Assessment of inflammatory suppression and fibroblast infiltration in tissue remodelling by supercritical CO2 acellular dermal matrix (scADM) utilizing Sprague Dawley models.

Human skin-derived ECM aids cell functions but can trigger immune reactions; therefore it is addressed through decellularization. Acellular dermal matrices (ADMs), known for their regenerative properties, are used in tissue and organ regeneration. ADMs now play a key role in plastic and reconstructive surgery, enhancing aesthetics and reducing capsular contracture risk. Innovative decellularization with supercritical carbon dioxide preserves ECM quality for clinical use. The study investigated the cytotoxicity, biocompatibility, and anti-inflammatory properties of supercritical CO2 acellular dermal matrix (scADM) in vivo based on Sprague Dawley rat models. Initial experiments in vitro with fibroblast cells confirmed the non-toxic nature of scADM and demonstrated cell infiltration into scADMs after incubation. Subsequent tests in vitro revealed the ability of scADM to suppress inflammation induced by lipopolysaccharides (LPS) presenting by the reduction of pro-inflammatory cytokines TNF-α, IL-6, IL-1ß, and MCP-1. In the in vivo model, histological assessment of implanted scADMs in 6 months revealed a decrease in inflammatory cells, confirmed further by the biomarkers of inflammation in immunofluorescence staining. Besides, an increase in fibroblast infiltration and collagen formation was observed in histological staining, which was supported by various biomarkers of fibroblasts. Moreover, the study demonstrated vascularization and macrophage polarization, depicting increased endothelial cell formation. Alteration of matrix metalloproteinases (MMPs) was analyzed by RT-PCR, indicating the reduction of MMP2, MMP3, and MMP9 levels over time. Simultaneously, an increase in collagen deposition of collagen I and collagen III was observed, verified in immunofluorescent staining, RT-PCR, and western blotting. Overall, the findings suggested that scADMs offer significant benefits in improving outcomes in implant-based procedures as well as soft tissue substitution.

To acellular dermal matrix or not to acellular dermal matrix?-outcomes of pre-pectoral prosthetic reconstruction after nipple-sparing mastectomy with and without acellular dermal matrix.

Background: Acellular dermal matrix (ADM) has been the go-to biomaterial in post-mastectomy breast reconstruction, particularly in pre-pectoral reconstruction. ADM is thought to decrease capsular contracture, control the pocket, and increase soft tissue, but may yield more complications. This study evaluated whether ADM is even needed. Methods: All patients undergoing immediate breast reconstruction with pre-pectoral tissue expander (TE) or direct-to-implant (DTI) after nipple-sparing mastectomy (NSM) by the senior author between April 2013 and January 2021, were included in this study. Cohorts were stratified into breasts with ADM or no-ADM. Complications within 30 days post-operatively were analyzed. Results: A total of 115 pre-pectoral reconstructions were performed in 66 patients. ADM was applied to 75 breasts. TEs were used in 80 breasts and DTI in 35 breasts. Controlling for implant type, breasts with ADM exhibited more nipple necrosis (28.0% vs. 10.0%, P=0.02). Controlling for ADM status, DTI compared to TE was associated with less necrosis of the nipple (11.4% vs. 26.3%, P=0.04), implant loss (5.7% vs. 38.8%, P=0.004), and surgery for any complication (14.3% vs. 27.5%, P=0.04). Conclusions: Outcomes of prosthetic reconstructions with ADM and no-ADM were similar. DTI reconstruction was associated with less complications, which was likely due to intraoperative bias and placement of TEs more often in breasts with perceived poorer vascularity.

Risk factor analysis and clinical experience of treating capsular contracture after prepectoral implant-based breast reconstruction.

Background: Capsular contracture is one of the most common and severe complications after implant-based breast reconstruction. Recently, prepectoral implant-based breast reconstruction using acellular dermal matrix (ADM) has become an alternative to subpectoral implant-based reconstruction. However, risk factors for capsular contracture associated with recent prepectoral reconstruction trends are not well refined yet. Thus, the aim of this study was to determine risk factors for capsular contracture, and share our experience of treating capsular contracture in prepectoral reconstruction. Methods: This retrospective comparative study focused on 110 patients who underwent prepectoral implant-based breast reconstruction with ADM. Risk factors of capsular contracture were analyzed by comparing a capsular contracture group (27 cases) and a non-capsular contracture group (83 cases). Secondary treatment after capsular contracture development was analyzed in capsular contracture group. Results: According to univariate and multivariate analyses of risk factors for capsular contracture, single staged implant-based reconstruction (direct-to-implant), infection, and postoperative radiotherapy were significantly related to the development of capsular contracture. Also, surgical intervention including capsulectomy and capsulotomy with implant change showed a significant higher remission rate than other groups. Conclusions: Our study provides insights into risk factors and treatment choices for capsular contracture after prepectoral implant-based breast reconstruction with ADM. These findings can aid selection of patients, postoperative care and preventative treatment before reconstruction.

Conceptualizing Automated Decision-Making in Organizational Contexts.

Despite growing interest in automated (or algorithmic) decision-making (ADM), little work has been done to conceptually clarify the term. This article aims to tackle this issue by developing a conceptualization of ADM specifically tailored to organizational contexts. It has two main goals: (1) to meaningfully demarcate ADM from similar, yet distinct algorithm-supported practices; and (2) to draw internal distinctions such that different ADM types can be meaningfully distinguished. The proposed conceptualization builds on three arguments: First, ADM primarily refers to the automation of practical decisions (decisions to φ) as opposed to cognitive decisions (decisions that p). Second, rather than referring to algorithms as literally making decisions, ADM refers to the use of algorithms to solve decision problems at an organizational level. Third, since algorithmic tools by nature primarily settle cognitive decision problems, their classification as ADM depends on whether and to what extent an algorithmically generated output p has an action triggering effect-i.e., translates into a consequential action φ. The examination of precisely this p-φ relationship, allows us to pinpoint different ADM types (suggesting, offloading, superseding). Taking these three arguments into account, we arrive at the following definition: ADM refers to the practice of using algorithms to solve decision problems, where these algorithms can play a suggesting, offloading, or superseding role relative to humans, and decisions are defined as action triggering choices.

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.

Oncogenic mutations in KRAS are present in approximately 95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation. However, low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of both an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56α promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.

CREB activation drives acinar to ductal reprogramming and promote pancreatic cancer progression in animal models of alcoholic chronic pancreatitis.

BACKGROUND AND AIMS: In vivo induction of alcoholic chronic pancreatitis (ACP) causes significant acinar damage, increased fibroinflammatory response, and heightened activation of cyclic response element binding protein 1 (CREB) when compared with alcohol (A) or chronic pancreatitis (CP) mediated pancreatic damage. However, the study elucidating the cooperative interaction between CREB and the oncogenic Kras G12D/+ (Kras*) in promoting pancreatic cancer progression with ACP remains unexplored. METHODS: Experimental ACP induction was established in multiple mouse models, followed by euthanization of the animals at various time intervals during the recovery periods. Tumor latency was determined in these mice cohorts. Here, we established CREB deletion (Creb fl/fl ) in Ptf1a CreERTM/+ ;LSL-Kras G12D+/-(KC) genetic mouse models (KCC-/-). Western blot, phosphokinase array, and qPCR were used to analyze the pancreata of Ptf1a CreERTM+/-, KC and KCC -/- mice. The pancreata of ACP-induced KC mice were subjected to single-cell RNA sequencing (scRNAseq). Further studies involved conducting lineage tracing and acinar cell explant cultures. RESULTS: ACP induction in KC mice had detrimental effects on the pancreatic damage repair mechanism. The persistent existence of acinar cell-derived ductal lesions demonstrated a prolonged state of hyperactivated CREB. Persistent CREB activation leads to acinar cell reprogramming and increased pro-fibrotic inflammation in KC mice. Acinar-specific Creb ablation reduced advanced PanINs lesions, hindered tumor progression, and restored acinar cell function in ACP-induced mouse models. CONCLUSIONS: Our findings demonstrate that CREB cooperates with Kras* to perpetuate an irreversible ADM and PanIN formation. Moreover, CREB sustains oncogenic activity to promote the progression of premalignant lesions toward cancer in the presence of ACP.

A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections.

Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights.

Resolution of Acinar Dedifferentiation Regulates Tissue Remodeling in Pancreatic Injury and Cancer Initiation.

BACKGROUND & AIMS: Acinar-to-ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma. However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human. METHODS: We identified Sox4 among the top up-regulated genes. We validated the analysis by RNA in situ hybridization. We performed experiments in mice with acinar-specific deletion of Sox4 (Ptf1a: CreER; Rosa26-LSL-YFPLSL-YFP; Sox4fl/fl) with and without an activating mutation in Kras (KrasLSL-G12D/+). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization, and single-cell RNA sequencing. RESULTS: We demonstrated that Sox4 is reactivated in ADM and pancreatic intraepithelial neoplasias. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression. CONCLUSIONS: Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 restrains acinar dedifferentiation and is necessary for the specification of acinar-derived metaplastic cells in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of pancreatic ductal adenocarcinoma.

Impact of HIV status on prognosis of malignancies among people living with HIV in Japan.

BACKGROUND: Antiretroviral therapy has reduced the incidence and mortality of AIDS-defining malignancies (ADM); however, non-AIDS-defining malignancies (NADM) are a major cause of death among people living with HIV (PLWH) today. Though current guidelines suggest that PLWH should receive the same treatment as the general population, there are limited studies focused on how HIV status affects the prognosis of cancers. The present study aimed to investigate the characteristics and prognosis of malignant diseases among PLWH in Japan. METHODS: Patients with HIV diagnosed with malignant diseases at our institution between 2011 and 2021 were retrospectively reviewed. RESULTS: There were 205 patients who were diagnosed with malignancies. Of these, 87 (42.4%) were diagnosed with ADM and 118 (57.6%) were diagnosed with NADM. Among 69 patients who received chemotherapy for ADM, 24 (34.8%) developed AIDS-defining opportunistic infections during treatment. In contrast, only one (1.8%) of the 56 patients administered chemotherapy for NADM developed AIDS-defining opportunistic infections. Complications of opportunistic infections at diagnosis of malignancies, low CD4+ T-cell count, positive HIV RNA, and nonadministration of antiretroviral therapy were associated with 5-year overall survival among patients with malignant lymphomas. However, the variables associated with HIV did not affect NADM prognosis. CONCLUSIONS: In this analysis, HIV status had a small impact on the prognosis of malignant diseases in PLWH. Few patients with NADM developed AIDS-defining opportunistic infections after receiving chemotherapy.

Prepectoral Prosthetic Breast Reconstruction Without ADM Using a Subfascial Approach.

BACKGROUND: Immediate prosthetic reconstruction has evolved to a prepectoral position. A technique is described where the pectoral and serratus fascia is raised from superiorly. Initially, Vicryl mesh was used to close the superior fascial defect, but later abandoned by using primary closure for tissue expanders, or creating a pocket in the infraclavicular pectoralis muscle after prosthesis (DTI) insertion. The inframammary fold is also reinforced. Patients with a BMI > 30 have axillary liposuction. METHOD: Retrospective analysis over a 4-year period. Data included age, number of breasts having expanders or DTI. Prosthetic extrusion and follow-up were recorded. The percentage coverage by fascia was calculated. RESULTS: Forty-seven patients (80 breasts) had mean age of 42 years (range 32-62), twelve patients (19 breasts) had Vicryl mesh inserted, while 35 patients (61 breasts) had closure as noted above. Tissue expanders were inserted in 39 breasts (10 mesh, 29 without). DTI (direct to implant) performed in 41 breasts (32 no mesh, 9 with mesh). Three patients with mesh developed recalcitrant seromas. The mean size of prosthesis used was 353ml (range 200-500 ml). Extrusion occurred in eight breasts (two with mesh, six without). Mean coverage of the prosthesis by fascia was 74% (range 50-100%), and nine patients also had bilateral axillary liposuction of the axillary roll. Mean follow-up was 13 months. CONCLUSION: Another technique for immediate prosthetic reconstruction providing an additional layer of prosthetic cover in prepectoral plane, without mesh. Applicable for all grades of ptosis. Extrusion rate is low. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Cytokine CCL9 Mediates Oncogenic KRAS-Induced Pancreatic Acinar-to-Ductal Metaplasia by Promoting Reactive Oxygen Species and Metalloproteinases.

Pancreatic ductal adenocarcinoma (PDAC) can originate from acinar-to-ductal metaplasia (ADM). Pancreatic acini harboring oncogenic Kras mutations are transdifferentiated to a duct-like phenotype that further progresses to become pancreatic intraepithelial neoplasia (PanIN) lesions, giving rise to PDAC. Although ADM formation is frequently observed in KrasG12D transgenic mouse models of PDAC, the exact mechanisms of how oncogenic KrasG12D regulates this process remain an enigma. Herein, we revealed a new downstream target of oncogenic Kras, cytokine CCL9, during ADM formation. Higher levels of CCL9 and its receptors, CCR1 and CCR3, were detected in ADM regions of the pancreas in p48cre:KrasG12D mice and human PDAC patients. Knockdown of CCL9 in KrasG12D-expressed pancreatic acini reduced KrasG12D-induced ADM in a 3D organoid culture system. Moreover, exogenously added recombinant CCL9 and overexpression of CCL9 in primary pancreatic acini induced pancreatic ADM. We also showed that, functioning as a downstream target of KrasG12D, CCL9 promoted pancreatic ADM through upregulation of the intracellular levels of reactive oxygen species (ROS) and metalloproteinases (MMPs), including MMP14, MMP3 and MMP2. Blockade of MMPs via its generic inhibitor GM6001 or knockdown of specific MMP such as MMP14 and MMP3 decreased CCL9-induced pancreatic ADM. In p48cre:KrasG12D transgenic mice, blockade of CCL9 through its specific neutralizing antibody attenuated pancreatic ADM structures and PanIN lesion formation. Furthermore, it also diminished infiltrating macrophages and expression of MMP14, MMP3 and MMP2 in the ADM areas. Altogether, our results provide novel mechanistic insight into how oncogenic Kras enhances pancreatic ADM through its new downstream target molecule, CCL9, to initiate PDAC.

A comparative analysis of transcriptomics of newly diagnosed multiple myeloma: exploring drug repurposing.

Multiple myeloma (MM) is an incurable malignant plasma cell disorder characterized by the infiltration of clonal plasma cells in the bone marrow compartment. Gene Expression Profiling (GEP) has emerged as a powerful investigation tool in modern myeloma research enabling the dissection of the molecular background of MM and allowing the identification of gene products that could potentially serve as targets for therapeutic intervention. In this study we investigated shared transcriptomic abnormalities across newly diagnosed multiple myeloma (NDMM) patient cohorts. In total, publicly available transcriptomic data of 7 studies from CD138+ cells from 281 NDMM patients and 44 healthy individuals were integrated and analyzed. Overall, we identified 28 genes that were consistently differentially expressed (DE) between NDMM patients and healthy donors (HD) across various studies. Of those, 9 genes were over/under-expressed in more than 75% of NDMM patients. In addition, we identified 4 genes (MT1F, PURPL, LINC01239 and LINC01480) that were not previously considered to participate in MM pathogenesis. Meanwhile, by mining three drug databases (ChEMBL, IUPHAR/BPS and DrugBank) we identified 31 FDA-approved and 144 experimental drugs that target 8 of these 28 over/under-expressed MM genes. Taken together, our study offers new insights in MM pathogenesis and importantly, it reveals potential new treatment options that need to be further investigated in future studies.

Pre-pectoral breast reconstruction with tissue expander entirely covered by acellular dermal matrix: feasibility, safety and histological features resulting from the first 64 procedures.

Background: Reconstructive options that can be used following conservative mastectomy, skin-, nipple-sparing and skin-reducing mastectomies, allow a remarkable variety of safe methods to restore the natural shape and aesthetics of the breast mound. In case of two-stage breast reconstruction, tissue expanders (TEs) are usually placed in a subpectoral position. The purpose of this retrospective cohort study is to evaluate the feasibility and safety of two-step reconstruction with TE in pre-pectoral position covered by acellular dermal matrix (ADM). Methods: Between March 2021 and May 2023, at the Azienda Ospedaliero Universitaria Careggi, University of Florence, 55 patients with BRCA 1/2 mutations or early breast cancer underwent conservative mastectomy with immediate pre-pectoral reconstruction using TE covered with ADM, followed by a second surgery with replacement of the expander with definitive prosthesis. Demographic, oncological, and histological data along with surgical complications were recorded. Results: A total of 64 conservative mastectomies were performed. In 2 patients (3.1%) complications were found that required reintervention and, in both cases, the TE had to be removed. Two patients developed hematoma and one patient developed seroma. Two patients showed wound dehiscence, both healed after conservative treatment and without implant exposure. No case of necrosis of the skin or nipple-areola complex has been observed, neither of capsular contracture. Capsule formed around TE was populated with cells and blood vessels and showed a thin area of synovial metaplasia. Conclusions: In selected cases it may be more cautious to perform a two-stage breast reconstruction after radical breast surgery by means of TEs. The placement of TEs in pre-pectoral position combines the excellent aesthetic and functional results of the pre-pectoral philosophy with a quite safer and more prudent two-step approach. Our experience reports optimistic results: the ADM covering the TE is seen successfully integrating during tissue expansion and becoming a vascularised new self-tissue. Complications rates are low and such ADM-assisted two-stage pre-pectoral reconstructive technique is a safe, practical, and reproducible method.

Lower Extremity Trauma: A Multidimensional Reconstructive Approach with Hyperbaric Oxygen Therapy.

Background: Distal lower extremity reconstruction is challenging. This study aims to propose a protocol for the treatment of traumatic soft tissue defects. The key concept is to combine the surgical armamentarium of the reconstructive surgeon with the advantages provided by hyperbaric oxygen therapy. Methods: This retrospective study analyzed data of 57 patients affected with unilateral or bilateral lower extremity trauma distal to the knee and involving soft tissues with no indication of immediate reconstruction between 2010 and 2021. Before the reconstructive procedure, all the patients underwent a stick swab procedure for the collection of microbiological samples and debridement. Patients were divided into two treatment groups and only one group underwent a combined therapeutic procedure with hyperbaric oxygen therapy. Negative pressure wound therapy (NPWT) was employed only if deemed necessary according to the defect's depth and wound exudate. Surgical techniques, outcomes, and complications were discussed. Results: All patients achieved a complete recovery with no major complications and only minor complications observed. The study group treated with HBOT had a lower complication rate and lower percentages of minimal and partial graft loss compared with the same complications observed in the control group. No patients experienced HBOT-related complications. Significant reductions in the time to complete healing and the time from reconstruction to healing were found (p = 0.002 and p < 0.00001, respectively). Conclusions: A lower complication rate was observed in the group treated with HBOT. The administration of HBOT prior to soft tissue reconstruction significantly reduced the time to complete healing and the time interval from skin grafting to healing. However, prospective studies and randomized trials with larger cohorts should be designed to investigate the efficacy of HBOT for the treatment of lower extremity injuries with extensive soft tissue defects.

Modeling key intermediates during anaerobic digestion of lipid rich kitchen waste with an extended ADM1.

Quantitative dynamics of the key intermediates, gases and carbohydrates during anaerobic digestion of different lipid rich kitchen waste and lipid rich model kitchen waste were modeled. Six batch reactors loaded with 25 g VS  l - 1 ( ∼ 39  g O 2  l - 1 ) kitchen waste and model kitchen waste during a batch experiment were considered in simulation. Observed dynamics of carbohydrates, volatile organic acids and gases were described by an extended benchmark simulation model no. 2 (BSM2). In this study the extended BSM2 included a more detailed ß -oxidation for prediction of caproic acid. Furthermore, the extensions included carbohydrate digestion with an additional intermediate before propionic acid was released. In addition, a novel simplification approach for initial pH estimation was successfully applied. For parameter estimation a Markov Chain Monte Carlo method was used to obtain parameter distributions. With the presented model it was possible even with no calibrated data to predict point of times of intermediates maxima and propionic acid with relative stable concentration over several days for kitchen waste.

Modelling of anaerobic digestion of microalgae biomass: Effect of overloading perturbation.

Anaerobic digestion (AD) of microalgae is an intriguing approach for bioenergy production. The scaling-up of AD presents a significant challenge due to the systematic efficiency losses related to process instabilities. To gain a comprehensive understanding of AD behavior, this study assessed a modified version of the anaerobic digestion model No1 (ADM1) + Contois kinetics to represent microalgae AD impacted by overloading. To this end, two new inhibition functions were implemented: inhibition by acetate for acidogenesis/acetogenesis and total volatile fatty acids for hydrolysis. This proposed ADM1 modification (including Contois kinetics) simulated AD behavior during the stable, disturbed and recovery periods, showing that the inhibition functions described in the original ADM1 cannot explain the AD performance under one of the most common perturbations at industrial scale (overloading). The findings underscore the importance of refining the inhibitions present in original ADM1 to better capture and predict the complexities of microalgae AD against overloading.

Thermally enhanced solid-liquid separation process in food waste biorefinery: modelling the anaerobic digestion of solid residues.

The biochemical valorization potential of food waste (FW) could be exploited by extracting decreasing added-value bio-based products and converting the final residues into energy. In this context, multi-purpose and versatile schemes integrating thermal and biochemical conversion processes will play a key role. An upstream thermal pretreatment + solid-liquid separation unit was here proposed to optimize the conversion of the liquid fraction of FW into valuable chemicals through semi-continuous fermentation process, and the conversion of the residual solid fraction into biomethane through anaerobic digestion. The solid residues obtained after thermal pretreatment presented a higher soluble COD fraction, which resulted in higher methane production with respect to the raw residues (0.33 vs. 0.29 Nm3CH4 kg-1VSfed) and higher risk of acidification and failure of methanogenesis when operating at lower HRT (20d). On the contrary, at HRT = 40 d, the pretreatment did not affect the methane conversion rates and both tests evidenced similar methane productions of 0.33 Nm3CH4 kg-1VSfed. In the reactor fed with pretreated residue, the association of hydrogenotrophic methanogens with syntrophic bacteria prevented the acidification of the system. Modelling proved the eligibility of the FW solid residues as substrates for anaerobic digestion, given their small inert fractions that ranged between 0% and 30% of the total COD content.

Identification and validation of a glycolysis-related taxonomy for improving outcomes in glioma.

BACKGROUND: Reprogramming of glucose metabolism is a prominent abnormal energy metabolism in glioma. However, the efficacy of treatments targeting glycolysis varies among patients. The present study aimed to classify distinct glycolysis subtypes (GS) of glioma, which may help to improve the therapy response. METHODS: The expression profiles of glioma were downloaded from public datasets to perform an enhanced clustering analysis to determine the GS. A total of 101 combinations based on 10 machine learning algorithms were performed to screen out the most valuable glycolysis-related glioma signature (GGS). Through RSF and plsRcox algorithms, adrenomedullin (ADM) was eventually obtained as the most significant glycolysis-related gene for prognostic prediction in glioma. Furthermore, drug sensitivity analysis, molecular docking, and in vitro experiments were utilized to verify the efficacy of ADM and ingenol mebutate (IM). RESULTS: Glioma patients were classified into five distinct GS (GS1-GS5), characterized by varying glycolytic metabolism levels, molecular expression, immune cell infiltration, immunogenic modulators, and clinical features. Anti-CTLA4 and anti-PD-L1 antibodies significantly improved the prognosis for GS2 and GS5, respectively. ADM has been identified as a potential biomarker for targeted glycolytic therapy in glioma patients. In vitro experiments demonstrated that IM inhibited glioma cell progression by inhibiting ADM. CONCLUSION: This study elucidates that evaluating GS is essential for comprehending the heterogeneity of glioma, which is pivotal for predicting immune cell infiltration (ICI) characterization, prognosis, and personalized immunotherapy regimens. We also explored the glycolysis-related genes ADM and IM to develop a theoretical framework for anti-tumor strategies targeting glycolysis.

Analysis of biogas production from sewage sludge combining BMP experimental assays and the ADM1 model.

The Anaerobic Digestion Model No. 1 (ADM1) was employed to simulate methane (CH4) production in an anaerobic reactor (AR), and the associated bench-scale biochemical methane potential (BMP) assay, having sewage sludge (SWS) from a municipal wastewater treatment plant (WWTP) as feedstock. The SWS presented the following physical-chemical characteristics: pH (7.4-7.6), alkalinity (2,382 ± 100 mg CaCO3 L-1), tCOD (21,903 ± 1,000 mg L-1), TOC (895 ± 100 mg L-1), TS, TVS, and VSS (2.0%, 1.1%, and 0.8%, respectively). The BMP assay was conducted in six replicates under anaerobic mesophilic conditions (37 ± 0.1°C) for 11 days with a CH4 yield registered of 137.6 ± 6.39 NmL CH4 or 124 ± 6.72 CH4 g-1 VS-1. When the results obtained with the BMP bench-scale reactors were compared to the output generated with computational data by the ADM1 model having as input data the same initial sewage tCOD, similar cumulative CH4 production curves were obtained, indicating the accuracy of the ADM1 model. This approach allowed the characterization of the sludge and estimation of its biogas production potential. The combination of BMP assays, experimental data, and ADM1 model simulations provided a framework for studying anaerobic digestion (AD) processes.

Potential oral VEGFR2 inhibitors: Treatment of wet age-related macular degeneration.

Wet age-related macular degeneration (w-AMD) is one of the leading causes of vision loss in industrialized countries. A large body of evidence suggests that inhibitors targeting VEGFR2 may be effective in the treatment of w-AMD. The identification of an oral VEGFR2 inhibitor for the treatment of w-AMD provides an opportunity for a route of administration other than intravitreal injection. While screening potent VEGFR2 inhibitors at the enzyme and cellular levels, ensuring the safety of the compounds was our primary strategy for screening optimal compounds. Finally, compound 16 was identified, exhibiting enhanced inhibition of VEGFR2 enzyme and proliferation of BaF3-TEL-VEGFR2 cells compared to Vorolanib. Compound 16 had a weak inhibitory effect on human Ether-a-go-go-related gene (hERG) channel currents, showing a cardiac safety profile similar to Vorolanib. Compound 16 showed no significant toxicity to human liver cell LX-2, indicating a liver safety profile similar to Vorolanib. The water solubility of compound 16 was found to be higher than that of Vorolanib when tested at pH = 7.4. In addition, compound 16 was found to inhibit VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner by WB assay. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 16 showed remarkable plasma stability and moderate liver microsomal stability. Based on in vivo pharmacokinetic studies in ICR mice, compound 16 exhibited acceptable oral bioavailability (F = 20.2 %). Overall, these findings provide evidence that compound 16 is a leading potential oral drug candidate for w-AMD.