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Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity of this cancer urgently demand the exploration of novel approaches for the development of effective therapeutic measures. Metabolic derangement is one of the hallmarks of cancers which restructures mitochondrial activities and biological pathways. Apart from their bioenergetic and biosynthetic functions, mitochondria are also implicated in a myriad of cellular functions including proliferation, differentiation, apoptosis, senescence, homeostasis, and other cell regulatory mechanisms. It has been noted that PC, like other types of cancers, exploits these activities in favor of tumor growth and survival by inducing mitochondrial dysfunctions such as mitochondrial-DNA mutation, metabolic enzyme modification, ROS generation, mitophagy, evasion of apoptosis, and mitochondrial biogenesis. During pancreatic carcinogenesis, a large number of onco-factors including Bcl-2 family proteins, NF-κB, HIFs, NRF2, NOX, MFNs, DRP1, DUSP6, Cyp-D, PARKIN, and others are dysregulated, resulting into reprogramming of metabolic pathways and cellular kinetics. Hence, targeted interventions in these metabolic derangements may present some effective anticancer approaches. The current review gives an insight into various mitochondrial disorders and their targetable molecules in PC which may provide certain novel opportunities in the pursuit of therapeutic development. Furthermore, we have also discussed certain treatment perspectives in PC based on specific mitochondrial activities. • Mitochondrial derangements can switch the metabolic phenotype to impart numerous tumorigenic features. • Mitochondrial derangements reinforce the oncogenic mechanisms of development, progression, and chemoresistance in pancreatic cancer. • The metabolic alterations present plausible mitochondrial targets and therapeutic opportunities. • The natural agents and small bioactive compounds are promising anticancer effects based on mitochondrial targets. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to evaluate overdilation of 10-mm standard and 8–10 mm controlled-expansion Viatorr stents to 12 mm during transjugular intrahepatic portosystemic shunt (TIPS) placement when insufficient reduction (<50%) in portosystemic gradient (PSG) is achieved with standard 10 mm dilation. Materials and Methods It is a single-institution, institutional review board-approved, retrospective review of TIPS (2013–2022) to identify patients in the overdilation group (12 mm dilation of a 10-mm stent) and a control group (10 mm dilation of a 10-mm stent) matched for age, indication, stent type, Model for End-Stage Liver Disease (MELD) score, pre-TIPS PSG, and variceal embolization. Stent diameter, technical success, clinical outcomes, and adverse events were assessed for both groups. Results TIPS was created for the overdilation group (n = 35, 57 ± 11 years, 69% male; MELD: 14 ± 5) and control group (n = 35, 57 ± 11 years, 83% male; MELD: 14 ± 5). Overdilation to 12 mm adequately reduced PSG by more than 50% (55 vs. 65% in the control group, p = 0.11). The stent diameter was larger in the overdilation group on cross-sectional imaging (9.8 ± 0.2 vs. 9.5 ± 0.4 mm, p < 0.001), with an estimated 57% higher volume flow rate (p = 0.002). Patients were followed for a median of 11.3 months (range: 0.03–75) and 15.6 months (range: 0.03–106) in the overdilation and control groups, respectively. There was an equivalent rate of ascites resolution (56 vs. 63%, p = 0.68) and rebleeding (13 vs. 17%, p = 0.82) in the overdilation and control groups, with a similar risk of new-onset hepatic encephalopathy (41 vs. 33%, p = 0.51) and TIPS occlusion (11 vs. 9%, p = 0.69). Overdilation did not result in any instance of stent fracture. Conclusion Overdilation of 10-mm Viatorr stents with 12 mm balloons may provide benefit by potentially reducing PSG further for patients initially having inadequate PSG reduction with short-term safety. [ABSTRACT FROM AUTHOR]

[Display omitted] • Trop2 played a vital role in metastasis by Trop2/β-catenin positive feedback loop. • Bruceine D inhibited cancer cells proliferation and metastasis by targeting Trop2. • Bruceine D suppressed Trop2-driven ECM-remodeling and EMT to reduce lung metastatic colonization in vivo. • Bruceine D blocked Trop2/β-catenin complex, inducing β-catenin degradation though ubiquitin. Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody–drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported. To screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action. Small molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting. Here we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model. These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition. [ABSTRACT FROM AUTHOR]

Hydroxychloroquine (HCQ) was initially promoted as an oral therapy for early treatment of coronavirus disease 2019 (COVID‐19). Conventional meta‐analyses cannot fully address the heterogeneity of different designs and outcomes of randomized controlled trials (RCTs) assessing the efficacy of HCQ in outpatients with mild COVID‐19. We conducted a pooled analysis of individual participant data from RCTs that evaluated the effect of HCQ on hospitalization and viral load reduction in outpatients with confirmed COVID‐19. We evaluated the overall treatment group effect by log‐likelihood ratio test (−2LL) from a generalized linear mixed model to accommodate correlated longitudinal binary data. The analysis included data from 11 RCTs. The outcome of virological effect, assessed in 1560 participants (N = 795 HCQ, N = 765 control), did not differ significantly between the two treatment groups (−2LL = 7.66; p = 0.18) when adjusting for cohort, duration of symptoms, and comorbidities. The decline in polymerase chain reaction positive tests from day 1 to 7 was 42.0 and 41.6 percentage points in the HCQ and control groups, respectively. Among the 2037 participants evaluable for hospitalization (N = 1058 HCQ, N = 979 control), we found no significant differences in hospitalization rate between participants receiving HCQ and controls (odds ratio 0.995; 95% confidence interval 0.614–1.610; −2LL = 0.0; p = 0.98) when adjusting for cohort, duration of symptoms, and comorbidities. This individual participant data meta‐analysis of 11 HCQ trials that evaluated severe acute respiratory syndrome‐coronavirus 2 viral clearance and COVID‐19 hospitalization did not show a clinical benefit of HCQ. Our meta‐analysis provides evidence to support the interruption in the use of HCQ in mild COVID‐19 outpatients to reduce progression to severe disease. [ABSTRACT FROM AUTHOR]

Aim: The present study was aimed to highlight the current prescribing pattern of oral hypoglycemia in type 2 diabetes mellitus and to evaluate the therapeutic effectiveness of these therapeutic categories in achieving target glycemic control. Methods: This is a prospective, cross-sectional, observational study of 6 months' duration conducted in a tertiary care hospital of Lahore, Pakistan. Results: The current research recruited 145 patients presented in diabetes management center of a tertiary care hospital in Lahore, Pakistan. Mean age of the participants was 50.2 (± 8.5) years. Out of the 145 patients, 63% were females and 37% were males. Most patients were diagnosed to have diabetes within the past 5 years. Diabetes-induced neuropathy was the most common complication (71.7%) among the patients. A large proportion of these patients (70.3%) were also suffering from other comorbidities among which the most common one is hypertension. The average number of prescribed medications was 1.31. Metformin was prescribed to a majority of patients (64%) as monotherapy while 28.96% received combination therapy. Mean glycated hemoglobin (HBA1c) before and after 3 months of treatment was 8.5 (± 2.3) and 8.04 (± 2.1), respectively. Inferential statistics show a strong association between HBA1c and life style modifications and adherence to medication therapy (P = 0.05). However, the correlation between HBA1c and Morisky score and duration of disease was inverse and weak (P = 0.6, 0.4). The t-test values show a small difference between HBA1c values before and after 3 months (t = 0.440 and 0.466, respectively). Conclusion: Optimization of medication regimen and continuous patient education regarding life style modification and adherence to medication therapy are necessitated to bring HBA1c values near to target. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to determine the feasibility of performing a comprehensive cardiac computed tomographic (CT) examination incorporating stress and rest myocardial perfusion imaging together with coronary computed tomography angiography (CTA). Background: Although cardiac CT can identify coronary stenosis, very little data exist on the ability to detect stress-induced myocardial perfusion defects in humans. Methods: Thirty-four patients who had a nuclear stress test and invasive angiography were included in the study. Dual-source computed tomography (DSCT) was performed as follows: 1) stress CT: contrast-enhanced scan during adenosine infusion; 2) rest CT: contrast-enhanced scan using prospective triggering; and 3) delayed scan: acquired 7 min after rest CT. Images for CTA, computed tomography perfusion (CTP), and single-photon emission computed tomography (SPECT) were each read by 2 independent blinded readers. Results: The DSCT protocol was successfully completed for 33 of 34 subjects (average age 61.4 ± 10.7 years; 82% male; body mass index 30.4 ± 5 kg/m2) with an average radiation dose of 12.7 mSv. On a per-vessel basis, CTP alone had a sensitivity of 79% and a specificity of 80% for the detection of stenosis ≥50%, whereas SPECT myocardial perfusion imaging had a sensitivity of 67% and a specificity of 83%. For the detection of vessels with ≥50% stenosis with a corresponding SPECT perfusion abnormality, CTP had a sensitivity of 93% and a specificity of 74%. The CTA during adenosine infusion had a per-vessel sensitivity of 96%, specificity of 73%, and negative predictive value of 98% for the detection of stenosis ≥70%. Conclusions: Adenosine stress CT can identify stress-induced myocardial perfusion defects with diagnostic accuracy comparable to SPECT, with similar radiation dose and with the advantage of providing information on coronary stenosis. [Copyright &y& Elsevier]