Is artificial intelligence for medical professionals serving the patients? : Protocol for a systematic review on patient-relevant benefits and harms of algorithmic decision-making.

BACKGROUND: Algorithmic decision-making (ADM) utilises algorithms to collect and process data and develop models to make or support decisions. Advances in artificial intelligence (AI) have led to the development of support systems that can be superior to medical professionals without AI support in certain tasks. However, whether patients can benefit from this remains unclear. The aim of this systematic review is to assess the current evidence on patient-relevant benefits and harms, such as improved survival rates and reduced treatment-related complications, when healthcare professionals use ADM systems (developed using or working with AI) compared to healthcare professionals without AI-related ADM (standard care)-regardless of the clinical issues. METHODS: Following the PRISMA statement, MEDLINE and PubMed (via PubMed), Embase (via Elsevier) and IEEE Xplore will be searched using English free text terms in title/abstract, Medical Subject Headings (MeSH) terms and Embase Subject Headings (Emtree fields). Additional studies will be identified by contacting authors of included studies and through reference lists of included studies. Grey literature searches will be conducted in Google Scholar. Risk of bias will be assessed by using Cochrane's RoB 2 for randomised trials and ROBINS-I for non-randomised trials. Transparent reporting of the included studies will be assessed using the CONSORT-AI extension statement. Two researchers will screen, assess and extract from the studies independently, with a third in case of conflicts that cannot be resolved by discussion. DISCUSSION: It is expected that there will be a substantial shortage of suitable studies that compare healthcare professionals with and without ADM systems concerning patient-relevant endpoints. This can be attributed to the prioritisation of technical quality criteria and, in some cases, clinical parameters over patient-relevant endpoints in the development of study designs. Furthermore, it is anticipated that a significant portion of the identified studies will exhibit relatively poor methodological quality and provide only limited generalisable results. SYSTEMATIC REVIEW REGISTRATION: This study is registered within PROSPERO (CRD42023412156).

Age-Related Decline in Pancreas Regeneration Is Associated With an Increased Proinflammatory Response to Injury.

Background and Aims: The regenerative capacity of the pancreas diminishes with age. Understanding acinar cell responses to injury and the resolution of regenerative processes is crucial for tissue homeostasis. However, knowledge about the impact of aging on these processes remains limited. Methods: To investigate the influence of aging on pancreas regeneration, we established a cohort of young (7-14 weeks) and old (18 months) C57bl/6 mice. Experimental pancreatitis was induced using caerulein, and pancreas samples were collected at various time points after induction, covering acute damage response, inflammation, peak proliferation, and inflammation resolution. Our analysis involved immunohistochemistry, quantitative imaging, and gene expression analyses. Results: Our study revealed a significant decline in the regenerative capacity of the pancreas in old mice. Despite similar morphology and transcriptional profiles between the pancreas of young and old mice under homeostasis, the aged pancreas is primed to generate an exacerbated proinflammatory reaction in response to injury. Specifically, we observed notable upregulation of Junb expression in acinar cells and aberrant myofibroblast activation in the aged pancreas. Conclusion: The response of acinar cells to injury in the pancreas of aged mice is characterized by an increased susceptibility to inflammation and stromal reactions. Our findings uncover a pre-existing proinflammatory state in aged acinar cells, offering insights into potential strategies to prevent the onset of pancreatic insufficiency and the development of inflammatory conditions. These insights hold implications for preventing conditions such as chronic pancreatitis and pancreatic ductal adenocarcinoma.

Diagnostic Modalities in Heart Failure: A Narrative Review.

Heart failure (HF) can present acutely or progress over time. It can lead to morbidity and mortality affecting 6.5 million Americans over the age of 20. The HF type is described according to the ejection fraction classification, defined as the percentage of blood volume that exits the left ventricle after myocardial contraction, undergoing ejection into the circulation, also called stroke volume, and is proportional to the ejection fraction. Cardiac catheterization is an invasive procedure to evaluate coronary artery disease leading to HF. Several biomarkers are being studied that could lead to early detection of HF and better symptom management. Testing for various biomarkers in the patient's blood is instrumental in confirming the diagnosis and elucidating the etiology of HF. There are various biomarkers elevated in response to increased myocardial stress and volume overload, including B-type natriuretic peptide (BNP) and its N-terminal prohormone BNP. We explored online libraries such as PubMed, Google Scholar, and Cochrane to find relevant articles. Our narrative review aims to extensively shed light on diagnostic modalities and novel techniques for diagnosing HF.

Combining thermal model and kinetics: Implications in dynamic simulation of anaerobic digesters.

In this study, ADM1-based kinetics were combined with a thermal model that accounts for various heat transfers inside and through the reactor's boundaries. Computing the energy of bioreactions based on kinetic rates prevented an overestimation of approximately 20% in the heat demand of the heat exchanger, compared to calculations using feedstock degradation heat. This also improved the representation of the digester's thermal and reactional inertia. Simulations across different climates demonstrated the necessity to tailor digester construction. In the North West United Kingdom, biogas auto-consumption was 23% higher than that of the same reactor in South West France. Enhancing the thermal insulation of the digester reduced heat losses by 37% in the United Kingdom. Therefore, coupling the kinetic and thermal models expands the insights that can be extracted from simulations, which can be valuable in optimizing the operation and design of biogas digesters.

BET Inhibition Rescues Acinar-Ductal-Metaplasia and Ciliogenesis and Ameliorates Chronic Pancreatitis-Driven Changes in Mice with Loss of the Polarity Protein Par3.

BACKGROUND & AIMS: The apical-basal polarity of pancreatic acinar cells is essential for maintaining tissue architecture. However, the mechanisms by which polarity proteins regulate acinar pancreas injury and regeneration are poorly understood. METHODS: Cerulein-induced pancreatitis was induced in mice with conditional deletion of the polarity protein Par3 in the pancreas. The impact of Par3 loss on pancreas injury and regeneration was assessed by histologic analyses and transcriptional profiling by RNA sequencing. Mice were pretreated with the bromodomain and extraterminal domain (BET) inhibitor JQ1 before cotreatment with cerulein to determine the effect of BET inhibition on pancreas injury and regeneration. RESULTS: Initially, we show that Par3 is increased in acinar-ductal metaplasia (ADM) lesions present in human and mouse chronic pancreatitis specimens. Although Par3 loss disrupts tight junctions, Par3 is dispensable for pancreatogenesis. However, with aging, Par3 loss results in low-grade inflammation, acinar degeneration, and pancreatic lipomatosis. Par3 loss exacerbates acute pancreatitis-induced injury and chronic pancreatitis-induced acinar cell loss, promotes pancreatic lipomatosis, and prevents regeneration. Par3 loss also results in suppression of chronic pancreatitis-induced ADM and primary ciliogenesis. Notably, targeting BET proteins attenuates chronic pancreatitis-induced loss of primary cilia and promotes ADM in mice lacking pancreatic Par3. Targeting BET proteins also attenuates cerulein-induced acinar cell loss and enhances recovery of acinar cell mass and body weight of mice lacking pancreatic Par3. CONCLUSIONS: Combined, this study demonstrates how Par3 restrains chronic pancreatitis-induced changes in the pancreas and identifies a potential role for BET inhibitors to attenuate pancreas injury and facilitate regeneration.

Soft sensor for substrate characterization through the reverse application of the ADM1 model for anaerobic digestion plant operations.

Accurately characterizing the substrate used in anaerobic digestion is crucial for predicting the biogas plant's performance. This issue makes particularly challenging the application of modeling in codigestion plants. In this work, a novel methodology called substrate prediction module (SPM) has been developed and tested, using virtual codigestion data. The SPM aims to estimate the inlet properties of the substrate based on the reverse application of the anaerobic digestion model n1 (ADM1). The results show that, while the SPM can estimate some properties of the substrate based on certain output parameters, there are limitations in accurately determining all required variables.

Breast cancer patients' postoperative outcomes in nipple-sparing mastectomy and reconstruction with subpectoral implant placement: a single center experience.

Background: The continuous increase in the rate of nipple sparing mastectomy (NSM), the development of several reconstructive techniques and the following introduction of acellular derma matrix (ADM) has revolutionized implant-based breast reconstruction. This study aimed to investigate postoperative complications, health-related quality of life (HRQoL) and patients' satisfaction in patients undergoing NSM and breast reconstruction with or without ADM. Methods: Enrolled patients were divided into three groups: immediate breast reconstruction (IBR) with definitive implant and ADM (Group A), IBR only with definitive prosthesis (Group B), and two-stage breast reconstruction (Group C). The postoperative complications, BREAST-Q outcomes and reoperations were compared. Results: A total of 105 BC patients were enrolled and a total of 139 post-mastectomy breast reconstructions were performed. Seroma was the most prevalent complication observed: 8.3% in Group A, 2.9% in Group B and 5.7% in Group C. Postoperative infection occurred in two patients of Group A (5.6%), one patient of Group B (2.9%) and one of Group C (2.9%). Group A reported larger drain volume (1,125±243.5 cc), longer drain period (13.2±2.8 days), and the lowest incidence of capsular contracture (5.6%). The BREAST-Q patient-reported outcome measures document that all patients aged ≥50 years presented a higher score in "Satisfaction with breast" (P<0.001) and "Satisfaction with outcome" domains (P<0.05). Performing a bilateral breast reconstruction was associated to higher scores in "Physical wellbeing chest domain" (P<0.05). In addition, patients in Group A and Group B reported higher score in "Satisfaction with the breast" domain (P<0.001) but only in Group B we reported a higher score in "Satisfaction with outcome" (P<0.001). Conclusions: Subpectoral IBR results in manageable complications and greater personal satisfaction. The ADM could improve breast reconstruction reducing the rate of capsular contracture. The prepectoral placement of ADM could minimize complications and optimize aesthetic results.

Current status of pre- and retropectoral breast reconstructions worldwide: a narrative review.

Background and Objective: Advances in breast cancer research and technology contribute to conservative ablative surgical approach with emphasis on reconstruction. The introduction of biologic membranes in breast surgery facilitates a one-stage implant reconstruction while the importance of the pectoralis major muscle involvement in the procedure becomes debatable. A subsequent increase in prepectoral implant placement procedures seems to close a cycle of innovations in implant-based breast reconstructions. This sparks a debate that calls for a critical review of existing literature considering that new challenges tend to arise along with new perspectives. The authors seek to scope the present status of prepectoral and subpectoral implant reconstruction worldwide, and answer recurring questions, including the novelty of presented innovations in the context of existing literature. Methods: The article is based on a literature search in PubMed with the keywords "prepectoral" or "subpectoral" and "breast reconstruction", in addition to the authors' experience with a large number of patients. Key Content and Findings: Recent studies focus on the comparative safety of prepectoral vs. subpectoral placement debating the use of biologic vs. non-biologic sheets and implant texture. There seems to be more emphasis on early post-operative safety of the procedures, rather than any long-term prospects of their comparison, up to this point. Skin and nipple sparing mastectomy (SSM/NSM) together with biological membranes have played a key role in current practice and cannot be overlooked. Conclusions: After reading this paper, the reader should have a firm understanding of the key elements of implant-based breast reconstruction in historical context with emphasis on muscle planes and their pros and cons.

Pro-adrenomedullin associates with congestion in acute heart failure patients.

AIM: Congestion is a major determinant of outcomes in acute heart failure. Its assessment is complex, making sufficient decongestive therapy a challenge. Residual congestion is frequent at discharge, increasing the risk of re-hospitalization and death. Mid-regional pro-adrenomedullin mirrors vascular integrity and may therefore be an objective marker to quantify congestion and to guide decongestive therapies in patients with acute heart failure. METHODS AND RESULTS: Observational, prospective, single-centre study in unselected patients presenting with acute heart failure. This study aimed to assess adrenomedullin's association with congestion and clinical outcomes: in-hospital death, post-discharge mortality and in-hospital worsening heart failure according to RELAX-AHF-2 trial criteria. Pro-adrenomedullin was quantified at baseline and at discharge. Congestion was assessed applying clinical scores. Cox and logistic regression models with adjustment for clinical features were fitted. N = 233, median age 77 years (IQR 67, 83), 148 male (63.5%). Median pro-adrenomedullin 2.0 nmol/L (IQR 1.4, 2.9). Eight patients (3.5%) died in hospital and 100 (44.1%) experienced in-hospital worsening heart failure. After discharge, 60 patients (36.6%) died over a median follow-up of 1.92 years (95% CI: 1.76, 2.46). Pro-adrenomedullin concentrations (logarithmized) were significantly associated with congestion, both at enrolment (ß = 0.36 and 0.81 depending on score, each P < 0.05) and at discharge (ß = 1.12, P < 0.001). Enrolment of pro-adrenomedullin was associated with in-hospital worsening heart failure [OR 4.23 (95% CI: 1.87, 9.58), P < 0.001], and pro-adrenomedullin at discharge was associated with post-discharge death [HR 3.93 (1.86, 8.67), P < 0.001]. CONCLUSION: Elevated pro-adrenomedullin is associated with in-hospital worsening heart failure and with death during follow-up in patients with acute heart failure. Further research is needed to validate this finding and to explore the ability of pro-adrenomedullin to guide decongestive treatment.

Dynamics and synchronization control of fractional conformable neuron system.

Dynamic analysis, electrical coupling and synchronization control of the conformable FitzHugh-Nagumo neuronal models have been presented in this work. Firstly, equations of the Adomian-Decomposition-Method and conformable neuron model have been introduced. The Adomian-Decomposition-Method has been employed for the numerical simulation analysis, since it converges fast and provides serial solutions. Fractional order and external current stimulus have been considered as bifurcation parameters and their effects on neuron model dynamics have been examined in detail. Then, the electrical coupling of the two conformable neuronal models without any controller has been revealed and the significance of the coupling strength parameter has been evaluated. To eliminate impact of the coupling strength parameter on synchronization status of neurons, Lyapunov control method has been employed for synchronization control. In the last step, the numerical simulation studies have been experimentally verified using the Texas Instrument Delfino digital signal processor board. Numerical simulation results together with experimental validation have showed that the types of dynamics of the related neuron model are not affected from the change of the fractional order of conformable derivative, but the frequency of the dynamic response of the neuronal model is changed from the alteration of the fractional order. The frequency of response of the neuron model increases with decreasing values of the fractional order. On the other hand, if there is no synchronization control method, the coupled neuron models exhibit response ranging from synchronous to asynchronous depending on the sign and value of the coupling parameter. Additionally, decreasing values of the fractional order may allow the coupled neurons to enter the synchronous state more quickly due to increasing frequency of response of the neuronal model. Finally, the coupled neuron models could exhibit synchronous behavior, that is determined by calculating the standard deviation results, regardless of the value of the coupling parameter by using the Lyapunov control method.

Carbohydrate Content Classification Using Postprandial Heart Rate Responses from Non-Invasive Wearables.

The rising incidence of type 2 diabetes underscores the need for technological innovations aimed at enhancing diabetes management by aiding individuals in monitoring their dietary intake. This has resulted in the development of technologies capable of tracking the timing and content of an individual's meals. However, the ability to use non-invasive wearables to estimate or classify the carbohydrate content of the food an individual has just consumed remains a relatively unexplored area. This study investigates carbohydrate content classification using postprandial heart rate responses from non-invasive wearables. We designed and developed timeStampr, an iOS application for collecting timestamps essential for data labeling and establishing ground truth. We then conducted a pilot study in controlled, yet naturalistic settings. Data were collected from 23 participants using an Empatica E4 device worn on the upper arm, while each participant consumed either low-carbohydrate or carbohydrate-rich foods. Due to sensor irregularities with dark skin tones and non-compliance with the study's health criteria, we excluded data from three participants. Finally, we configured and trained a Light Gradient Boosting Machine (LGBM) model for carbohydrate content classification. Our classifiers demonstrated robust performance, with the carbohydrate content classification model consistently achieving at least 84% in accuracy, precision, recall, and AUCROC within a 60 s window. The results of this study demonstrate the potential of postprandial heart rate responses from non-invasive wearables in carbohydrate content classification.

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.

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.

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.

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.

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.