The Significance of Mitochondrial Dysfunction in Cancer.

As an essential organelle in nucleated eukaryotic cells, mitochondria play a central role in energy metabolism, maintenance of redox balance, and regulation of apoptosis. Mitochondrial dysfunction, either due to the TCA cycle enzyme defects, mitochondrial DNA genetic mutations, defective mitochondrial electron transport chain, oxidative stress, or aberrant oncogene and tumor suppressor signaling, has been observed in a wide spectrum of human cancers. In this review, we summarize mitochondrial dysfunction induced by these alterations that promote human cancers.

Early elevations of RAS protein level and activity are critical for the development of PDAC in the context of inflammation.

The KRASG12D mutation was believed to be locked in a GTP-bound form, rendering it fully active. However, recent studies have indicated that the presence of mutant KRAS alone is insufficient; it requires additional activation through inflammatory stimuli to effectively drive the development of pancreatic ductal adenocarcinoma (PDAC). It remains unclear to what extent RAS activation occurs during the development of PDAC in the context of inflammation. Here, in a mouse model with the concurrent expression of KrasG12D/+ and inflammation mediator IKK2 in pancreatic acinar cells, we showed that, compared to KRASG12D alone, the cooperative interaction between KRASG12D and IKK2 rapidly elevated both the protein level and activity of KRASG12D and NRAS in a short term. This high level was sustained throughout the rest phase of PDAC development. These results suggest that inflammation not only rapidly augments the activity but also the protein abundance, leading to an enhanced total amount of GTP-bound RAS (KRASG12D and NRAS) in the early stage. Notably, while KRASG12D could be further activated by IKK2, not all KRASG12D proteins were in the GTP-bound state. Overall, our findings suggest that although KRASG12D is not fully active in the context of inflammation, concurrent increases in both the protein level and activity of KRASG12D as well as NRAS at the early stage by inflammation contribute to the rise in total GTP-bound RAS.

Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress.

Bile acid (BA) homeostasis is vital for various physiological processes, whereas its disruption underlies cholestasis. The farnesoid X receptor (FXR) is a master regulator of BA homeostasis via the ileal fibroblast growth factor (FGF)15/19 endocrine pathway, responding to postprandial or abnormal transintestinal BA flux. However, the de novo paracrine signal mediator of hepatic FXR, which governs the extent of BA synthesis within the liver in non-postprandial or intrahepatic cholestatic conditions, remains unknown. We identified hepatic Fgf4 as a direct FXR target that paracrinally signals to downregulate Cyp7a1 and Cyp8b1. The effect of FXR-FGF4 is mediated by an uncharted intracellular FGF receptor 4 (FGFR4)-LRH-1 signaling node. This liver-centric pathway acts as a first-line checkpoint for intrahepatic and transhepatic BA flux upstream of the peripheral FXR-FGF15/19 pathway, which together constitutes an integral hepatoenteric control mechanism that fine-tunes BA homeostasis, counteracting cholestasis and hepatobiliary damage. Our findings shed light on potential therapeutic strategies for cholestatic diseases.

Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma.

KRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain unclear. In this study, we compared the differential effects of a high-carbohydrate diet (HCD), an HFD, and a high-protein diet (HPD) in PDAC development using a mouse model expressing an endogenous level of mutant KRASG12D specifically in pancreatic acinar cells. Our study showed that although with a lower tumorigenic capacity than chronic HFD, chronic HCD promoted acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions with increased inflammation, fibrosis, and cell proliferation compared to the normal diet (ND) in KrasG12D/+ mice. By contrast, chronic HPD showed no significant adverse effects compared to the ND. Furthermore, ablation of pancreatic acinar cell cyclooxygenase 2 (Cox-2) in KrasG12D/+ mice abrogated the adverse effects induced by HCD, suggesting that diet-induced pancreatic inflammation is critical for promoting oncogenic KRAS-mediated neoplasia. These results indicate that diets rich in different macronutrients have differential effects on pancreatic tumorigenesis in which the ensuing inflammation exacerbates the process. Management of macronutrient intake aimed at thwarting inflammation is thus an important preventive strategy for patients harboring oncogenic KRAS.

Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) mutations have been considered a critical driver of PDAC initiation and progression. However, the effects of mutant KRAS alone do not recapitulate the full spectrum of pancreatic pathologies associated with PDAC development in adults. Historically, mutant KRAS was regarded as constitutively active; however, recent studies have shown that endogenous levels of mutant KRAS are not constitutively fully active and its activity is still subject to up-regulation by upstream stimuli. Obesity is a metabolic disease that induces a chronic, low-grade inflammation called meta-inflammation and has long been recognized clinically as a major modifiable risk factor for pancreatic cancer. It has been shown in different animal models that obesogenic high-fat diet (HFD) and pancreatic inflammation promote the rapid development of mutant KRAS-mediated PDAC with high penetrance. However, it is not clear why the pancreas with endogenous levels of mutant KRAS is vulnerable to chronic HFD and inflammatory challenges. Recently, the discovery of fibroblast growth factor 21 (FGF21) as a novel anti-obesity and anti-inflammatory factor and as a downstream target of mutant KRAS has shed new light on this problem. This review is intended to provide an update on our knowledge of the vulnerability of the pancreas to KRAS-mediated invasive PDAC in the context of challenges engendered by obesity and associated inflammation.

Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.

Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RASG12D and RASG12V, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRASG12V-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation.

Rapid and sensitive detection of the vanA resistance gene from clinical Enterococcus faecium and Enterococcus faecalis isolates by loop-mediated isothermal amplification.

OBJECTIVES: Vancomycin resistance in Enterococcus spp., mediated mainly by the vanA resistance gene, has become a major health concern as it has spread worldwide. Therefore, a rapid method is urgently required to detect the vanA gene for timely and appropriate antimicrobial control of resistant Enterococcus infections. METHODS: The loop-mediated isothermal amplification (LAMP) assay was optimised for vanA detection in Enterococcus spp. isolates. RESULTS: The LAMP primer set designed in this study could reliably recognise seven distinct regions of the vanA gene and amplify the gene within 25min at an isothermal temperature of 65°C with high specificity. The sensitivity of the optimised assay was high, with a detection limit for vanA as low as 100pg/µL, which is 100-fold more sensitive than the PCR assay. A special advantage of this optimised LAMP method is that the vanA gene could be detected directly from clinical specimens. CONCLUSION: This optimised LAMP assay has great application potential for efficient detection of vanA in clinical diagnosis and epidemiological studies.

Development of Sensorised Resistance Band for Objective Exercise Measurement: Activities Classification Trial.

Resistance bands are often used in resistance training programs for older adults. Despite their widespread use, there is a lack of objective assessment of the actual strength, speed and precision of the movements during these exercises. Therefore, this paper presents the development of a sensorised resistance-band and a preliminary trial of activities classification by using artificial intelligence. The results show that in the preliminary trial, the classification accuracy of 4 different activities reached over 96% using accelerometer data only. A future study will be based on the sensorised resistance band to quantify resistance band exercises objectively in elderly people.