Suppressor Effect Research Articles

A multifunctional DNA repair enzyme and magnetic dual-triggered theranostic nanosystem for intelligent drug delivery

Due to the high specificity and efficiency of enzymes, enzyme-responsive drug delivery systems are important in cancer therapy and diagnosis. Human apurinic/apyrimidinic endonuclease (APE1) is a representative DNA repair enzyme overexpressed in various cancer cells, which is also proven to be a promising stimuli in our previous studies. In this work, to realize targeted chemotherapy, an APE1 and magnetic dual-responsive nanocarrier was designed. The carrier is composed of Fe3O4@SiO2 nanoparticles and specially designed AP-DNA strand that can be effectively hydrolyzed by APE1. The chemotherapeutic drug doxorubicin (DOX) was loaded onto the AP-DNA to form the theranostic nanosystem (FS@DNA-DOX). As the AP-DNA was parted under the hydrolysis of APE1 in cancer cells, DOX was released to inhibit tumor growth. In vitro experiment results indicated that the nanosystem possesses a high specificity to APE1 and effectively release DOX in MCF-7 cells. In vivo experiments demonstrated that the targeted delivery of the nanosystem to the tumor site was successfully achieved and that strong tumor suppressor effects were observed. Overall, the FS@DNA-DOX is a multifunctional and theranostic nanosystem for the chemotherapy of cancer by increasing the therapeutic effect as well as reducing the toxicity of drugs.

In vivo Drug Screening to Identify Anti-metastatic Drugs in Twist1a-ERT2 Transgenic Zebrafish.

Here, we present an in vivo drug screening protocol using a zebrafish model of metastasis for the identification of anti-metastatic drugs. A tamoxifen-controllable Twist1a-ERT2 transgenic zebrafish line was established to serve as a platform for the identification. By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of the epidermal growth factor receptor) transgenic zebrafish, which develop hepatocellular carcinoma, approximately 80% of the double transgenic zebrafish show spontaneous cell dissemination of mCherry-labeled hepatocytes from the liver to the entire abdomen and tail regions in five days, through induction of epithelial to mesenchymal transition (EMT). This rapid and high-frequency induction of cell dissemination makes it possible to perform an in vivo drug screen for the identification of anti-metastatic drugs targeting metastatic dissemination of cancer cells. The protocol evaluates the suppressor effect of a test drug on metastasis in five days, by comparing the frequencies of the fish showing abdominal and distant dissemination patterns in the test drug-treated group with those in the vehicle-treated group. Our study previously identified that adrenosterone, an inhibitor for hydroxysteroid (11-beta) dehydrogenase 1 (HSD11β1), has a suppressor effect on cell dissemination in the model. Furthermore, we validated that a pharmacologic and genetic inhibition of HSD11β1 suppressed metastatic dissemination of highly metastatic human cell lines in a zebrafish xenotransplantation model. Taken together, this protocol opens new routes for the identification of anti-metastatic drugs. Graphical overview Timing Day 0: Zebrafish spawning Day 8: Primary tumor induction Day 11: Chemical treatment Day 11.5: Metastatic dissemination induction in the presence of a test chemical Day 16: Data analysis.

LncRNA ZNRD1-AS1 promotes malignant lung cell proliferation, migration, and angiogenesis via the miR-942/TNS1 axis and is positively regulated by the m6A reader YTHDC2

RationaleLung cancer is the most prevalent form of cancer and has a high mortality rate, making it a global public health concern. The N6-methyladenosine (m6A) modification is a highly dynamic and reversible process that is involved in a variety of essential biological processes. Using in vitro, in vivo, and multi-omics bioinformatics, the present study aims to determine the function and regulatory mechanisms of the long non-coding (lnc)RNA zinc ribbon domain-containing 1-antisense 1 (ZNRD1-AS1).MethodsThe RNAs that were bound to the m6A ‘reader’ were identified using YTH domain-containing 2 (YTHDC2) RNA immunoprecipitation (RIP)-sequencing. Utilizing methylated RIP PCR/quantitative PCR, pull-down, and RNA stability assays, m6A modification and ZNRD1-AS1 regulation were analyzed. Using bioinformatics, the expression levels and clinical significance of ZNRD1-AS1 in lung cancer were evaluated. Using fluorescent in situ hybridization and quantitative PCR assays, the subcellular location of ZNRD1-AS1 was determined. Using cell migration, proliferation, and angiogenesis assays, the biological function of ZNRD1-AS1 in lung cancer was determined. In addition, the tumor suppressor effect of ZNRD1-AS1 in vivo was validated using a xenograft animal model. Through bioinformatics analysis and in vitro assays, the downstream microRNAs (miRs) and competing endogenous RNAs were also predicted and validated.ResultsThis study provided evidence that m6A modification mediates YTHDC2-mediated downregulation of ZNRD1-AS1 in lung cancer and cigarette smoke-exposed cells. Low levels of ZNRD1-AS1 expression were linked to adverse clinicopathological characteristics, immune infiltration, and prognosis. ZNRD1-AS1 overexpression was shown to suppress lung cancer cell proliferation, migration, and angiogenesis in vitro and in vivo, and to reduce tumor growth in nude mice. ZNRD1-AS1 expression was shown to be controlled by treatment of cells with either the methylation inhibitor 3-Deazaadenosine or the demethylation inhibitor Meclofenamic. Furthermore, the miR-942/tensin 1 (TNS1) axis was demonstrated to be the downstream regulatory signaling pathway of ZNRD1-AS1.ConclusionsZNRD1-AS1 serves an important function and has clinical relevance in lung cancer. In addition, the findings suggested that m6A modification could mediate the regulation of the ZNRD1-AS1/miR-942/TNS1 axis via the m6A reader YTHDC2.Graphical

Natural Compound Allicin Containing Thiosulfinate Moieties as Transmembrane Protein 16A (TMEM16A) Ion Channel Inhibitor for Food Adjuvant Therapy of Lung Cancer.

Cancer is one of the most serious malignant diseases, and chemotherapy is cancer's main clinical treatment method. However, chemotherapy inevitably produces drug resistance, and side effects accompany them. Adjuvant therapy is an effective way to enhance chemotherapeutic drug sensitivity and reduce side effects. This study found allicin, garlic's active ingredient, is an inhibitor of transmembrane protein 16A (TMEM16A), a novel drug target of lung adenocarcinoma. Allicin concentration-dependently inhibited TMEM16A currents with an IC50 of 24.35 ± 4.14 μM. Allicin thiosulfinate moieties bound with R535A/E624A/E633A residues of TMEM16A blocked the ion transport function and downregulated TMEM16A protein expression affecting the mitogen-activated protein kinase signal transduction. Then, allicin reduced the viability and migration of LA795 cells, and induced cell apoptosis. Moreover, multitarget combination administration results indicated that the therapeutic effect of 3.56 mg/kg allicin and 3 mg/kg cisplatin combined administration was superior to the superposition of the two drugs alone, demonstrating that the anticancer effects of allicin and cisplatin were synergistic. In addition, low-concentration combined administration also avoided the side effects of cisplatin in mice. Based on the good tumor suppressor effect and high biosafety of allicin and cisplatin combination in vivo, allicin can be used for food adjuvant therapy of cisplatin chemotherapy.

TRIM31: A molecule with a dual role in cancer.

Tripartite motif (TRIM) 31 is a new member of the TRIM family and functions as an E3 ubiquitin ligase. Abnormal TRIM31 expression leads to a variety of pathological conditions, such as cancer, innate immunity diseases, sepsis-induced myocardial dysfunction, cerebral ischemic injury, nonalcoholic fatty liver disease and hypertensive nephropathy. In this review, we comprehensively overview the structure, expression and regulation of TRIM31 in cancer. Moreover, we discuss the dual role of TRIM31 in human cancer, and this dual role may be linked to its involvement in the selective regulation of several pivotal cellular signaling pathways: the p53 tumor suppressor, mTORC1, PI3K-AKT, NF-κB and Wnt/β-catenin pathways. In addition, we also discuss the emerging role of TRIM31 in innate immunity, autophagy and its growing sphere of influence across multiple human pathologies. Finally, a better understanding of the dual role of TRIM31 in cancer may provide new therapeutic strategies aimed at inhibiting the cancer-promoting effects of TRIM31 without affecting its tumor suppressor effects.

The emerging role of miR-20b in human cancer and other disorders: Pathophysiology and therapeutic implications.

miR-20b is a microRNA with diverse and somehow contradictory roles in the pathogenesis of human disorders, especially cancers. It has been known to be a tumor suppressor in colon cancer, renal cell carcinoma, prostate cancer, osteosarcoma and papillary thyroid cancer. In lung cancer and breast cancers, both tumor suppressor and oncogenic effects have been identified for this miRNA. Finally, in T cell leukemia, hepatocellular carcinoma, esophageal squamous cell carcinoma and cervical and gastric cancers, miR-20b is regarded as an oncogenic miRNA. In several types of cancer, dysregulation of miR-20b has been recognized as a predictive marker for patients' survival. Dysregulation of miR-20b has also been recognized in Alzheimer's disease, diabetic retinopathy, myocardial ischemia/infarction, chronic hepatitis B and multiple sclerosis. In the current review, we have summarized the miR-20b targets and related cellular processes. We have also provided a review of participation of this miRNA in different human disorders.

A novel ROS-activable self-immolative prodrug for tumor-specific amplification of oxidative stress and enhancing chemotherapy of mitoxantrone

Reactive oxygen species (ROS) as well-known endogenous stimuli has been widely used to activate drug delivery systems (DDSs) for tumor-specific therapy. Unfortunately, endogenous ROS in the tumor microenvironment (TME) is not enough to achieve effective therapeutic efficacy and cancer cells have adapted to high oxidative stress by upregulating glutathione (GSH) level. Herein, we devised a novel ROS-activable self-immolative prodrug CASDB with both GSH-depletion ability and ROS self-supply competence. Then, an stimuli-responsive nanoplatform integrating CASDB with clinical chemotherapeutics mitoxantrone (MTO) and PLGA was fabricated (denoted as CMPs) through nanoprecipitation method. The CMPs could achieve desired accumulation at tumor tissues through enhanced permeability and retention (EPR) effects. Then the accumulated CMPs could induce tumor cell apoptosis efficiently. Especially, ROS in tumor sites could trigger the immolation of CASDB to generate CA and quinone methide (QM). Then CA and QM cooperatively promoted damage of mitochondria due to oxidative stress and led to cancer cells more sensitive to MTO. Accordingly, MTO could perturb cellular microenvironment of cancer cells then promote the degradation of CASDB. The experiment results demonstrated that CMPs were ideal for desirable synergetic tumor-specific anticancer therapy with negligible systemic toxicity. The half-maximal inhibitory concentrations (IC50) value of CMPs was 6.53 μM, while the IC50 values of MTO was 14.76 μM. And the CMPs group showed the strongest tumor suppressor effect with the tumor sizes increased to 1.2-fold (Control group: 20.6-fold, MTO only: 3.0-fold). This study should be inspirational for designing efficient prodrugs to overcome the handicaps of traditional chemotherapy.

MiR-22-3p regulates the proliferation, migration and invasion of colorectal cancer cells by directly targeting KDM3A through the Hippo pathway.

Colorectal cancer (CRC) has one of the highest incidences and mortality rates of all malignancies worldwide. microRNAs (miRNAs) have been reported to be involved in many biological processes of diseases. MiR-22-3p is considered to be involved in cancer progression, but its role in CRC remains unclear. In this study, we detected that in CRC, the level of miR-22-3p is downregulated. MiR-22-3p has antitumor effects in CRC. miR-22-3p can reduce the proliferative, invasive and migrative capacity of CRC cells. Luciferase reporter analyses confirmed that KDM3A was a target of miR-22-3p, which can directly target the 3'UTR of KDM3A and decrease the expression of KDM3A in CRC cells. Our study also confirmed that KDM3A plays a role as an oncogene in CRC. KDM3A overexpression attenuated the tumor suppressor effects of miR-22-3p in CRC cells, demonstrating that miR-22-3p exerts antitumor effects by targeting KDM3A. Overexpression of miR-22-3p in CRC reduced YAP1 expression, whereas overexpression of KDM3A restored the expression of YAP1. In summary, miR-22-3p might inhibit the progression of CRC by targeting KDM3A to regulate the HIPPO signaling pathway, which may provide an opportunity for the treatment of CRC.

Relationship between serum testosterone and sex hormone- binding globulin levels and some metabolic changes in Iraqi men with type 2 diabetes mellitus

The present study aimed to assess the interrelationship between serum total testosterone (S.Tes) as well as sex hormone binding globulin (SHBG) and the main components of metabolic syndrome (MetS) in type 2 diabetic men. One hundred and sixty patients having T2DM were enrolled in this study. The following characteristics were reported: age, gender, duration of T2DM , Body mass index (BMI) and arterial blood pressure.. Serum hormonal profile analyses (S.Tes, SHBG and prolactin). Serum lipid analyses (T.ch TG, HDL-C, and LDL-C). The mean age of study subjects was 49.8 5.7 years and the mean duration of disease was 5.45.2 years. Body mass index (BMI) of study group was found to be within the range of either overweight or obese class . The means of HbA1c ratio and FSG levels were 9.4 %  2.1 and 200.9  75.2 mg/dl respectively which indicated that our patients were in a bad glycemic control. All components of S. lipid profile were within normal range . Serum Testosterone and SHBG levels were within normal range but in the low values( 4.49±2.11 ,28.88±18.12 ng/ml respectively) while serum prolactin level was within normal range but in the high values (11.22±9.42 ng/ml). When study analytes were compared according to the presence of one or more metabolic syndrome characteristic then there was a significant decrease in mean value of testosterone level between obese and non obese diabetics ( 3.89±1.87 vs. 4.79±2.17 ng/ ml, P < 0.001) . If hypertension was present in addition to obesity and diabetes then SHBG level was also significantly decreased in comparison with diabetics who were hypertensive but not obese (25.16±13.42 vs. 33.58±13.73 ng/ ml respectively , P <0.05 ). If hypertension and obesity were present as well as lower HDL-C then significant decreases in both S. SHBG and S. Tes were detected ( (30.63±14.93 vs. 40.7± 6.33 ng/ ml and 3.73±1.9 vs. 5.57±1.53 ng/ ml respectively , P<0.01). In conclusion; our T2DM patients have a bad glycemic state and are characterized by a significantly lower S. Tes mean level if they were obese. Still, the accumulation of other main characteristics of MetS which included hypertension and lower S. HDL- C results in a significantly lower mean levels of both S. Tes and S. SHBG. Obesity, among the other core characteristics of MetS, seems to have the main suppressor effect on serum testosterone and SHBG in T2DM.

Siremadlin in Combination with Venetoclax (VEN) Plus Azacitidine (AZA) in Adult Patients with Acute Myeloid Leukemia (AML) Who Are Ineligible for Intensive Chemotherapy: A Phase Ib/II Trial

Background: Patients with AML who are ineligible for intensive chemotherapy have limited treatment options. Adding VEN to standard-of-care hypomethylating agents (HMAs) improves remission rates and survival for these patients. However, relapse rates with VEN+HMA are high, and many patients do not achieve a complete remission (CR)/CR with incomplete hematological recovery (CRi), or do so and remain measurable residual disease-positive (DiNardo CD, N Engl J Med, 2020), which is associated with poor outcomes. Murine double minute 2 (MDM2) is a key negative regulator of tumor protein 53 (p53; encoded by the TP53 gene). Inhibition of the p53-MDM2 interaction upregulates the tumor suppressor effects of p53. Siremadlin (HDM201) is a selective inhibitor of the p53-MDM2 interaction. In combination with VEN, siremadlin had durable antitumor responses in p53-wild-type AML patient-derived xenograft models (Wang Y, Cancer Res, 2019). Siremadlin was tolerable and demonstrated preliminary single-agent antitumor activity in patients with relapsed/refractory AML in a first-in-human Phase I trial (Stein EM, Clin Cancer Res, 2021; NCT02143635). In combination with VEN, siremadlin also demonstrated promising preliminary antileukemic activity in a Phase Ib trial in patients with relapsed/refractory AML (Wei AH, ASH 2021; NCT03940352). Study design: This international, multicenter, Phase Ib/II, open-label, dose-confirmation, proof-of-concept trial will provide a dosing recommendation and assess the preliminary efficacy of siremadlin in combination with VEN+AZA in adults (≥18 years) with AML who are ineligible for intensive chemotherapy (NCT05155709). For this Phase Ib/II trial, patients must have an Eastern Cooperative Oncology Group performance status of 0-2 (if age ≥75 years) or 0-3 (if age ≥18-74 years) with at least 1 predefined comorbidity rendering the patient ineligible for intensive chemotherapy. Patients with TP53 mutations, chromosomal del17p, or prior MDM2-inhibitor or FLT3-inhibitor treatment are ineligible. Patients will be enrolled into 2 arms: (Arm 1) patients who have received 2-4 cycles of first-line VEN+AZA without achieving a best response of CR, CR with partial hematological recovery (CRh), CRi, or morphologic leukemia-free state, and (Arm 2) newly diagnosed patients with adverse genetic risk as defined in Figure 1. The trial has 2 parts: (Part 1) a safety run-in to assess the safety and confirm the recommended Phase II dose (RP2D) of siremadlin+VEN+AZA and (Part 2) an expansion phase to evaluate the preliminary efficacy of siremadlin in combination with VEN+AZA. Treatment will be administered in 28-day cycles until disease progression, relapse, or unacceptable toxicity. In Part 1, 3-6 patients per arm will receive the starting dose of siremadlin (20 mg; once-daily oral capsule) from Day 1 to Day 5 in each 28-day treatment cycle in combination with VEN+AZA. For Arm 1, VEN and AZA will be administered at doses determined prior to trial enrollment. For Arm 2, VEN will be administered once daily at 400 mg on each day of the cycle, following a 3-day ramp-up, and AZA will be administered intravenously or subcutaneously at 75 mg/m2 either on Days 1-7, or Days 1-5 and Days 8-9 (according to standard local clinical practice). If the starting dose of siremadlin is deemed safe, an additional ~6-9 patients will receive dose level +1 (30 mg) of siremadlin to determine the RP2D for Part 2. Approximately 26 patients will receive siremadlin at the RP2D in combination with VEN+AZA in Part 2. Two primary outcomes will be assessed: in Arms 1 and 2, the proportion of patients with dose-limiting toxicities reported during the first cycle (28 days); and in Arm 1 only, the proportion of patients at the expansion dose who achieve CR. Secondary outcomes include, in Arm 2 only, proportion of patients who achieve CR, and in Arms 1 and 2, duration of CR; proportion of patients who achieve CR, or CRh, or CRi; duration of CR/CRh and CR/CRi; overall survival; pharmacokinetics; proportion of CR-MRD negative overall and MRD negativity in patients achieving a CR, CR/CRh, and CR/CRi. Conclusions: This Phase Ib/II trial investigates siremadlin in combination with VEN+AZA in patients with AML who are ineligible for intensive chemotherapy and will aid in the understanding of the effectiveness of an MDM2 inhibitor with venetoclax combination in patients with AML. The trial is in progress and expected to enroll approximately 55 patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The effect of quaternary ammonium salts with different chain lengths on copper filling behavior in blind holes of printed circuit board

The rapid and defect free blind hole copper super filling is the key technology to ensure the quality and development of printed circuit boards (PCBs). The linear quaternary ammonium compounds with a low molecular weight are expected to act as a potential suppressor for blind hole copper filling. Here, three quaternary ammonium salts with different molecular chain lengths (the dodecyl trimethyl ammonium chloride, the cetyl trimethyl ammonium chloride and the stearyl trimethyl ammonium chloride) were selected to study the effects of the molecular chain length of quaternary ammonium salt on the copper filling behavior of the PCB blind holes. The electrochemical results show that the three quaternary ammonium salts show greater inhibition ability on copper deposition compared with the traditional additives (polyethylene glycol (PEG) and Cl−) and furthermore, the suppressor effect becomes stronger with the increase of molecular weight. The blind hole copper filling experiment of PCB is also carried out to study the copper filling capacity of three quaternary ammonium salts. The filling experiment reveals that compared with the traditional suppressors (PEG and Cl−), the filling quality of blind hole copper is significantly improved when the three quaternary ammonium salts are used as suppressors. Moreover, under the coordination of accelerator (bis (3-sulfopropyl) disulfide (SPS)), the three quaternary ammonium salts can realize more rapid copper super filling without chloride ion in the electrolyte. Cross-section and surface morphological analysis further illuminates that the quaternary ammonium salt as an suppressor can also more effectively inhibit the deposition of copper on the PCB surface and reduce the roughness of the copper layer. The present results imply that quaternary ammonium salts have greater advantages for copper filling and are expected to replace traditional suppressors as new suppressors.

Radioimmunotherapy study of 131I-labeled Atezolizumab in preclinical models of colorectal cancer

BackgroundProgrammed cell death 1 ligand 1(PD-L1) is overexpressed in many tumors. The radionuclide-labeled anti-PD-L1 monoclonal antibody can be used for imaging and therapy of PD-L1 overexpressing cancer. Here, we described 131I-labeled Atezolizumab (131I-Atezolizumab, targeting PD-L1) as a therapeutic agent for colorectal cancer with PD-L1 overexpression.Methods131I-Atezolizumab was prepared by the Iodogen method. The expression levels of PD-L1 in different human colorectal cells were determined by flow cytometry, western blot and cell binding assay. The immunoreactivity of 131I-Atezolizumab to PD-L1 high-expressing cells was determined by immunoreactive fraction. The killing abilities of different concentrations of 131I-Atezolizumab on cells with high and low expression of PD-L1 were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cerenkov luminescence imaging (CLI) and radioimmunotherapy (RIT) of 131I-Atezolizumab were performed on two human colorectal cancer models. The distribution and tumor targeting of 131I-Atezolizumab were evaluated by imaging. Tumor volume and survival time were used as indicators to evaluate the anti-tumor effect of 131I-Atezolizumab.ResultsThe expression level of PD-L1 in vitro determined by the cell binding assay was related to the data of flow cytometry and western blot. 131I-Atezolizumab can specifically bind to PD-L1 high-expressing cells in vitro to reflect the expression level of PD-L1. Immunoreactive fraction of PD-L1 high-expressing RKO cells with 131I-Atezolizumab was 52.2%. The killing ability of 131I-Atezolizumab on PD-L1 high-expressing cells was higher than that of low-expressing cells. CLI proved that the specific uptake level of tumors depends on the expression level of PD-L1. Effect of 131I-Atezolizumab RIT showed an activity-dependent tumor suppressor effect on RKO tumor-bearing mice with high PD-L1 expression. 131I-Atezolizumab (37 MBq) can improve the median survival time of mice (34 days), compared to untreated mice (27 days) (P = 0.027). Although a single activity(37 MBq) of 131I-Atezolizumab also inhibited the tumors of HCT8 tumor-bearing mice with low PD-L1 expression (P < 0.05), it could not prolong the survival of mice(P = 0.29).Conclusion131I-Atezolizumab can be used as a CLI agent for screening PD-L1 expression levels. It may be used as a radioimmunotherapy drug target for PD- L1 overexpressing tumors.

Regulation of IGF2BP1 by miR-186 and its impact on downstream lncRNAs H19, FOXD2-AS1, and SNHG3 in HCC

AimWe have previously characterized oncogenic properties of IGF2BP1 in HCC, and its regulation by short noncoding RNAs (ncRNAs). Recent evidence suggests that IGF2BP1 itself may regulate long ncRNAs (lncRNAs). Therefore, this study aimed at exploring the interplay between IGF2BP1 and various upstream and downstream ncRNAs and its link to HCC pathogenesis. Materials and methodsBioinformatic analysis was used to identify up- and downstream ncRNAs interacting with IGF2BP1. Huh-7 cells were transfected with siRNAs against IGF2BP1 and microRNA mimics. Relative gene expression was determined using RTqPCR and IGF2BP1 protein was quantified by western blot. Luciferase binding assay was used to explore the targeting of IGF2BP1 3’UTR. HCC tumorigenesis was measured by MTT assay, BrdU-incorporation assay, colony-forming assay, and scratch assay. Key findingsBioinformatic analysis identified three oncogenic lncRNAs – namely H19, FOXD2-AS1, and SNHG3 – potentially regulated by IGF2BP1. Knockdown of IGF2BP1 decreased the expression of all three oncogenic lncRNAs and inhibited malignant cell behaviors. miR-186 was revealed as a possible upstream regulator of IGF2BP1. miR-186 mimics decreased IGF2BP1 mRNA and protein levels. miR-186 was significantly lower while IGF2BP1 was elevated in cancerous tissues from ten HCC patients compared to five healthy controls. In addition, miR-186 mimics caused a downregulation of the oncogenic lncRNAs H19, SNHG3, and FOXD2-AS1 and a concomitant decrease in cell viability, proliferation, migration, and clonogenicity. SignificancemiR-186 may exert tumor suppressor effects in HCC by repressing oncogenic lncRNAs H19, SNHG3, and FOXD2-AS1 through its effect on IGF2BP1.

The Proximal Effect of Alcohol on Intimate Partner Violence: Comparing the Antecedents of Intoxicated and Sober Men's Violent Acts.

Alcohol use is known to correlate with intimate partner violence (IPV) perpetration, yet little research examines how alcohol influences how the violence unfolds. The current study used sequential analysis to examine descriptions of past violent incidents and explore the behaviors that preceded men's perpetration of IPV. In accordance with the alcohol myopia model of alcohol use, it was hypothesized that intoxicated men would respond violently to a wide range of partner cues, whereas men who were sober would only react violently in response to the most threatening partner cues. Moreover, intoxicated men were expected to demonstrate less inhibition of violence to suppressor cues of the partners' distress as compared to sober men. Participants were 80 couples reporting male-to-female IPV within the past year. Female partners' descriptions of two past violent events were coded and entered into sequential analysis. Antecedents to the men's first violent action were examined. While sober men were likely to react violently to their partner's physical threat and perceived threat, intoxicate men did not. Sober men were less likely to become violent after their partners displayed distress cues, whereas there was no suppressor effect of women's distress for intoxicated men. The precursors of the violence of intoxicated men appears to be indiscriminate and unpredictable. Clinical interventions that rely on behavioral strategies or communication skills training are unlikely to be effective for those who have an unmanaged alcohol use disorder.

The true role that suppressor effects play in condition-based regression analysis: None. A reply to Fiedler (2021).

Condition-based regression analysis (CRA) is a statistical method for testing self-enhancement effects. That is, CRA indicates whether, in a set of empirical data, people with higher values on the directed discrepancy self-view S minus reality criterion R (i.e., S-R) tend to have higher values on some outcome variable (e.g., happiness). In a critical comment, Fiedler (2021) claims that CRA yields inaccurate conclusions in data with a suppressor effect. Here, we show that Fiedler's critique is unwarranted. All data that are simulated in his comment show a positive association between S-R and H, which is accurately detected by CRA. By construction, CRA indicates an association between S-R and H only when it is present in the data. In contrast to Fiedler's claim, it also yields valid conclusions when the outcome variable is related only to the self-view or when there is a suppressor effect. Our clarifications provide guidance for evaluating Fiedler's comment, clear up with the common heuristic that suppressor effects are always problematic, and assist readers in fully understanding CRA. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Impact of anxiety and depression on academic achievement among underserved school children: evidence of suppressor effects.

Anxiety and depression symptoms may leave children at risk for lower academic scores, though this unique linkage to academic achievement in underserved youth is less well established. This study aimed to examine how anxiety and depression are uniquely related to spelling and math achievement beyond attention and hyperactivity deficits in children in underserved schools. Children aged 8 to 11 (n = 1085, 47.3% female) from historically underserved groups (Hispanic 75.3%, American Indian 6.4%, Black 4.9%, and White 1.5%) from 13 schools across two public school districts in California participated in the assessment of emotional and behavioral health symptoms that included a spelling and math assessment. While there was no relationship between anxiety or hyperactivity on spelling and math scores, depression and attention problems were significantly negatively related to spelling and math scores. However, when entered simultaneously, evidence of suppressor effects emerged. Anxiety and hyperactivity both became positively predictive of math. Similarly, anxiety became positively predictive of spelling. Subsample analyses showed that these suppressor effects were only in females. The associations among anxiety, depression, attention, and hyperactivity with spelling and math achievement are complex, and when controlling for depression and attention, anxiety levels and hyperactivity may be motivating some level of achievement in these areas.

How to Make Primary Healthcare More Popular: Evidence from the Middle-Aged and Elderly in China.

Since 2001, China has been an aging society; it is expected to become superaged by 2033. This rapid aging trend poses a challenge to the elderly regarding their pension services and healthcare. Primary healthcare has great potential for serving older adults in the community, yet it is not popular. This study used 1977 samples from the 2018 China Health and Retirement Longitudinal Study database to explore the use of outpatient services in primary care institutions among the middle-aged and elderly. Using a structural equations model, we constructed a framework to explore pathways leading to primary outpatient use. We discovered that the supply of primary health services had a significant direct and mediating effect on the utilization of primary outpatient services, and that community pension services may indirectly discourage it. In addition, the supply of primary health services has a suppressor effect between medical insurance and primary outpatient utilization. Health insurance directly promotes primary outpatient utilization, while the supply of primary care institutions suppresses the positive influence of medical insurance on the utilization of primary outpatient services. Therefore, community pension services should pay attention to differentiated services. Moreover, adjusting the coordinated development of medical insurance and the supply of primary healthcare could enhance the positive effects of medical insurance for outpatients.

Role of TP53 Gene Mutations in the Pathogenesis of Colorectal Carcinoma

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the world. The underlying molecular mechanisms that drive colorectal carcinogenesis are not fully known. However, P53 gene mutation, the most reported somatic mutation, is observed in about 50% of colorectal cancer patients.&#x0D; Colorectal carcinoma is multifactorial. TP53 gene, the most novel tumor suppressor gene, acts as a major gatekeeper by preserving the genetic composition of a cell and prevents the oncogenic transformation of a cell. MDM2 and CUL-4A belong to the E3 ubiquitin ligase family, blocks P53 activation, and thus act as an oncogene. TRIM67 also has defective ligase activity, and its mutation is seen in about 80% of colorectal carcinomas. miRNA inhibits the tumor suppressor effect of TP53 and downstream signaling pathways, resulting in carcinogenesis. K RAS, WT1, IGF-1 are other markers of colorectal carcinoma. P53 antibodies produce by colorectal carcinomatous tissue are the markers used for screening and diagnosis.&#x0D; P53 mutation drives a phenomenon of colorectal tumorigenesis. It serves as a biomarker, a prognostic factor, and a therapeutic target of colorectal carcinoma. Further studies are strongly recommended to improve the therapeutic approach of colorectal carcinoma.

The potential therapeutic effect of klotho on cell viability in human colorectal adenocarcinoma HT-29 cells.

Klotho is an anti-aging, anti-inflammator, and anti-oxidative protein and has been shown to important role in tumorigenesis, proliferation, survival, autophagy, and resistance to tumor suppressor effects in several types of human cancers. In this study, we aimed to investigate possible anti-tümör and apoptotic effects of exogen klotho in human colorectal adenocarcinoma cells (HT-29) and healthy colon cells (CCD 841 CoN). The WST-8 test was used to determine the half-maximum inhibitory concentration (IC50) of the klotho protein. AO-PI fluorescent staining techniques and Annexin V-PI flow cytometry was utilized to observe and detect the apoptosis of cancer cells induced by klotho. Our results demonstrated that klotho had a cytotoxic effect against colorectal adenocarcinoma cells in a dose-dependent manner. Our Annexin V-PI flow cytometric and AO-PI fluorescent analyses showed that klotho induced quantitative and morphological changes that indicate apoptotic induction in the human colorectal adenocarcinoma. This study results proved for the first time that klotho may be an effective potential therapeutic agent that may be used in adjuvant therapy in human colorectal adenocarcinoma it does not affect selectively healthy colon cells and but leading cancer cells to apoptosis.

The possibility of angiogenesis inhibition in cutaneous melanoma by bevacizumab-loaded lipid-chitosan nanoparticles.

Cutaneous malignant melanoma is fastest-growing cancer in white populations with a large majority of dermal cancer death. The activity of vascular endothelial growth factors (VEGFs) results in the signaling of a variety of downstream intracellular pathways that ultimately leads to cell activation, proliferation, migration, and angiogenesis. VEGF inhibitors such as bevacizumab are widely used in chemotherapy with systemic administration, which in many cases is associated with a variety of side effects. Here, we designed and synthesized a lipid-polymer nanoparticle for local administration of bevacizumab. Drug release, dermal absorption, and the effects of synthesized nanoparticles containing bevacizumab on cell proliferation and in vitro and in vivo angiogenesis were investigated. Encapsulating bevacizumab in the synthesized nanoparticles resulted in a significant increase in its dermal absorption compared to free bevacizumab. Also, the suppressor effects of bevacizumab encapsulated in the synthesized nanoparticle on cell proliferation and angiogenesis were significantly more than those of free bevacizumab. Our findings indicate the remarkable effects of lipid-polymer nanoparticles in dermal absorption and in maintaining bevacizumab bioactivity, suggesting therapeutic benefits of local bevacizumab administration for angiogenesis-related disorders such as cutaneous melanoma. Chitosan nanoparticles containing bevacizumab antibody were synthesized by ion exchange method, and finally, these nanoparticles were coated with lipid (Lip-Chi-Bev NPs). In this study, the effect of synthesized nanoparticles on dermal absorption of bevacizumab was evaluated and its potential in inhibiting angiogenesis was evaluated by in vitro and in vivo models.