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Background: Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) channel. For people with CF (pwCF) affected by the most common pathogenic variant F508del, a tritherapy, named Trikafta/Kaftrio (ETI: elexacaftor (VX-445) /tezacaftor (VX-661) / ivacaftor (VX-770)) was successfully developed. However, in CF airway epithelial cells the calcium homeostasis is also disturbed; it is observed an increased calcium mobilization in CF cells compared to non-CF cells. Here, we studied the effects of ETI on intracellular calcium levels in F508del-CFTR airway epithelial cells to determine whether these compounds, individually or collectively, could normalize intracellular calcium levels. Methods: We measured intracellular calcium variations using human airway epithelial cells (hAEC) from pwCF, human bronchial epithelial CFBE41o- F508del-CFTR cells and Chinese Hamster Ovary (CHO) cells using the fluorescent probe Fluo4-AM, in the presence or absence of extracellular calcium. The rescue to the plasma membrane of F508del-CFTR protein by ETI was determined by western blot. The SarcoEndoplasmic Reticulum Calcium ATPase (SERCA), was also analysed by western blotting and by interference assay. Results: We show that ETI normalizes calcium homeostasis in our cellular models. However, we also found that (1) each ETI-corrector compound is capable of mobilizing calcium acutely in the absence of CFTR, and (2) tezacaftor mobilizes calcium from the endoplasmic reticulum (ER) probably via inhibition of the SERCA pump. Conclusions: We show that ETI not only corrects the abnormal trafficking and function of F508del-CFTR but also normalizes calcium homeostasis in our cellular models. Finally, we identified SERCA as a potential intracellular target for tezacaftor. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium channels (VGSCs) initiate action potentials in electrically excitable cells and tissues. Surprisingly, some VGSC genes are aberrantly expressed in a variety of cancers, derived from "non-excitable" tissues that do not generate classic action potentials, showing potential as a promising pharmacological target for cancer. Most of the previous review articles on this topic are limited in scope, and largely unable to provide researchers with a comprehensive understanding of the role of VGSC in cancers. Here, we review the expression patterns of all nine VGSC α-subunit genes (SCN1A-11A) and their four regulatory β-subunit genes (SCN1B-4B). We reviewed data from the Cancer Genome Atlas (TCGA) database, complemented by an extensive search of the published papers. We summarized and reviewed previous independent studies and analyzed the VGSC genes in the TCGA database regarding the potential impact of VGSC on cancers. A comparison between evidence gathered from independent studies and data review was performed to scrutinize potential biases in prior research and provide insights into future research directions. The review supports the view that VGSCs play an important role in diagnostics as well as therapeutics of some cancer types, such as breast, colon, prostate, and lung cancer. This paper provides an overview of the current knowledge on voltage-gated sodium channels in cancer, as well as potential avenues for further research. While further research is required to fully understand the role of VGSCs in cancer, the potential of VGSCs for clinical diagnosis and treatment is promising. [ABSTRACT FROM AUTHOR]

Background: The respiratory tract is protected from inhaled particles and microbes by mucociliary clearance, mediated by the mucus and the cilia creating a flow to move the mucus cephalad. Submucosal glands secrete linear MUC5B mucin polymers and because they pass through the gland duct before reaching the airway surface, bundled strands of 1000–5000 parallel molecules exit the glands. In contrast, the surface goblet cells secrete both MUC5AC and MUC5B. Methods: We used mass-spectrometry based proteomic analysis of unstimulated and carbachol stimulated newborn wild-type (WT) and cystic fibrosis transmembrane conductance regulator (CFTR) null (CF) piglet airways to study proteins in the airway surface liquid and mucus, to investigate if levels of MUC5AC and MUC5B were affected by carbachol stimulation and whether the proteins clustered according to function. Results: Proteins in the first four extracted fractions clustered together and the fifth fraction contained the mucus cluster, mucins and other proteins known to associate with mucins, whereas the traditional airway surface liquid proteins clustered to fraction 1–4 and were absent from the mucus fraction. Carbachol stimulation resulted in increased MUC5AC and MUC5B. Conclusions: These results indicate a distinct separation between proteins in the washable surface liquid and the mucus fraction. In fractions 1–4 from newborn CF piglets an additional cluster containing acute phase proteins was observed, suggesting an early inflammatory response in CF piglets. Alternatively, increased levels of these proteins could indicate altered lung development in the CF piglets. This observation suggests that CF airway disease is present at birth and thus, treatment should commence directly after diagnosis. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming, fundamentally pivotal in carcinogenesis and progression of cancer, is considered as a promising therapeutic target against tumors. In chronic lymphocytic leukemia (CLL) cells, metabolic abnormalities mediate alternations in proliferation and survival compared with normal B cells. However, the role of metabolic reprogramming is still under investigation in CLL. In this review, the critical metabolic processes of CLL were summarized, particularly glycolysis, lipid metabolism and oxidative phosphorylation. The effects of T cells and stromal cells in the microenvironment on metabolism of CLL were also elucidated. Besides, the metabolic alternation is regulated by some oncogenes and tumor suppressor regulators, especially TP53, MYC and ATM. Thus, the agents targeting metabolic enzymes or signal pathways may impede the progression of CLL. Both the inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) statins and the lipoprotein lipase inhibitor orlistat induce the apoptosis of CLL cells. In addition, a series of oxidative phosphorylation inhibitors play important roles in decreasing the proliferation of CLL cells. We epitomized recent advancements in metabolic reprogramming in CLL and discussed their clinical potentiality for innovative therapy options. Metabolic reprogramming plays a vital role in the initiation and progression of CLL. Therapeutic approaches targeting metabolism have their advantages in improving the survival of CLL patients. This review may shed novel light on the metabolism of CLL, leading to the development of targeted agents based on the reshaping metabolism of CLL cells. [ABSTRACT FROM AUTHOR]

Background: Ion channels are emerging as promising oncological targets. The potassium channels Kv1.3 and IKCa are highly expressed in the plasma membrane and mitochondria of human chronic lymphocytic leukemia (CLL) cells, compared to healthy lymphocytes. In vitro, inhibition of mitoKv1.3 by PAPTP was shown to kill ex vivo primary human CLL cells, while targeting IKCa with TRAM-34 decreased CLL cell proliferation. Methods: Here we evaluated the effect of the above drugs in CLL cells from ibrutinib-resistant patients and in combination with Venetoclax, two drugs used in the clinical practice. The effects of the drugs were tested also in the Eμ-TCL1 genetic CLL murine model, characterized by a lympho-proliferative disease reminiscent of aggressive human CLL. Eμ-TCL1 mice showing overt disease state were treated with intraperitoneal injections of non-toxic 5 nmol/g PAPTP or 10 nmol/g TRAM-34 once a day and the number and percentage of pathological B cells (CD19+CD5+) in different, pathologically relevant body districts were determined. Results: We show that Kv1.3 expression correlates with sensitivity of the human and mouse neoplastic cells to PAPTP. Primary CLL cells from ibrutinib-resistant patients could be killed with PAPTP and this drug enhanced the effect of Venetoclax, by acting on mitoKv1.3 of the inner mitochondrial membrane and triggering rapid mitochondrial changes and cytochrome c release. In vivo, after 2 week- therapy of Eμ-TCL1 mice harboring distinct CLL clones, leukemia burden was reduced by more than 85%: the number and percentage of CLL B cells fall in the spleen and peritoneal cavity and in the peripheral blood, without signs of toxicity. Notably, CLL infiltration into liver and spleen and splenomegaly were also drastically reduced upon PAPTP treatment. In contrast, TRAM-34 did not exert any beneficial effect when administered in vivo to Eμ-TCL1 mice at non-toxic concentration. Conclusion: Altogether, by comparing vehicle versus compound effect in different Eμ-TCL1 animals bearing unique clones similarly to CLL patients, we conclude that PAPTP significantly reduced leukemia burden in CLL-relevant districts, even in animals with advanced stage of the disease. Our results thus identify PAPTP as a very promising drug for CLL treatment, even for the chemoresistant forms of the disease. [ABSTRACT FROM AUTHOR]

Background: Overweight is associated with an increased cardiovascular risk which is only partially explained by conventional risk factors. The objective of this study was to evaluate lipoprotein(a) [Lp(a)] plasma levels and apolipoprotein(a) [apo(a)] phenotypes in relation to coronary heart disease (CHD) in overweight subjects. Methods: A total of 275 overweight (BMI ≥ 27 kg/m²) subjects, of which 155 had experienced a CHD event, 337 normal weight subjects with prior CHD and 103 CHD-free normal weight subjects were enrolled in the study. Lp(a) levels were determined by an ELISA technique and apo(a) isoforms were detected by a high-resolution immunoblotting method. Results: Lp(a) levels were similar in the three study groups. Overweight subjects with CHD had Lp(a) concentrations significantly higher than those without [median (interquartile range): 20 (5-| 50.3) versus 12.6 (2.6-38.6) mg/dl, P < 0.05]. Furthermore, overweight subjects with CHD showed a higher prevalence of low molecular weight apo(a) isoforms than those without (55.5% versus 40.8%, P < 0.05) and with respect to the control group (55.5% versus 39.8%, P < 0.05). Stepwise regression analysis showed that apo(a) phenotypes, but not Lp(a) levels, entered the model as significant independent predictors of CHD in overweight subjects. Conclusions: Our data indicate that small-sized apo(a) isoforms are associated with CHD in overweight subjects. The characterization of apo(a) phenotypes might serve as a reliable biomarker to better assess the overall CHD risk of each subject with elevated BMI, leading to more intensive treatment of modifiable cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Background: Nomograms are rarely employed to estimate the survival of patients with advanced and metastatic pancreatic cancer (PC). Herein, we developed a comprehensive approach to using a nomogram to predict survival probability in patients with advanced and metastatic PC.Methods: A total of 323 patients with advanced and metastatic PC were identified from the Chinese People's Liberation Army (PLA) General Hospital. A baseline nomogram was constructed using baseline variables of 323 patients. Additionally, 233 patients, whose tumors showed initial responses to first-line chemotherapy, were enrolled in the chemotherapy response-based model. 128 patients and 108 patients with advanced and metastatic PC from January 2019 to April 2021 were selected for external validating baseline model and chemotherapy response-based model. The 1-year and 2-year survival probability was evaluated using multivariate COX regression models. The discrimination and calibration capacity of the nomograms were assessed using C-statistic and calibration plots. The predictive accuracy and net benefit of the nomograms were evaluated using ROC curve and DCA, respectively.Results: In the baseline model, six variables (gender, KPS, baseline TB, baseline N, baseline WBC and baseline CA19-9) were used in the final model. In the chemotherapy response-based model, nine variables (KPS, gender, ascites, baseline N, baseline CA 19-9, baseline CEA, change in CA 19-9 level at week, change in CEA level at week and initial response to chemotherapy) were included in the final model. The C-statistics of the baseline nomogram and the chemotherapy response-based nomogram were 0.67 (95% CI, 0.62-0.71) and 0.74 (95% CI, 0.69-0.77), respectively.Conclusion: These nomograms were constructed to predict the survival probability of patients of advanced and metastatic PC. The baseline model and chemotherapy response-based model performed well in survival prediction. [ABSTRACT FROM AUTHOR]

Background: There is little data on the relationship between novel cardiovascular risk factors and silent coronary artery disease (CAD) in diabetic patients. We investigated whether Lipoprotein(a), homocysteine and apolipoprotein(a) polymorphism are associated with angiographically assessed asymptomatic coronary artery disease (CAD) in diabetic patients. Methods: 1,971 type 2 diabetic patients without clinical signs of cardiovascular diseases and with a negative history of CAD were consecutively evaluated. Among them, 179 patients showed electrocardiographic abnormalities suggestive of ischemia or previous asymptomatic myocardial infarction. These 179 patients were subjected to a non-invasive test for CAD (ECG stress testing and/or scintigraphy). Among patients with a highly positive stress testing (n = 19) or a positive scintigraphy (n = 74), 75 showed an angiographically documented CAD (CAD group). Seventy-five patients without CAD (NO CAD group) were matched by age, sex and duration of diabetes to CAD patients. In NO CAD patients an exercise ECG test, a 48-hour ambulatory ECG and a stress echocardiogram were negative for CAD. Results: Lipoprotein(a) levels (22.0 ± 18.9 versus 16.0 ± 19.4 mg/dl; p < 0.05), homocysteine levels (13.6 ± 6.6 versus 11.4 ± 4.9 mmol/l; p < 0.05) and the percentage of subjects with at least one small apolipoprotein(a) isoform (70.7% versus 29.3%; p < 0.0001) were higher in CAD than NO CAD group. Logistic regression analysis showed that apolipoprotein(a) polymorphism (OR:8.65; 95%CI:3.05-24.55), microalbuminuria (OR:6.16; 95%CI:2.21-17.18), smoking (OR:2.53; 95%CI:1.05-6.08), HDL (OR:3.16; 95%CI:1.28-7.81), homocysteine (OR:2.25; 95%CI:1.14-4.43) and Lipoprotein(a) (OR:2.62; 95%CI:1.01-6.79) were independent predictors of asymptomatic CAD. Conclusions: The present investigation shows an independent association of Lipoprotein(a), homocysteine and apo(a) polymorphism with silent CAD. Other studies are needed to establish whether these parameters are suitable for CAD screening in diabetic patients. [ABSTRACT FROM AUTHOR]