation and progression, we used and heterotypic recombinant models of human b ronchial e pithelial c ells (hBECs) and fibroblasts. We demonstrate that injury-associated TGF-β signaling creates a fibroblast state dependent upon HSP47 upregulation.

Wild and domesticated animal abundance is associated with greater late-Holocene alpine plant diversity.

In the face of human land use and climate dynamics, it is essential to know the key drivers of plant species diversity in montane regions. However, the relative roles of climate and ungulates in alpine ecosystem change is an open question. Neither observational data nor traditional palaeoecological data have the power to resolve this issue over decadal to centennial timescales, but sedimentary ancient DNA (sedaDNA) does.

Phase 2 trial of perioperative chemo-immunotherapy for gastro-esophageal adenocarcinoma: The role of M2 macrophage landscape in predicting response.

We present the clinical results of a phase 2 trial combining neoadjuvant docetaxel, cisplatin, 5 Flourouracil, and the PD-L1 inhibitor avelumab in locally advanced gastro-esophageal adenocarcinoma (GEA). Fifty-one patients receive neoadjuvant therapy with 50 proceeding to surgery. Grade 3-4 adverse events occur in 40%; complete/major pathological response is found in 7/50 (14%) and 9/50 (18%), with 2-year disease-free survival of 67.

Bioturbation in the hadal zone.

The hadal zone, >6 km deep, remains one of the least understood ecosystems on Earth. We address bioturbational structures in sediment cores from depths exceeding 7.5 km, collected during the IODP Expedition 386 in the Japan Trench.

Removal of dissolved organic carbon in the West Pacific hadal zones.

The deep oceans are environments of complex carbon dynamics that have the potential to significantly impact the global carbon cycle. However, the role of hadal zones, particularly hadal trenches (water depth > 6 km), in the oceanic dissolved organic carbon (DOC) cycle is not thoroughly investigated. Here we report distinct DOC signatures in the Japan Trench bottom water.

Comparative single-cell genomics of Atribacterota JS1 in the Japan Trench hadal sedimentary biosphere.

Deep-sea and subseafloor sedimentary environments host heterotrophic microbial communities that contribute to Earth's carbon cycling. However, the potential metabolic functions of individual microorganisms and their biogeographical distributions in hadal ocean sediments remain largely unexplored. In this study, we conducted single-cell genome sequencing on sediment samples collected from six sites (7,445-8,023 m water depth) along an approximately 500 km transect of the Japan Trench during the International Ocean Discovery Program Expedition 386.

Single-cell gene set scoring with nearest neighbor graph smoothed data (gssnng).

Summary: Gene set scoring (or enrichment) is a common dimension reduction task in bioinformatics that can be focused on the differences between groups or at the single sample level. Gene sets can represent biological functions, molecular pathways, cell identities, and more. Gene set scores are context dependent values that are useful for interpreting biological changes following experiments or perturbations.

Earthquake-enhanced dissolved carbon cycles in ultra-deep ocean sediments.

Hadal trenches are unique geological and ecological systems located along subduction zones. Earthquake-triggered turbidites act as efficient transport pathways of organic carbon (OC), yet remineralization and transformation of OC in these systems are not comprehensively understood. Here we measure concentrations and stable- and radiocarbon isotope signatures of dissolved organic and inorganic carbon (DOC, DIC) in the subsurface sediment interstitial water along the Japan Trench axis collected during the IODP Expedition 386.

Concerted epithelial and stromal changes during progression of Barrett's Esophagus to invasive adenocarcinoma exposed by multi-scale, multi-omics analysis.

Esophageal adenocarcinoma arises from Barrett's esophagus, a precancerous metaplastic replacement of squamous by columnar epithelium in response to chronic inflammation. Multi-omics profiling, integrating single-cell transcriptomics, extracellular matrix proteomics, tissue-mechanics and spatial proteomics of 64 samples from 12 patients' paths of progression from squamous epithelium through metaplasia, dysplasia to adenocarcinoma, revealed shared and patient-specific progression characteristics. The classic metaplastic replacement of epithelial cells was paralleled by metaplastic changes in stromal cells, ECM and tissue stiffness.

Genetic Variants Determine Treatment Response in Autoimmune Hepatitis.

Background: Autoimmune hepatitis (AIH) is a rare entity; in addition, single-nucleotide polymorphisms (SNPs) may impact its course and outcome. We investigated liver-related SNPs regarding its activity, as well as in relation to its stage and treatment response in a Central European AIH cohort.

Methods: A total of 113 AIH patients (i.

Validation of seismic hazard curves using a calibrated 14 ka lacustrine record in the Eastern Alps, Austria.

Seismic hazard maps are crucial for earthquake mitigation and mostly rely on probabilistic seismic hazard analysis (PSHA). However, the practise and value of PSHA are under debate because objective testing procedures for seismic hazard maps are scarce. We present a lacustrine turbidite record revealing 44 earthquakes over the last ~ 14 ka and use it to test seismic hazard curves in southern Austria.

Hepatitis D virus (HDV) prevalence in Austria is low but causes considerable morbidity due to fast progression to cirrhosis.

Background: Hepatitis D virus (HDV) coinfection aggravates the course of hepatitis B virus (HBV). The prevalence of HDV in Austria is unknown.

Objective: This national study aimed at (i) recording the prevalence of HDV-infection in Austria and (ii) characterizing the "active" HDV cohort in Austria.

A tsunamigenic delta collapse and its associated tsunami deposits in and around Lake Sils, Switzerland.

Unlabelled: Large lacustrine mass movements and delta collapses are increasingly being considered as potential tsunamigenic sources and therefore hazardous for the population and infrastructure along lakeshores. Although historical reports document tsunami events in several lakes in Switzerland, and although the propagation of lake tsunamis has been studied by numerical wave modeling, only little is known about on- and offshore lacustrine tsunami deposits. In Lake Sils, Switzerland, a large prehistoric mass-movement deposit originating from the Isola Delta with a minimum estimated volume of 6.

What controls the remobilization and deformation of surficial sediment by seismic shaking? Linking lacustrine slope stratigraphy to great earthquakes in South-Central Chile.

Remobilization and deformation of surficial subaqueous slope sediments create turbidites and soft sediment deformation structures, which are common features in many depositional records. Palaeoseismic studies have used seismically-induced turbidites and soft sediment deformation structures preserved in sedimentary sequences to reconstruct recurrence patterns and - in some cases - allow quantifying rupture location and magnitude of past earthquakes. However, current understanding of earthquake-triggered remobilization and deformation lacks studies targeting where these processes take place, the subaqueous slope and involving direct comparison of sedimentary fingerprint with well-documented historical earthquakes.

Liver-related Mortality is Increased in Lean Subjects with Non- alcoholic Fatty Liver Disease Compared to Overweight and Obese Subjects.

Background And Aims: Although non-alcoholic fatty liver disease (NAFLD) is linked to obesity, a proportion of lean subjects also have NAFLD with potentially distinct clinical features. We studied the outcome of lean NAFLD subjects.

Methods: 299 consecutive patients (215 male, 84 female, 49.

PNPLA3 is the dominant SNP linked to liver disease severity at time of first referral to a tertiary center.

Background: Single nucleotide polymorphisms (SNPs) in genes including PNPLA3, TM6SF2, HSD17B13 and SERPINA1 have been identified as risk modifiers of progression in chronic liver disease (CLD). However, it is unclear whether genotyping for these risk variants is useful in clinical routine.

Methods: Liver disease severity was assessed by liver stiffness measurement (LSM) and by presence of clinical manifestations of advanced-chronic liver disease (ACLD) in 779 consecutive CLD patients at the time of referral to a tertiary center.

Seismic control of large prehistoric rockslides in the Eastern Alps.

Large prehistoric rockslides tend to occur within spatio-temporal clusters suggesting a common trigger such as earthquake shaking or enhanced wet periods. Yet, trigger assessment remains equivocal due to the lack of conclusive observational evidence. Here, we use high-resolution lacustrine paleoseismology to evaluate the relation between past seismicity and a spatio-temporal cluster of large prehistoric rockslides in the Eastern Alps.

Similar clinical outcome of AMA immunoblot-M2-negative compared to immunoblot-positive subjects over six years of follow-up.

: The detection of anti-mitochondrial antibodies (AMA) is considered a hallmark in diagnosing primary biliary cholangitis (PBC). The most important AMA-subtype is AMA-M2 directed against the E2-subunit of pyruvate dehydrogenase. It is common clinical interpretation that lack of M2 due to immunoblotting (IB) indicates absence of specific auto-reactivity.

Mesenchymal iron deposition is associated with adverse long-term outcome in non-alcoholic fatty liver disease.

Background & Aims: Approximately one-third of patients with non-alcoholic fatty liver disease (NAFLD) show signs of mild-to-moderate iron overload. The impact of histological iron deposition on the clinical course of patients with NAFLD has not been established.

Methods & Results: For this retrospective study, 299 consecutive patients with biopsy-proven NAFLD and a mean follow-up of 8.

Earthquake Impact on Active Margins: Tracing Surficial Remobilization and Seismic Strengthening in a Slope Sedimentary Sequence.

Strong earthquakes at active ocean margins can remobilize vast amounts of surficial slope sediments and dynamically strengthen the margin sequences. Current process understanding is obtained from resulting event deposits and low-resolution shear strength data, respectively. Here we directly target a site offshore Japan where both processes are expected to initiate, that is, at the uppermost part (15 cm) of a sedimentary slope sequence.

Cancer cell population growth kinetics at low densities deviate from the exponential growth model and suggest an Allee effect.

Most models of cancer cell population expansion assume exponential growth kinetics at low cell densities, with deviations to account for observed slowing of growth rate only at higher densities due to limited resources such as space and nutrients. However, recent preclinical and clinical observations of tumor initiation or recurrence indicate the presence of tumor growth kinetics in which growth rates scale positively with cell numbers. These observations are analogous to the cooperative behavior of species in an ecosystem described by the ecological principle of the Allee effect.