AGREE II Evaluation of Clinical Practice Guidelines on Generalized Cancer Pain Management.

PURPOSE: While several clinical practice guidelines (CPGs) exist to guide clinical decision-making in patients with generalized cancer pain, to date there has been no comprehensive review of their quality. Our aim was to address this deficiency via the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. DESIGN: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline-based systematic literature search followed by AGREE II appraisal of identified CPGs. METHODS: Embase, MEDLINE via PubMed, and Scopus were searched from inception to March 3, 2021, for relevant CPGs. Four authors (FR, AR, JN, JH) independently performed assessments and evaluations of the selected CPGs using the AGREE II instrument. Scaled domain percentage scores were calculated with 60% as the satisfactory quality threshold. Intraclass correlation coefficients (ICCs) were also calculated to assess interrater reliability. RESULTS: Twelve guidelines were selected for inclusion. Two guidelines were classified high quality, three guidelines as average quality, and seven as low quality. Domains of clarity of presentation (82.41% ± 18.20%) and scope and purpose (56.48% ± 30.59%) received the highest mean scores, while domains of applicability (44.53% ± 26.61%) and stakeholder involvement (36.81% ± 21.24%) received the lowest. ICCs showed high consistency between reviewers (range 0.85-0.98). CONCLUSIONS: Most CPGs for generalized cancer pain are of low quality. Future guidelines can be improved by better-defining scope and purpose, stakeholder involvement, rigor of development, applicability, and editorial independence during development. CLINICAL IMPLICATIONS: We hope these critiques improve the quality of published guidelines to promote an improved quality of care and method to measure quality outcomes.

Clinical practice guidelines in the management of pediatric foreign body aspiration and ingestion: a systematic evaluation using the AGREE II instrument.

PURPOSE: Several clinical practice guidelines (CPGs) have been produced to optimize the diagnosis and management of pediatric foreign body aspiration and ingestion. However, to date there have been no critical evaluations of their methodological rigor or quality. Herein, we address this need via the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. METHODS: A literature search of Embase, MEDLINE via PubMed, and Scopus was performed up until February 25, 2021. Identified CPGs were then assessed by four independent reviewers trained in AGREE II. A scaled domain score of >60% was indicated as satisfactory quality. Intraclass correlation coefficients (ICC) were calculated to assess inter-reviewer agreement. RESULTS: 11 guidelines were assessed with only one being classified as high quality and others being either average (two) or low quality (eight). Domain 4 (clarity of presentation) achieved the highest mean score (66.41 ± 13.33%), while domain 5 (applicability) achieved the lowest score (10.80 ± 10.37%). ICC analysis revealed generally strong agreement between reviewers with a range of 0.60-0.98. CONCLUSION: Quality appraisal using the AGREE II instrument suggests that the methodologic rigor and quality of current guidelines for the diagnosis and management of pediatric foreign body aspiration and ingestion need significant improvement.

Comparative and combination study of simvastatin alone and in combination with Beta vulgaris in hyperlipidemia patients.

Phytomedicine is gaining acceptance as well preference in health care management for various diseases. Drug combinations are mostly used clinically for hyperlipidemia, as single-agent therapy is insufficient. Statins remain the cornerstone of hyperlipidemia. The objective of the present research is to manage hyperlipidemia with the least amount of medicine effective clinically, thereby limiting its side effects. Study was carried out with 140 registered hyperlipidemia patients, divided into two groups. Group-A received simvastatin 20mg oral daily & Group B received a combination of simvastatin and beta-valgaris capsules twice a day for 90 days. Pre and post treatment values were compared within the groups and between the groups. Group B shows statistically significant decrease (p<0.05) in serum total cholesterol, low density lipoprotein (LDL), triglycerides (TG) and CRP levels. Also significant improvement (p<0.05) was noted for high density lipoprotein (HDL) levels (20.1% to 57.4%) in group B after completion of study. On the basis of our study results, we can conclude that statins remained to be the mainstay treatment for patients with elevated cholesterol levels. However, the combination has a synergistic effect and reduces oxidative stress (OS) as well.

Update on Hepatobiliary Plasticity.

The liver field has been debating for decades the contribution of the plasticity of the two epithelial compartments in the liver, hepatocytes and biliary epithelial cells (BECs), to derive each other as a repair mechanism. The hepatobiliary plasticity has been first observed in diseased human livers by the presence of biphenotypic cells expressing hepatocyte and BEC markers within bile ducts and regenerative nodules or budding from strings of proliferative BECs in septa. These observations are not surprising as hepatocytes and BECs derive from a common fetal progenitor, the hepatoblast, and, as such, they are expected to compensate for each other's loss in adults. To investigate the cell origin of regenerated cell compartments and associated molecular mechanisms, numerous murine and zebrafish models with ability to trace cell fates have been extensively developed. This short review summarizes the clinical and preclinical studies illustrating the hepatobiliary plasticity and its potential therapeutic application.

Pore-forming activity of S. pneumoniae pneumolysin disrupts the paracellular localization of the epithelial adherens junction protein E-cadherin.

Streptococcus pneumoniae, a common cause of community-acquired bacterial pneumonia, can cross the respiratory epithelial barrier to cause lethal septicemia and meningitis. S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers robust neutrophil (PMN) infiltration that promotes bacterial transepithelial migration in vitro and disseminated disease in mice. Apical infection of polarized respiratory epithelial monolayers by S. pneumoniae at a multiplicity of infection (MOI) of 20 resulted in recruitment of PMNs, loss of 50% of the monolayer, and PMN-dependent bacterial translocation. Reducing the MOI to 2 decreased PMN recruitment two-fold and preserved the monolayer, but apical-to-basolateral translocation of S. pneumoniae remained relatively efficient. At both MOI of 2 and 20, PLY was required for maximal PMN recruitment and bacterial translocation. Co-infection by wild-type S. pneumoniae restored translocation by a PLY-deficient mutant, indicating that PLY can act in trans. Investigating the contribution of S. pneumoniae infection on apical junction complexes in the absence of PMN transmigration, we found that S. pneumoniae infection triggered the cleavage and mislocalization of the adherens junction (AJ) protein E-cadherin. This disruption was PLY-dependent at MOI of 2 and was recapitulated by purified PLY, requiring its pore-forming activity. In contrast, at MOI of 20, E-cadherin disruption was independent of PLY, indicating that S. pneumoniae encodes multiple means to disrupt epithelial integrity. This disruption was insufficient to promote bacterial translocation in the absence of PMNs. Thus, S. pneumoniae triggers cleavage and mislocalization of E-cadherin through PLY-dependent and -independent mechanisms, but maximal bacterial translocation across epithelial monolayers requires PLY-dependent neutrophil transmigration.

Clinical trial transparency in gastrointestinal endoscopy research.

BACKGROUND: Under-reporting of clinical trial results can lead to negative consequences that include inhibiting propagation of knowledge, limiting the understanding of how devices work, affecting conclusions of meta-analyses, and failing to acknowledge patient participation. Therefore clinical trial transparency, through publication of trial results on ClinicalTrials.gov or in manuscript form, is important. We aimed to examine clinical trial transparency in endoscopic clinical trials. METHODS: The ClinicalTrials.gov database was searched for endoscopy trials up to October 2019. Adherence to the reporting of results to the database or in publication form was recorded for each trial. RESULTS: The final analysis included 923 trials, of which 801 were completed and 122 were either terminated or suspended. Results were available either on ClinicalTrials.gov or in publication for 751/923 trials (81.4 %). Other fields have reported a publication rate of 40 %-63 %. Results were available on ClinicalTrials.gov for 168 trials (18.2 %) and in the form of a publication for 720 trails (78.0 %). CONCLUSIONS: Compared with other fields in medicine, endoscopy clinical trials have a high rate of clinical trial transparency. However, there is room for improvements as close to one-fifth of trials fail to report results and 81.8 % do not report results to ClinicalTrials.gov.

Celecoxib and bevacizumab synergistically inhibit non-small cell lung cancer by inducing apoptosis and modulating VEGF and MMP-9 expression.

Lung cancer is the most typical form of cancer that results in death worldwide. Patients with non-small cell lung cancer (NSCLC) have an around 15% survival rate despite of advancement in cancer treatment. This study aimed to evaluate the combined effect of celecoxib and bevacizumab on NSCLC using A549 cells as an in vitro model. The A549 cells were culture and treated with celecoxib, bevacizumab and their combination and the cell proliferation was assessed using MTT assay, whereas cell apoptosis was analyzed using flowcytometry. The effects on the apoptotic genes were examined using western blotting, while qPCR was used for analyzing the VEGF and MMP-9 expression. Celecoxib, bevacizumab and their combination exhibited a dose dependent inhibition (p<0.001). The rate of apoptosis was 14.1% and 26.5% but when the two drugs were combined, the rate of apoptosis was significantly increased due to synergism by 52.2% (p<0.001). Western blotting displayed that co-treatment significantly up regulated proapoptotic genes (caspase-3 and -9) and down regulated anti-apoptotic gene (Bcl-2) (p<0.001). Additionally, VEGF and MMP-9 expression were both significantly reduced with co-treatment compared to the control (p<0.001). Celecoxib combined with bevacizumab synergistically inhibited NSCLC by inducing apoptosis and modulating VEGF and MMP-9 expression.

Clinical Practice Guidelines in the Management of Breakthrough Cancer Pain: A Systematic Review using the Appraisal of Guidelines for Research and Evaluation (AGREE II) Instrument.

BACKGROUND: Several clinical practice guidelines (CPGs), consensus statements, and recommendations currently exist for the diagnosis and management of breakthrough cancer pain (BTcP). These documents have considerable variability amongst them, and to date, their quality and methodologic rigor have not been appraised. AIM: We aim to identify and perform a quality appraisal of CPGs for the diagnosis and management of BTcP using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. METHODS: A comprehensive literature search was performed in MEDLINE (via PubMed), EMBASE, and SCOPUS databases up until January 1, 2021. Four reviewers independently evaluated each guideline using the AGREE II instrument. Scaled domain scores were generated and the threshold used for satisfactory quality was >60%. Additionally, intraclass correlation coefficients (ICC) were calculated to determine level of agreement between reviewers. RESULTS: Eleven guidelines were selected for final evaluation based on inclusion/exclusion criteria. Only one guideline was classified of "average" quality while the rest were classified as "low" quality. The "Editorial Independence" (70.46 ± 35.7) and "Scope and Purpose" (64.78 ± 12.5) domains received the highest mean scores, while the "Applicability" (32.58 ± 13.5) and "Rigor of Development" (35.04 ± 9.0) domains received the lowest mean scores. ICC statistical analysis showed high magnitude of agreement between reviewers with a range of (0.790-0.988). CONCLUSIONS: Reflecting upon our quality appraisal, it is evident that the quality and methodologic rigor of BTcP guidelines can be improved upon in the future. Our findings also elucidate the existing variability/discrepancies among guidelines in diagnostic criteria and management of BTcP.

Promising role of Metformin in reducing the viability of breast cancerous cells.

To evaluate the anticancerous effects of different dilutions of metformin were evaluated for in vitro anti-cancerous effects, primarily breast cancer cells (MCF-7, MDA-MB-231). This prospective experimental study was conducted in Department of Pharmacology & Therapeutics BMSI in alliance with PCMD. The duration of study was from March 2016 to February 2017. For evaluating the anticancerous effects of different dilutions of Metformin (0.5µM -100µM) we used 4 different cancerous cells lines; MCF-7, HT-29, MDA-MB-231 and Hela. For assessment of anticancerous effects we used MTT assay by which assessed IC50, SI, % viability of all cells and Trypan blue exclusion assay for only MCF-7 cell line. The % viability of MCF-7 was significantly decreases (χ2 (2) = 26.48, p=<0.001) in dose dependent manner from 99.8±0.2 to 39.71±1.3. For MDA-MB-231% viability significantly reduced (χ2 (2) =26.48, p=<0.001) from 99.474± 0.298 to 51.55±4. However Metformin had statistically no significant dose dependent effects on % viability of MCF-10 (χ2 (2) = 11.709, p=0.069). Metformin significantly exhibited the anticancerous effects on breast cancerous cells by selectively target the cancerous cells without any effects on normal epithelial cells of breast.

Atorvastatin as an adjuvant with betamethasone valerate reduces disease severity and cardiovascular risks in Psoriasis.

OBJECTIVES: To evaluate the effect of Atorvastatin as an adjuvant with betamethasone valerate on disease severity and cardiovascular risks in chronic plaque type psoriatic patients. METHODS: It is an interventional study conducted in Pharmacology Department of BMSI, JPMC with the collaboration of Dermatology Department of JPMC, Karachi. The duration of study was from June 2013 to June 2016. Seventy five psoriatic patients were prescribed Tablet Atorvastatin 40-20 mg/day (40mg for first three months twice daily followed by 20mg once daily for the next three month) plus topical Betamethasone Valerate 0.1% once daily for 6 months (three week apply than one week interval). The efficacy and safety profile of drugs was measured by PASI, DLQI, hsCRP, LFTS and Lipid profile. RESULTS: The percentage change of PASI is 86.749±0.547, DLQI is 82.697±.2.61 and hsCRP is 40.371±8.505, which showed highly significant improvement in patient at the end of last follow up. LFTs and CPK for safety profile of therapy showed non-significant results. CONCLUSION: Atorvastatin used as an adjuvant therapy with currently existing standard therapy (topical betamethasone) in patients having mild to moderate plaque type psoriasis reduces disease severity and cardiovascular risks.

Morin mitigates acetaminophen-induced liver injury by potentiating Nrf2 regulated survival mechanism through molecular intervention in PHLPP2-Akt-Gsk3ß axis.

Acetaminophen (APAP) is frequently taken to relieve pain. Staggered APAP overdoses have been reported to cause acetaminophen-induced liver injury (AILI). Identification of efficacious therapeutic modalities to address complications imposed by accidental/intentional long-term APAP ingestion is needed. Morin, a plant-derived phytochemical, possesses a multitude of pharmacological properties including hepatoprotective action; however, the underlying mechanisms have been inadequately explored. Our present report demonstrates significant attenuation of APAP-mediated liver injury by morin supplementation in vivo as indicated by reduction in histological and serum markers of hepatotoxicity. Morin not only limited necroinflammation as revealed by reduced HMGB1 release, NALP3 and caspase-1 maturation, but also suppressed oxidative stress and mitochondrial dysfunction. This suggests that morin may have exerted its cytoprotective role by way of early intervention in the pathway leading to perpetuation of AILI. Morin reinforced cellular defenses by suppressing Nrf2 ubiquitination and promoting nuclear Nrf2 retention as well as ARE-Nrf2 binding affinity. The effects were observed to be a result of molecular intervention in the activity of PHLPP2, a phosphatase previously reported by us to subdue cellular Nrf2 responses via Fyn kinase activation. Morin was observed to inhibit APAP-induced increase in PHLPP2 activity ex vivo as well as its association with cellular target Akt1. As a result, morin prevented oxidative stress induced deactivation of Akt (Ser473) leading to suppression in GSK3ß and Fyn kinase activation. The study supports the inhibitory action of morin against PHLPP2-regulated Nrf2-suppression and hence indentifies Nrf2-potentiating property of morin that may be exploited in developing novel therapeutic strategy to address AILI.

Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice.

Primary human hepatocyte (PHH) transplantation is a promising alternative to liver transplantation, whereby liver function could be restored by partial repopulation of the diseased organ with healthy cells. However, currently PHH engraftment efficiency is low and benefits are not maintained long-term. Here we refine two male mouse models of human chronic and acute liver diseases to recapitulate compromised hepatocyte proliferation observed in nearly all human liver diseases by overexpression of p21 in hepatocytes. In these clinically relevant contexts, we demonstrate that transient, yet robust expression of human hepatocyte growth factor and epidermal growth factor in the liver via nucleoside-modified mRNA in lipid nanoparticles, whose safety was validated with mRNA-based COVID-19 vaccines, drastically improves PHH engraftment, reduces disease burden, and improves overall liver function. This strategy may overcome the critical barriers to clinical translation of cell therapies with primary or stem cell-derived hepatocytes for the treatment of liver diseases.

Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy to treat murine liver diseases.

Primary human hepatocyte (PHH) transplantation is a promising alternative to liver transplantation, whereby liver function could be restored by partial repopulation of the diseased organ with healthy cells. However, currently PHH engraftment efficiency is low and benefits are not maintained long-term. Here we refine two mouse models of human chronic and acute liver diseases to recapitulate compromised hepatocyte proliferation observed in nearly all human liver diseases by overexpression of p21 in hepatocytes. In these clinically relevant contexts, we demonstrate that transient, yet robust expression of human hepatocyte growth factor and epidermal growth factor in the liver via nucleoside-modified mRNA in lipid nanoparticles, whose safety was validated with mRNA-based COVID-19 vaccines, drastically improves PHH engraftment, reduces disease burden, and improves overall liver function. This novel strategy may overcome the critical barriers to clinical translation of cell therapies with primary or stem cell-derived hepatocytes for the treatment of liver diseases.

Naringenin prevents high glucose-induced mitochondria-mediated apoptosis involving AIF, Endo-G and caspases.

Oxidative stress is implicated in hyperglycemia-induced alterations in cell signaling pathways. We examined the toxicity of high glucose in primary rat hepatocytes and its amelioration by naringenin. Incubation of hepatocytes with 40 mM glucose for 1.5 h exhibited significant decrease in cell viability confirmed by MTT reduction and Alamar blue assay. At the same time primary rat hepatocytes exhibited significant decrease in mitochondrial membrane potential indicating organelle dysfunction. Enhanced translocation of Cyt-c from mitochondria to cytosol and AIF/Endo-G from mitochondria to nucleus, activation of caspase-9/3, DNA damage, and chromatin condensation were observed in glucose-stressed hepatocytes, indicating the involvement of mitochondrial pathway in high glucose-induced apoptosis. Transcript levels of antioxidant enzymes were significantly altered along with corresponding changes in their enzymatic activities. The level of intracellular antioxidant glutathione as well as superoxide dismutase, catalase, and glutathione peroxidase activities were observed to be significantly decreased in hepatocytes treated with high concentration of glucose. Naringenin, a flavanone, was effective in preventing loss of cell viability, reactive oxygen species generation, and decline in antioxidant defense. Translocation of AIF, Endo-G, and Cyt-c from mitochondria was also inhibited by naringenin in glucose-stressed cells. Messenger RNA expression of anti-apoptotic and apoptotic genes, externalization of phosphatidyl serine, DNA damage, chromatin condensation, and sub-diploid cell population were effectively altered by naringenin indicating its anti-apoptotic potential in vitro. Our data suggests that naringenin can prevent apoptosis induced by high glucose through scavenging of reactive oxygen species and modulation of mitochondria-mediated apoptotic pathway.

Is Artificial Intelligence the Cost-Saving Lens to Diabetic Retinopathy Screening in Low- and Middle-Income Countries?

Diabetes is a rapidly growing global health crisis disproportionately affecting low- and middle-income countries (LMICs). The emergence of diabetes as a global pandemic is one of the major challenges to human health, as long-term microvascular complications such as diabetic retinopathy (DR) can lead to irreversible blindness. Leveraging artificial intelligence (AI) technology may improve the diagnostic accuracy, efficiency, and accessibility of DR screenings across LMICs. However, there is a gap between the potential of AI technology and its implementation in clinical practice. The main objective of this systematic review is to summarize the currently available literature on the health economic assessments of AI implementation for DR screening in LMICs. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We conducted an extensive systematic search of PubMed/MEDLINE, Scopus, and the Web of Science on July 15, 2023. Our review included full-text English-language articles from any publication year. The Joanna Briggs Institute's (JBI) critical appraisal checklist for economic evaluations was used to rate the quality and rigor of the selected articles. The initial search generated 1,423 records and was narrowed to five full-text articles through comprehensive inclusion and exclusion criteria. Of the five articles included in our systematic review, two used a cost-effectiveness analysis, two used a cost-utility analysis, and one used both a cost-effectiveness analysis and a cost-utility analysis. Across the five articles, LMICs such as China, Thailand, and Brazil were represented in the economic evaluations and models. Overall, three out of the five articles concluded that AI-based DR screening was more cost-effective in comparison to standard-of-care screening methods. Our systematic review highlights the need for more primary health economic analyses that carefully evaluate the economic implications of adopting AI technology for DR screening in LMICs. We hope this systematic review will offer valuable guidance to healthcare providers, scientists, and legislators to support appropriate decision-making regarding the implementation of AI algorithms for DR screening in healthcare workflows.

Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury.

Background and Aims: Acetaminophen (APAP) overdose is the leading cause of acute liver failure, with one available treatment, N-acetyl cysteine (NAC). Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. This study addresses this need by deciphering a mechanism of sexual dimorphism in APAP-induced liver injury, and leveraging it to accelerate liver recovery via growth hormone (GH) treatment. GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. Here, we aim to establish GH as a novel therapy to treat APAP hepatotoxicity. Approach and Results: Our results demonstrate sex-dependent APAP toxicity, with females showing reduced liver cell death and faster recovery than males. Single-cell RNA sequencing analyses reveal that female hepatocytes have significantly greater levels of GH receptor expression and GH pathway activation compared to males. In harnessing this female-specific advantage, we demonstrate that a single injection of recombinant human GH protein accelerates liver recovery, promotes survival in males following sub-lethal dose of APAP, and is superior to standard-of-care NAC. Alternatively, slow-release delivery of human GH via the safe nonintegrative lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP), a technology validated by widely used COVID-19 vaccines, rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice. Conclusions: Our study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients.

VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis.

The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial-cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via nonintegrative and safe nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNPs) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and elimination of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This work defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals unexpected therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases.

VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis.

The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via non-integrative and safe nucleoside-modified mRNA encapsulated into lipid-nanoparticles (mRNA-LNP) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and reversion of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals novel therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases. Highlights: Complementary mouse and zebrafish models of liver injury demonstrate the therapeutic impact of VEGFA-KDR axis activation to harness BEC-driven liver regeneration.VEGFA mRNA LNPs restore two key features of the chronic liver disease in humans such as steatosis and fibrosis.Identification in human cirrhotic ESLD livers of KDR-expressing BECs adjacent to clusters of KDR+ hepatocytes suggesting their BEC origin.KDR-expressing BECs may represent facultative adult progenitor cells, a unique BEC population that has yet been uncovered.

FDA Approval Summary: Abemaciclib With Endocrine Therapy for High-Risk Early Breast Cancer.

PURPOSE: The US Food and Drug Administration approved abemaciclib in combination with endocrine therapy (ET) for the adjuvant treatment of adult patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score ≥ 20%. PATIENTS AND METHODS: The approval was based on monarchE, a phase III, open-label, 2-cohort, multicenter trial of patients with EBC randomly assigned to receive abemaciclib plus ET (n = 2,808) or ET alone (n = 2,829). Abemaciclib was given at 150 mg orally twice daily for 2 years. RESULTS: Invasive disease-free survival (IDFS) in the intent-to-treat population was statistically significant at the second IDFS interim analysis (IA; March 2020; hazard ratio [HR; 95% CI], 0.747 [0.598 to 0.932]; P = .0096); however, only 12.5% of patients had completed adjuvant therapy, and the HR for overall survival (OS) was > 1. A prespecified, controlled analysis of IDFS in patients with Ki-67 ≥ 20% in cohort 1 was statistically significant at the final IDFS analysis (July 2020; HR [95% CI], 0.643 [0.475 to 0.872]; P = .0042). At the first OS IA (April 2021), the majority of patients had completed adjuvant therapy, IDFS remained consistent, and potential detriment in OS was not observed for this subgroup (HR [95% CI], 0.767 [0.511 to 1.152]). The HR for OS in the intent-to-treat population at OS IA remained > 1 (HR [95% CI], 1.091 [0.818 to 1.455]). More patients in the abemaciclib plus ET arm experienced treatment emergent adverse events (all grades 98.4% v 88.8%, grade 3 ≥ 49.7% v 16.3%). CONCLUSION: The approval of abemaciclib in adjuvant EBC was limited to patients with high risk of recurrence and Ki-67 ≥ 20%, given their favorable benefit:risk with a statistically significant IDFS advantage and no observed detriment on survival.

Preclinical meritorious anticancer effects of Metformin against breast cancer: An In vivo trial.

OBJECTIVE: This research aims to evaluate the preclinical meritorious and anticancer effects of Metformin in a Xenograft model of breast cancer. METHODS: This interventional trial was conducted during a defined period of 5 months (August 2016 January 2017). We used a Xenograft model of nude BALB/c mice. A sample size of 50 mice, allocated into two groups and designated as Group A and Group B for Metformin and negative control groups, respectively. The anticancer activity of Metformin has been evaluated by comparing the tumour volume, tumour weight, tumour regression ratio, percentage regression, and survival rate. RESULTS: Compared with the control group, Metformin can significantly reduce the progression of tumour in the Xenograft model of breast cancer induced by MCF-7. This is reflected by significant differences in tumour volume at the final follow-up (p = <0.001). Our findings are further supported by a significant reduction of the tumour growth rate (p = <0.001) and tumour weight (p = <0.001) in the Metformin group than in the control group. Similarly, the total survival rate and tumour regression are more significantly correlated in the Metformin group. CONCLUSION: This study demonstrates that Metformin can significantly reduce the tumour growth and can increase the survival rate in a Xenograft model of breast cancer.