Precision Colorectal Cancer Fecal Immunological Test Screening With Fecal-Hemoglobin-Concentration-Guided Interscreening Intervals.

Importance: Given a gradient relationship between fecal hemoglobin (f-Hb) concentration and colorectal neoplasia demonstrated previously, using f-Hb-guided interscreening interval has increasingly gained attention in population-based fecal immunological test (FIT), but it is very rare to address how to implement such a precision strategy and whether it can economize the use of FIT and colonoscopy. Objective: To demonstrate the applicability of personalized colorectal cancer (CRC) screening with f-Hb-guided screening intervals to reduce the number of FITs and colonoscopy with as equivalent efficacy as universal biennial screening. Design, Setting, and Participants: A retrospective cohort study for developing f-Hb-guided precision interscreening interval was conducted using data on a Taiwanese biennial nationwide FIT screening program that enrolled more than 3 million participants aged 50 to 74 years between 2004 and 2014. The cohort was followed up over time until 2019 to ascertain colorectal neoplasia and causes of death. A comparative study was further designed to compare the use of FIT and colonoscopy between the personalized f-Hb-guided group and the universal biennial screening group given the equivalent efficacy of reducing CRC-related outcomes. Main Outcomes and Measurements: A spectrum of f-Hb-guided intervals was determined by using the Poisson regression model given the equivalent efficacy of a universal biennial screening. The use of FIT and colonoscopy for the pragmatic f-Hb-guided interval group was measured compared with the universal biennial screening group. Data analysis was performed from September 2022 to October 2023. Results: Using data from the 3 500 250 participants (mean [SD] age, 57.8 [6.0] years) enrolled in the Taiwanese biennial nationwide FIT screening program, an incremental increase in baseline f-Hb associated with colorectal neoplasia and CRC mortality consistently was observed. Participants with different f-Hb levels were classified into distinct risk categories. Various screening intervals by different f-Hb levels were recommended. Using the proposed f-Hb-guided screening intervals, it was found that the personalized method was imputed to reduce the number of FIT tests and colonoscopies by 49% and 28%, respectively, compared with the universal biennial screening. Conclusion and Relevance: The gradient relationship between f-Hb and colorectal neoplasia and CRC mortality was used to develop personalized FIT screening with f-Hb-guided screening intervals. Such a precision interscreening interval led to the reduced use of FIT test and colonoscopy without compromising the effectiveness of universal biennial screening.

The intrinsic substrate specificity of the human tyrosine kinome.

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.

A systematic review on sonoelastography for rotator-cuff post-repair assessment.

Surgical repair of rotator cuff tears is performed routinely; however, the risks of re-tears and the associated consequences are significant. Sonoelastography, an imaging modality that evaluates the mechanical properties of tissues, can examine the dynamic transitions in rotator cuff stiffness following retear and investigate the relationship between these changes and the occurrences of retears. This systematic review aimed to summarize the role of perioperative sonoelastography in repaired rotator cuffs. A comprehensive search of the PubMed, Embase, and Cochrane databases was conducted, covering studies published until June 19, 2023. The Newcastle-Ottawa scale was used for quality assessment. The key information extracted from each study included the injury/surgery type, follow-up duration, sonoelastography mode, and main sonoelastographic findings. Eleven eligible studies comprising 355 patients were included. All studies focused on supraspinatus muscles and tendons with previous arthroscopic repairs. During the postoperative 1st - 6th months, muscle stiffness increased in the supraspinatus and decreased in the ipsilateral deltoid. Failure to recover supraspinatus muscle elasticity might be indicative of potential tendon re-tear; however, it is imperative to first establish correlations with other imaging modalities. Conflicting findings have been observed regarding stiffening or softening of the supraspinatus tendon after surgical repair. The preoperative stiffness of the supraspinatus tendon did not correlate with postoperative tendon integrity or function.

Structure of the p53 degradation complex from HPV16.

Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3-ligase E6AP, also known as UBE3A, to promote degradation of the tumor suppressor, p53. In this study, we present a single-particle cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53, determined at a resolution of ~3.3 Å. Our structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. These findings shed light on the molecular basis of the ternary complex, which has been pursued as a potential therapeutic target for HPV-driven cervical, anal, and oropharyngeal cancers over the last two decades. Understanding the structural and mechanistic underpinnings of this complex is crucial for developing effective therapies to combat HPV-induced cancers. Our findings may help to explain why previous attempts to disrupt this complex have failed to generate therapeutic modalities and suggest that current strategies should be reevaluated.

Cardiac contraction and relaxation are regulated by distinct subcellular cAMP pools.

Cells interpret a variety of signals through G-protein-coupled receptors (GPCRs) and stimulate the generation of second messengers such as cyclic adenosine monophosphate (cAMP). A long-standing puzzle is deciphering how GPCRs elicit different physiological responses despite generating similar levels of cAMP. We previously showed that some GPCRs generate cAMP from both the plasma membrane and the Golgi apparatus. Here we demonstrate that cardiomyocytes distinguish between subcellular cAMP inputs to elicit different physiological outputs. We show that generating cAMP from the Golgi leads to the regulation of a specific protein kinase A (PKA) target that increases the rate of cardiomyocyte relaxation. In contrast, cAMP generation from the plasma membrane activates a different PKA target that increases contractile force. We further validated the physiological consequences of these observations in intact zebrafish and mice. Thus, we demonstrate that the same GPCR acting through the same second messenger regulates cardiac contraction and relaxation dependent on its subcellular location.

Epinephrine inhibits PI3Kα via the Hippo kinases.

The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.

The diverse structural modes of tRNA binding and recognition.

tRNAs are short noncoding RNAs responsible for decoding mRNA codon triplets, delivering correct amino acids to the ribosome, and mediating polypeptide chain formation. Due to their key roles during translation, tRNAs have a highly conserved shape and large sets of tRNAs are present in all living organisms. Regardless of sequence variability, all tRNAs fold into a relatively rigid three-dimensional L-shaped structure. The conserved tertiary organization of canonical tRNA arises through the formation of two orthogonal helices, consisting of the acceptor and anticodon domains. Both elements fold independently to stabilize the overall structure of tRNAs through intramolecular interactions between the D- and T-arm. During tRNA maturation, different modifying enzymes posttranscriptionally attach chemical groups to specific nucleotides, which not only affect translation elongation rates but also restrict local folding processes and confer local flexibility when required. The characteristic structural features of tRNAs are also employed by various maturation factors and modification enzymes to assure the selection, recognition, and positioning of specific sites within the substrate tRNAs. The cellular functional repertoire of tRNAs continues to extend well beyond their role in translation, partly, due to the expanding pool of tRNA-derived fragments. Here, we aim to summarize the most recent developments in the field to understand how three-dimensional structure affects the canonical and noncanonical functions of tRNA.

Preoperative lung ultrasound for confirming the double-lumen endotracheal tube position for one-lung ventilation: A systematic review and meta-analysis.

Objectives: Insertion of a double-lumen endotracheal tube (DLT) is the most commonly used method for one-lung ventilation (OLV). This meta-analysis was aimed at investigating the performance of lung ultrasound in assessing the DLT position in OLV. Methods: Electronic databases were searched for related trials from inception to October 2022. The primary outcome was the performance of ultrasound or clinical evaluation in confirming the correctness of the DLT position, using fiberoptic bronchoscopy or intraoperative direct visualization of lung collapse as the gold standard. The secondary outcome was the time required to confirm or adjust the DTL position. Results: Five randomized controlled trials and three observational studies involving 771 patients were included in the meta-analysis. The pooled sensitivity and specificity of ultrasound were 0.93 (95% confidence interval [CI]: 0.79-0.98) and 0.61 (95% CI: 0.41-0.77), respectively, while those of clinical evaluation were 0.93 (95% CI: 0.73-0.99) and 0.35 (95% CI: 0.25-0.47), respectively. The pooled procedure duration was 122.27 s (95% CI: 20.85-223.69) with ultrasound and 112.03 s (95% CI: 95.30-128.76) with clinical evaluation. The area under the curve for discriminating the DLT position was 0.86 (95% CI: 0.82-0.88) for ultrasound and 0.52 (95% CI: 0.48-0.57) for clinical evaluation. Conclusions: Compared to clinical evaluation, ultrasound has a similar sensitivity but a better specificity for confirming the correctness of the DLT position. Ultrasound is an acceptable imaging tool for assessing DTL placement in OLV.

A novel ELP1 mutation impairs the function of the Elongator complex and causes a severe neurodevelopmental phenotype.

BACKGROUND: Neurodevelopmental disorders (NDDs) are heterogeneous, debilitating conditions that include motor and cognitive disability and social deficits. The genetic factors underlying the complex phenotype of NDDs remain to be elucidated. Accumulating evidence suggest that the Elongator complex plays a role in NDDs, given that patient-derived mutations in its ELP2, ELP3, ELP4 and ELP6 subunits have been associated with these disorders. Pathogenic variants in its largest subunit ELP1 have been previously found in familial dysautonomia and medulloblastoma, with no link to NDDs affecting primarily the central nervous system. METHODS: Clinical investigation included patient history and physical, neurological and magnetic resonance imaging (MRI) examination. A novel homozygous likely pathogenic ELP1 variant was identified by whole-genome sequencing. Functional studies included in silico analysis of the mutated ELP1 in the context of the holo-complex, production and purification of the ELP1 harbouring the identified mutation and in vitro analyses using microscale thermophoresis for tRNA binding assay and acetyl-CoA hydrolysis assay. Patient fibroblasts were harvested for tRNA modification analysis using HPLC coupled to mass spectrometry. RESULTS: We report a novel missense mutation in the ELP1 identified in two siblings with intellectual disability and global developmental delay. We show that the mutation perturbs the ability of ELP123 to bind tRNAs and compromises the function of the Elongator in vitro and in human cells. CONCLUSION: Our study expands the mutational spectrum of ELP1 and its association with different neurodevelopmental conditions and provides a specific target for genetic counselling.

Case report of new-onset ulcerative colitis after MVC-COVI1901 vaccine injection for SARS-CoV-2.

A 23-year-old man suffered from diarrhea after receiving the MVC-COVI1901 vaccine. The patient then presented to our emergency department due to swelling and pain in his right knee. Synovial effusion studies of the right knee revealed inflammation. Gram and acid-fast stains reported negative results and no crystals were found under a polarized light microscope. During his hospitalization, the patient underwent a colonoscopy and computed tomography (CT) due to bloody stool. Pancolitis was suspected under colonoscopy and an abdominal CT scan supported our diagnosis showing wall thickening and mucosal enhancement. Pathology showed distorted crypt architecture and acute cryptitis with abscesses. After excluding other causes of ulcerative colitis (UC), the patient was diagnosed with MVC-COV1901 vaccine-related UC and inflammatory bowel disease arthropathy. Subsequent presentation of UC and inflammatory bowel disease-related arthropathy after receiving the MVC-COVI1901 vaccine has not previously been reported. We speculate that the pathogenesis could be correlated to the vaccine's components (spike protein S-2P adjuvanted with CpG 1018 and aluminum hydroxide) through the combination of 2 effects: the activation of Toll-like receptor (TLR) 4 by S-2P, and the activation of TLR9 and expression of interleukin-13 by CpG-1018 adjuvant. In conclusion, it is remarkable that the MVC-COVI1901 vaccine may lead to the incidence of autoinflammatory diseases such as UC.

Influence of chronic obstructive pulmonary disease on long-term hospitalization and mortality in patients with heart failure with reduced ejection fraction.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) can coexist with chronic obstructive pulmonary disease (COPD), which complicates the clinical situation and worsens quality of life. The study used standard diagnostic criteria for detecting COPD in hospitalized HFrEF patients and to survey the influence of other comorbidities and medications on the long-term outcomes of HFrEF + COPD patients. METHODS: We retrospectively recruited patients hospitalized due to HFrEF in a tertiary medical center and examined and followed up clinical outcomes, including length of hospital stay, mortality, and readmission episodes, for a 5-year period. Risk factors for mortality were analyzed using multivariate analysis. RESULTS: Of the 118 hospitalized HFrEF study participants, 68 had concurrent COPD whereas 50 did not. There was a significant increase in the male predominance, smoking history, higher hemoglobin level and increased length of hospital stay in the HF + COPD group than in the HF-only group. Lower left ventricular ejection fraction was found in the HF and COPD comorbidity group. In multivariate analysis, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) use independently associated with a beneficial effect on survival in HF patients with COPD. Oral corticosteroid uses and stroke as a comorbidity were independently associated with a shorter time to the first readmission episode. CONCLUSION: In HFrEF patients, COPD was associated with a prolonged length of hospital stay. ACEI/ARB use might relate to a beneficial effect on survival in HF patients with COPD. The use of maintenance oral corticosteroid in patients with both HF and COPD should be crucially evaluated to determine the clinical benefit and disadvantages.

Assessing overdiagnosis of fecal immunological test screening for colorectal cancer with a digital twin approach.

Evaluating the magnitude of overdiagnosis associated with stool-based service screening for colorectal cancer (CRC) beyond a randomized controlled trial is often intractable and understudied. We aim to estimate the proportion of overdiagnosis in population-based service screening programs for CRC with the fecal immunochemical test (FIT). The natural process of overdiagnosis-embedded disease was first built up to learn transition parameters that quantify the pathway of non-progressive and progressive screen-detected cases calibrated with sensitivity, while also taking competing mortality into account. The Markov algorithms were then developed for estimating these transition parameters based on Taiwan FIT service CRC screening data on 5,417,699 residents aged 50-69 years from 2004 to 2014. Following the digital twin design with the parallel universe structure for emulating the randomized controlled trial, the screened twin, mirroring the control group without screening, was virtually recreated by the application of the above-mentioned trained parameters to predict CRC cases containing overdiagnosis. The ratio of the predicted CRCs derived from the screened twin to the observed CRCs of the control group minus 1 was imputed to measure the extent of overdiagnosis. The extent of overdiagnosis for invasive CRCs resulting from FIT screening is 4.16% (95% CI: 2.61-5.78%). The corresponding figure is increased to 9.90% (95% CI: 8.41-11.42%) for including high grade dysplasia (HGD) and further inflated to 15.83% (95% CI: 15.23-16.46%) when the removal adenoma is considered. The modest proportion of overdiagnosis modelled by the digital twin method, dispensing with the randomized controlled trial design, suggests the harm done to population-based FIT service screening is negligible.

Mechanism Underlying Metformin Action and Its Potential to Reduce Gastric Cancer Risk.

Diabetes mellitus is associated with a high risk of developing gastric cancer (GC). Metformin, which is conventionally used to treat type 2 diabetes, induces AMP-activated protein kinase signaling and suppresses gluconeogenesis. Recent studies have reported that metformin is associated with beneficial effects in cancer prevention and treatment owing to its anti-tumor effects. This makes metformin a potential medication for GC therapy. However, contradicting reports have emerged regarding the efficacy of metformin in reducing the risk of GC. This review summarizes the impact of metformin on mitigating GC risk by analyzing clinical databases. The mechanism underlying the anti-tumor effect of metformin on GC is also discussed.

Impact of sarcopenia on the prognosis and treatment of lung cancer: an umbrella review.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality worldwide. Sarcopenia, defined as the loss of muscle mass and function, is known to cause adverse health outcomes. The purpose of this umbrella review was to integrate published systematic reviews and meta-analyses exploring sarcopenia and lung cancer to provide comprehensive knowledge on their relationship. METHODS: Eligible studies were searched from scientific databases until June 28, 2022. Critical appraisal was performed using A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2. The impact of sarcopenia on the pathophysiology, prevalence, and prognosis of lung cancer is summarized at the level of systematic reviews or meta-analyses. RESULTS: Fourteen reviews and meta-analyses were conducted. The methodological quality was high for one review, low for nine, and critically low for four. The most common standard for diagnosing sarcopenia in the lung cancer population is computed tomography (CT) to measure the skeletal muscle index at the third lumbar vertebra (L3). Sarcopenia was highly prevalent among patients with lung cancer, with a pooled prevalence ranging from 42.8% to 45.0%. The association between sarcopenia and increased postoperative complications and decreased disease control rates with immune checkpoint inhibitors has been demonstrated. Mortality was significantly higher in sarcopenic patients than in non-sarcopenic patients with lung cancer, regardless of the stage of disease or type of treatment. CONCLUSIONS: Sarcopenia is a poor prognostic factor for lung cancer. Future studies are necessary to clarify the pathophysiology of sarcopenia and develop effective interventions for sarcopenia in patients with lung cancer.

Increased Interleukin-17 and Glucocorticoid Receptor-ß Expression in Interstitial Lung Diseases and Corticosteroid Insensitivity.

Background: Treatment responsiveness to corticosteroids is excellent for cryptogenic organizing pneumonia (COP) and sarcoidosis, but suboptimal for idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). We hypothesise that the differential expression of IL-17 contributes to variable corticosteroid sensitivity in different interstitial lung diseases. Objective: To determine the associations among expression of IL-17, glucocorticoid receptor-ß and responsiveness to corticosteroid treatment in interstitial lung diseases. Methods: Immunohistochemical (IHC) staining was performed on formalin-fixed paraffin-embedded (FFPE) lung tissues obtained by bronchoscopic, CT-guided or surgical biopsies, and quantified by both cell counting (% positive cells) by individuals and by software IHC Profiler plugin of ImageJ (opacity density score). We studied the effect of IL-17 on corticosteroid sensitivity in human fibroblast MRC5 cell line. Results: Compared with specimens from patients with COP (n =13) and sarcoidosis (n =13), those from IPF patients (n = 21) had greater GR-ß and IL-17 expression and neutrophil infiltration. Radiographic progression after oral corticosteroid treatment was positively correlated with the expression in IL-17 and GR-ß/GR-α ratio in all patients (COP, sarcoidosis and IPF) and also within the IPF subgroup only. IL-17 expression level was positively associated with GR-ß and GR-ß/GR-α ratio. In MRC5 cells, exogenous IL-17 increased the production of collagen I and up-regulated GR-ß expression and dexamethasone's suppressive effect on collagen I production was impaired by IL-17, and silencing IL-17 receptor A gene attenuated the effect of IL-17. Conclusion: Up-regulation of GR-ß/GR-α ratio by IL-17 could be associated with the relative corticosteroid-insensitivity of IPF.

Hemophagocytic Lymphohistiocytosis Following BNT162b2 mRNA COVID-19 Vaccination.

Although serious adverse events have remained uncommon, cases of myocarditis induced by messenger RNA (mRNA) COVID-19 vaccines have been reported. Here, we presented a rare but potentially fatal disorder, hemophagocytic lymphohistiocytosis, in a 14-year-old previously healthy adolescent after BNT162b2 mRNA vaccination. The initial evaluation showed splenomegaly, pancytopenia, hyperferritinemia, and hypofibrinogenemia. Further examination revealed positive blood EBV DNA, and other infectious pathogen surveys were all negative. Hemophagocytosis was observed in the bone marrow aspiration and biopsy. HLH was confirmed and intravenous immunoglobulin (IVIG) and methylprednisolone pulse therapy were given. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) was set up for cardiopulmonary support for 3 days due to profound hypotension. The patient was kept on oral prednisolone treatment for 28 days with the following gradual tapering. The hemogram and inflammatory biomarkers gradually returned to normal, and the patient was discharged. The fulminant presentation of HLH in our case could be the net result of both acute immunostimulation after COVID-19 vaccination and EBV infection. Our case suggests that the immune activation after COVID-19 vaccination is likely to interfere with the adequate immune response to certain infectious pathogens, resulting in a hyperinflammatory syndrome.

The effects of mechanical insufflation-exsufflation on lung function and complications in cardiac surgery patients: a pilot study.

BACKGROUND: Postoperative positive pressure lung expansion is associated with decreased pulmonary complications and improved clinical outcomes. The aim of the present study was to compare the differences in post-operative pulmonary complications and clinical outcomes between two groups of study subjects who underwent cardiac surgery; one included subjects who received mechanical insufflation-exsufflation (MI-E) and the other included subjects who received intermittent positive pressure breathing (IPPB) therapy. METHODS: This retrospective study included 51 subjects, who underwent cardiac surgery in an intensive care unit of a tertiary hospital during the time period from June 2017 to February 2018. After liberation from mechanical ventilation, the subjects received lung expansion therapy by means of two types of positive pressure devices, MI-E (n = 21) or IPPB (n = 30). The pulmonary complications, lung function, and clinical outcomes were compared between the two groups. RESULTS: Subjects in both groups displayed similar baseline characteristics and underwent similar types of surgical procedures. Compared to subjects who received non-oscillatory therapy, those who received MI-E therapy had higher post-operative force vital capacity (58.4 ± 4.74% vs. 46.0 ± 3.70%, p = 0.042), forced expiratory volume in one second (62.4 ± 5.23% vs. 46.8 ± 3.83%, p = 0.017), and peak flow rate (67.1 ± 5.53 L vs. 55.7 ± 4.44 L p = 0.111). However, the incidence of chest pain was higher in the MI-E group (n = 13, 61.9%) than in the IPPB group (n = 4, 16.7%; odds ratio, 0.123, 95% confidence interval, 0.03-0.45; p = 0.002). The length of hospital and ICU stay, development of atelectasis, pneumonia, and pleural effusion were similar in both the groups. CONCLUSION: Both IPPB and MI-E therapies have similar effects on preventing post-operative complications in cardiac surgery patients. However, compared to IPPB therapy, MI-E therapy was associated with better-preserved pulmonary function and higher incidence of chest pain.

Anticancer Effects of Midazolam on Lung and Breast Cancers by Inhibiting Cell Proliferation and Epithelial-Mesenchymal Transition.

Despite improvements in cancer treatments resulting in higher survival rates, the proliferation and metastasis of tumors still raise new questions in cancer therapy. Therefore, new drugs and strategies are still needed. Midazolam (MDZ) is a common sedative drug acting through the γ-aminobutyric acid receptor in the central nervous system and also binds to the peripheral benzodiazepine receptor (PBR) in peripheral tissues. Previous studies have shown that MDZ inhibits cancer cell proliferation but increases cancer cell apoptosis through different mechanisms. In this study, we investigated the possible anticancer mechanisms of MDZ on different cancer cell types. MDZ inhibited transforming growth factor ß (TGF-ß)-induced cancer cell proliferation of both A549 and MCF-7 cells. MDZ also inhibited TGF-ß-induced cell migration, invasion, epithelial-mesenchymal-transition, and Smad phosphorylation in both cancer cell lines. Inhibition of PBR by PK11195 rescued the MDZ-inhibited cell proliferation, suggesting that MDZ worked through PBR to inhibit TGF-ß pathway. Furthermore, MDZ inhibited proliferation, migration, invasion and levels of mesenchymal proteins in MDA-MD-231 triple-negative breast cancer cells. Together, MDZ inhibits cancer cell proliferation both in epithelial and mesenchymal types and EMT, indicating an important role for MDZ as a candidate to treat lung and breast cancers.

Statins' Regulation of the Virulence Factors of Helicobacter pylori and the Production of ROS May Inhibit the Development of Gastric Cancer.

Conventionally, statins are used to treat high cholesterol levels. They exhibit pleiotropic effects, such as the prevention of cardiovascular disease and decreased cancer mortality. Gastric cancer (GC) is one of the most common cancers, ranking as the third leading global cause of cancer-related deaths, and is mainly attributed to chronic Helicobacter pylori infection. During their co-evolution with hosts, H. pylori has developed the ability to use the cellular components of the host to evade the immune system and multiply in intracellular niches. Certain H. pylori virulence factors, including cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), and cholesterol-α-glucosyltransferase (CGT), have been shown to exploit host cholesterol during pathogenesis. Therefore, using statins to antagonize cholesterol synthesis might prove to be an ideal strategy for reducing the occurrence of H. pylori-related GC. This review discusses the current understanding of the interplay of H. pylori virulence factors with cholesterol and reactive oxygen species (ROS) production, which may prove to be novel therapeutic targets for the development of effective treatment strategies against H. pylori-associated GC. We also summarize the findings of several clinical studies on the association between statin therapy and the development of GC, especially in terms of cancer risk and mortality.