Clinical implication of megestrol acetate in metastatic gastric cancer: a big data analysis from Health Insurance Review and Assessment (HIRA) database.

OBJECTIVE: Megestrol acetate (MA) is used to manage anorexia and cachexia in patients with advanced cancer. This study investigated the prescription patterns of MA in patients with metastatic gastric cancer, as well as evaluated its impact on survival outcomes and the incidence of venous thromboembolism (VTE). METHODS: A Health Insurance Review and Assessment (HIRA) service database was used to investigate differences in baseline characteristics, survival, and the incidence of VTE according to MA prescription patterns (i.e., prescription vs. no prescription) in patients diagnosed with metastatic gastric cancer from July 2014 to December 2015. RESULTS: A total of 1938 patients were included in this study. In total, 65% of the patients were prescribed MA. Older age, treatment in tertiary hospitals, and palliative chemotherapy were statistically significant predictive factors for MA prescription. Continuous prescription of MA was observed in 37% of patients. There was no statistically significant difference in survival between the MA and non-MA prescription groups on multivariate analysis. Among the 1427 patients included in the analysis for VTE incidence, 4.3% and 2.9% were diagnosed with VTE during the follow-up period in the MA and non-MA prescription groups, respectively. However, there was no statistically significant difference in VTE diagnosis between the groups on multivariate analysis. CONCLUSION: MA is commonly prescribed for metastatic gastric cancer, especially in elderly patients and those undergoing palliative chemotherapy, without significantly affecting survival or VTE risk.

Transcription factor ATMIN facilitates chemoresistance in nasopharyngeal carcinoma.

Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients' survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.

RORα-GABP-TFAM axis alleviates myosteatosis with fatty atrophy through reinforcement of mitochondrial capacity.

BACKGROUND: Fat infiltration in muscle, called 'myosteatosis', precedes muscle atrophy, which subsequently results in sarcopenia. Myosteatosis is frequently observed in patients with nonalcoholic fatty liver disease (NAFLD). We have previously reported that retinoic acid receptor-related orphan receptor-α (RORα) regulates mitochondrial dynamics and mitophagy in hepatocytes, resulting in an alleviation of NAFLD. In this study, we aimed to investigate the role of RORα in skeletal muscle and to understand molecular mechanisms by which RORα controls mitochondrial capacity, using an NAFLD-associated myosteatosis mouse model. METHODS: To establish a myosteatosis model, 7-week-old C57BL/6N mice were fed with high-fat diet (HFD). After 15 weeks of diet feeding, an adeno-associated virus vector encoding RORα (AAV-RORα) was injected to gastrocnemius (GA) muscles, or after 7 weeks of HFD feeding, JC1-40, an RORα agonistic ligand, was administered daily at a dose of 5 mg/kg/day by oral gavage for 5 weeks. Histological, biochemical and molecular analyses in various in vivo and in vitro experiments were performed. RESULTS: First, the number of oxidative MyHC2a fibres with intensive lipid infiltration increased by 3.8-fold in the red region of the GA of mice with myosteatosis (P < 0.001). RORα was expressed around MyHC2a fibres, and its level increased by 2.7-fold after HFD feeding (P < 0.01). Second, treatment of RORα ligands in C2C12 myoblasts, such as cholesterol sulfate and JC1-40, enhanced the number of oxidative fibres stained for MyHC1 and MyHC2a by two-fold to four-fold (P < 0.01), while it reduced the lipid levels in MyHC2a fibres by 20-50% (P < 0.001) in the presence of palmitic acids. Third, mitochondrial membrane potential (P < 0.01) and total area of mitochondria (P < 0.01) were enhanced by treatment of these ligands. Chromatin immunoprecipitation analysis showed that RORα bound the promoter of GA-binding protein α subunit gene that led to activation of mitochondrial transcription factor A (TFAM) in C2C12 myoblasts (P < 0.05). Finally, intramuscular transduction of AAV-RORα alleviated the HFD-induced myosteatosis with fatty atrophy; lipid contents in MyHC2a fibres decreased by 48% (P < 0.001), whereas the number of MyHC2b fibre increased by 22% (P < 0.001). Also, administration of JC1-40 improved the signs of myosteatosis in that it decreased the level of adipose differentiation-related protein (P < 0.01) but increased mitochondrial proteins such as cytochrome c oxidase 4 and TFAM in GA muscle (P < 0.01). CONCLUSIONS: RORα plays a versatile role in regulating the quantity of mitochondria and the oxidative capacity, ultimately leading to an improvement in myosteatosis symptoms.

Oral lipid nanocomplex of BRD4 PROteolysis TArgeting Chimera and vemurafenib for drug-resistant malignant melanoma.

BRAF inhibitors (BRAFi) like vemurafenib (VEM) provide initial regression in mutated melanoma but rapidly develop resistance. Molecular pathways responsible for development of resistance against VEM finally converge towards the activation of oncogenic c-Myc. We identified an epigenetic approach to inhibit the c-Myc expression and resensitize BRAFi-resistant melanoma cells. ARV-825 (ARV) was employed as a BRD4 targeted PROteolysis TArgeting Chimera that selectively degrades the BRD4 to downregulate c-Myc. ARV synergistically enhanced the cytotoxicity of VEM in vitro to overcome its resistance in melanoma. Development of ARV and VEM-loaded lipid nanocomplex (NANOVB) significantly improved their physicochemical properties for oral delivery. Most importantly, oral administration of NANOVB substantially inhibited tumor growth at rate of 41.07 mm3/day in nude athymic mice. NANOVB treatment resulted in prolonged survival with 50% of mice surviving until the experimental endpoint. Histopathological analysis revealed significant tumor necrosis and downregulation of Ki-67 and BRD4 protein in vivo. Promising in vivo antitumor activity and prolonged survival demonstrated by NANOVB signifies its clinical translational potential for BRAFi-resistant melanoma.

European Headache Federation (EHF) critical reappraisal and meta-analysis of oral drugs in migraine prevention - part 3: topiramate.

OBJECTIVE: Topiramate is a repurposed first-line treatment for migraine prophylaxis. The aim of this systematic review and meta-analysis is to critically re-appraise the existing evidence supporting the efficacy and tolerability of topiramate. METHODS: A systematic search in MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis as of August 13, 2022, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Randomized controlled trials in adult patients that used topiramate for the prophylactic treatment of migraine, with placebo as active comparator, were included. Two reviewers independently screened the retrieved studies and extracted all data. Outcomes of interest were the 50% responder rates, the reduction in monthly migraine days, and adverse events leading to treatment discontinuation. Results were pooled and meta-analyzed, with sensitivity analysis based on the risk of bias of the studies, the monthly migraine days at baseline, and the previous use of other prophylactic treatments. Certainty evidence was judged according to the GRADE framework. RESULTS: Eight out of 10,826 studies fulfilled the inclusion/exclusion criteria, accounting for 2,610 randomized patients. Six studies included patients with episodic migraine and two with chronic migraine. Topiramate dose ranged from 50 to 200 mg/day, and all studies included a placebo arm. There was a high certainty that topiramate: 1) increased the proportion of patients who achieved a 50% responder rate in monthly migraine days, compared to placebo [relative risk: 1.61 (95% confidence interval (CI): 1.29-2.01); absolute risk difference: 168 more per 1,000 (95% CI: 80 to 278 more)]; 2) was associated with 0.99 (95% CI: 1.41-0.58) fewer migraine days than placebo; 3) and had a higher proportion of patients with adverse events leading to treatment discontinuation [absolute risk difference 80 patients more per 1,000 (95% CI: 20 to 140 more patients)]. CONCLUSIONS: There is high-quality evidence of the efficacy of topiramate in the prophylaxis of migraine, albeit its use poses a risk of adverse events that may lead to treatment discontinuation, with a negative effect on patient satisfaction and adherence to care.

Biomarkers-Based Cost-Effectiveness of Toripalimab Plus Chemotherapy for Patients with Treatment-Naive Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: This study examined the cost-effectiveness of first-line toripalimab plus chemotherapy (TC) for patients with advanced non-small cell lung cancer (NSCLC), excluding patients with nonsquamous NSCLC and EGFR/ALK mutations. It further analyzed the cost-effectiveness of this strategy in biomarker-based subgroups, all within the context of the Chinese healthcare system. METHODS: Eighteen Markov models with 21-day Markov cycle lengths and 30-year time horizons were constructed in this study. Clinical effectiveness data were derived from the CHOICE-01 trial. Health state utilities and costs data were obtained from various sources. The primary outputs were the calculation of incremental cost-effectiveness ratios (ICERs), which were then compared to a willingness-to-pay (WTP) threshold of $17,961 per quality-adjusted life-year (QALY). This comparison was used to determine the treatment that offered greater cost-effectiveness. To account for uncertainty in the model, sensitivity analyses were conducted. RESULTS: For the overall patient population, the estimated ICER between first-line TC and placebo plus chemotherapy (PC) was $9445/QALY, significantly lower than the WTP threshold used in the model. In subgroups based on pathologic types, first-line TC had an ICER of $16,757/QALY for patients with nonsquamous NSCLC, slightly below the WTP threshold; first-line TC demonstrated dominance in patients with squamous NSCLC, indicating both better effectiveness and lower costs compared to first-line PC. In biomarkers-based subgroups, first-line TC was dominant over first-line PC in the subgroups with programmed cell death ligand 1 (PD-L1) expression ≥ 50% and SMARCA4 mutations. Moreover, first-line TC had ICERs lower than the WTP threshold in other subgroups, except for the subgroup with RB1 mutations. Sensitivity analysis confirmed the robustness of these findings. CONCLUSION: From the perspective of the Chinese healthcare system, this study's findings suggested that first-line TC represents a cost-effective strategy for patients with advanced NSCLC. However, the cost-effectiveness of first-line TC varied across different subgroups when considering predictive biomarkers.

HOXC13-driven TIMM13 overexpression promotes osteosarcoma cell growth.

TIMM13 (translocase of inner mitochondrial membrane 13) located at the mitochondrial intermembrane space is vital for the integrity and function of mitochondria. We found that the mitochondrial protein TIMM13 is upregulated in human OS tissues and cells. In patient-derived primary OS cells and established cell lines, TIMM13 shRNA or knockout provoked mitochondrial dysfunction, causing mitochondrial depolarization, reactive oxygen species production, and oxidative injury, as well as lipid peroxidation, DNA damage, and ATP depletion. Moreover, TIMM13 depletion provoked OS cell apoptosis and inhibited cell proliferation and migration. Conversely, ectopic TIMM13 overexpression increased ATP contents, enhancing OS cell proliferation and migration. Moreover, we discovered that Akt-mTOR activation was inhibited with TIMM13 depletion in primary OS cells. Further studies revealed that HOXC13 (Homeobox C13)-dependent TIMM13 transcription was significantly increased in OS tissues and cells. Whereas TIMM13 transcription and expression were decreased following HOXC13 silencing in primary OS cells. In vivo, TIMM13 KO potently inhibited OS xenograft growth in the proximal tibia of nude mice. TIMM13 KO also induced Akt-mTOR inactivation, ATP depletion, oxidative injury, and apoptosis in the in situ OS tumors. Together, upregulation of the mitochondrial protein TIMM13 is important for OS cell growth, representing a novel and promising therapeutic target.

Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank.

BACKGROUND: Metformin, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related diseases, but so far little experimental evidence is available. We sought to assess the target-specific effect of metformin on biomarkers of ageing in the UK Biobank. METHODS: In this drug target mendelian randomisation study, we assessed the target-specific effect of four putative targets of metformin (AMPK, ETFDH, GPD1, and PEN2), involving ten genes. Genetic variants with evidence of causation of gene expression, glycated haemoglobin A1c (HbA1c), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA1c lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte telomere length. To triangulate the evidence, we also assessed the effect of HbA1c on the outcomes using a polygenic mendelian randomisation design and assessed the effect of metformin use on these outcomes using a cross-sectional observational design. FINDINGS: GPD1-induced HbA1c lowering was associated with younger PhenoAge (ß -5·26, 95% CI -6·69 to -3·83) and longer leukocyte telomere length (ß 0·28, 0·03 to 0·53), and AMPKγ2 (PRKAG2)-induced HbA1c lowering was associated with younger PhenoAge (ß -4·88, -7·14 to -2·62) but not with longer leukocyte telomere length. Genetically predicted HbA1c lowering was associated with younger PhenoAge (ß -0·96 per SD lowering of HbA1c, 95% CI -1·19 to -0·74) but not associated with leukocyte telomere length. In the propensity score matched analysis, metformin use was associated with younger PhenoAge (ß -0·36, 95% CI -0·59 to -0·13) but not with leukocyte telomere length. INTERPRETATION: This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPKγ2 (PRKAG2), and the effect could be in part due to its glycaemic property. Our findings support further clinical research into metformin and longevity. FUNDING: Healthy Longevity Catalyst Award, National Academy of Medicine, and Seed Fund for Basic Research, The University of Hong Kong.

[Clinicopathological and gene mutation characteristics of uterine carcinosarcoma].

To explore the clinicopathological characteristics, immunophenotype, diagnosis and differential diagnosis of uterine carcinosarcoma (UCS), and to explore the gene mutation characteristics and tumor mutation burden (TMB) of UCS. The clinical imaging, pathomorphological data and immunohistochemical expression of 4 cases of UCS, which were archived in the Department of Pathology of the Second Affiliated Hospital of Soochow University from January 2021 to May 2022 were retrospectively analyzed. All exon groups of 4 cases of UCS were sequenced. All the 4 patients were female, aged 47-81 years. The maximum diameter of the tumor was 4.0-13.0 cm, and the boundary was unclear. Microscopically, the tumor was composed of malignant epithelium and sarcoma. Immunohistochemistry showed that the epithelial components of 4 patients expressed broad-spectrum cytokeratin (AE1/E3), the sarcoma components expressed Vimentin, PAX8, ER, PR were expressed to varying degrees, and Ki-67 positive index was high (60%-90%). There were 3 p53 missense mutations, 1 nonsense mutation, 4 MLH1, PMS2, MSH2, MSH6 were positive and PD-L1 was negative. The sequencing results of the whole exon group of 4 UCS patients showed that TP53, BCL9L, BRD4, CLTCLI, PSMD1I, PLEC genes showed a high mutation ratio, which was 3/4, 2/4, 2/4, 2/4, 2/4, 2/4, respectively. TMB analysis showed that the TMB of 4 cases of UCS was<5 mut/Mb. UCS is a rare and highly malignant endometrial tumor. The sequencing results of the whole exon group suggested that TP53, BCL9L, BRD4 and other genes had high mutation rates, suggesting that the occurrence and development of UCS may be closely related to Wnt signaling pathway. Molecular typing indicated that 3 cases of UCS were of high copy number type/p53 mutation type, and 1 case had POLD1 mutation. Microsatellite stability, low PD-L1 expression and TMB results suggested that UCS patients have no obvious advantage in immunotherapy.

New targeted treatments for advanced sarcomas.

PURPOSE OF REVIEW: The purpose of this review is to provide the rationale and results behind recent clinical trials regarding molecular-targeted agents for advanced sarcomas. RECENT FINDINGS: Tazemetostat, a first-in-class EZH2 inhibitor, was approved to treat advanced epithelioid sarcoma. In synovial sarcoma, the interaction between pathognomonic SS18-SSX fusion protein and the BAF complex has brought insight in using BRD9 inhibitors as a treatment based on synthetic lethality. MDM2 overexpression is an important mechanism to suppress p53 function, and MDM2 gene amplification is pathognomonic in well differentiated and dedifferentiated liposarcoma. Two MDM2 inhibitors, milademetan and BI907828, have both reached the optimal dosing and have shown promising efficacy in MDM2-amplified liposarcoma. Late-stage pivotal studies are ongoing for both of these MDM2 inhibitors. The co-amplification of CDK4 and MDM2 in liposarcoma also provided a rationale for CDK4/6 inhibitors as a potential therapy. Selinexor, an exportin-1 inhibitor, has shown single-agent activity in dedifferentiated liposarcoma and action in gastrointestinal stromal tumour in combination with imatinib. Lastly, a new formulation of mTOR inhibitor, nab-sirolimus, was recently approved for perivascular epithelioid cell tumour (PEComa). SUMMARY: Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.

Current progress in the targeted therapy of breast cancer: Structure-activity correlation and docking studies (2015-2021).

Despite cancer research and therapy, breast cancer remains a complicated health crisis in women and represents a top biomedical research priority. Nowadays, breast cancer is an extremely heterogeneous disease and is known as the leading cause of death among women worldwide. The incidence and mortality rates of breast cancer have been increasing gradually for the past decades. Nowadays, common treatments for breast cancer are chemotherapy, endocrine therapy, immunotherapy, radiotherapy, and surgery. The most common targets in breast cancer treatment are human epidermal growth factor receptor 2 (HER2) and estrogen receptors. The literature suggests that several targets/pathways are also involved in the development of breast cancer, that is, poly(ADP-ribose) polymerase (PARP), bromodomain-containing protein 4 (BRD4), cyclin-dependent kinase 4/6 (CDK4/6), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), polo-like kinase 1 (PLK1), phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), histone deacetylase (HDAC), nuclear factor kappa B (NF-κB), PD-L1, and aromatase inhibitors. Meanwhile, the study of breast cancer is a hot topic in the current scenario of basic/clinical research. This review article provides information on different targets associated with breast cancer and summarizes the progress of current research on synthesized inhibitors as anti-breast cancer agents from 2015 to 2021. The review aims to provide structure-activity relationship and docking studies for designing novel compounds for breast cancer therapy.

Menin-MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers.

Encoded by the MEN1 gene, menin protein is a fusion protein that is essential for the oncogenic transformation of mixed-lineage leukemia (MLL) and leads to acute leukemia (AL). Therefore, accumulating evidence has demonstrated that inhibition of the high-affinity relationship between menin and mixed-lineage leukemia 1 (MLL1 and KMT2A) is an effective treatment for MLL-rearranged (MLL-r) leukemia in vitro and in vivo. Meanwhile, recent studies found that menin-MLL1 interaction inhibitors exhibited a firm tumor suppressive ability in specific cancer cells, such as prostate cancer, breast cancer, liver cancer, and lung cancer. Overall, it seems to serve as a novel therapeutic means for cancers. Herein, we review the recent progress in exploring the inhibitors of small molecule menin-MLL1 interactions. The molecular mechanisms of these inhibitors' functions and their application prospects in the treatment of AL and cancers are explored.

A Multicenter, Phase II Trial of Schedule Modification for Nab-Paclitaxel in Combination with Ramucirumab for Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: The B-RAX Trial (JACCRO GC-09).

BACKGROUND: This study investigated whether schedule modification of bi-weekly nanoparticle albumin-bound paclitaxel (nab-PTX) plus ramucirumab (RAM) is efficacious against gastric cancer (GC) or gastroesophageal junction cancer (GJC). PATIENTS AND METHODS: Patients with unresectable GC or GJC who were previously treated with fluoropyrimidine-containing regimens received nab-PTX (100 mg/m2) on days 1, 8, and 15 and RAM (8 mg/kg) on days 1 and 15 of a 28-day cycle. Based on the incidence of severe adverse events (AEs) during the first cycle, patients were modified to bi-weekly therapy from the second cycle. The primary endpoint was progression-free survival (PFS) in the bi-weekly therapy population. Based on the hypothesis that bi-weekly nab-PTX plus RAM would improve PFS from 4.5 to 7.0 months, 40 patients were required for power of 0.8 with a one-sided α of 0.05. RESULTS: Of the 81 patients enrolled, 47 patients (58%) were assigned to bi-weekly therapy. Patient characteristics were Eastern Cooperative Oncology Group performance status of 1 (19%) and diffuse type (45%). Median PFS was 4.7 months (95% confidence interval [CI] 3.7-5.6 months) and overall response rate was 25% (95% CI 11-39%). Severe AEs of grade 3 or worse were mainly neutropenia (83%) and hypertension (23%). EQ-5D scores were maintained during the treatment. In patients who continued standard-schedule therapy, median PFS was 2.7 months (95% CI 1.8-4.0 months). CONCLUSIONS: The primary endpoint for PFS was statistically not met, but modification of nab-PTX plus RAM to a bi-weekly schedule might be a feasible treatment option as second-line treatment for advanced GC/GJC patients, especially elderly patients, with severe AEs during the first cycle.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 1: amitriptyline.

OBJECTIVE: The aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis. METHODS: We report our methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared amitriptyline with placebo for migraine prophylaxis in adults. Our outcomes of interest were informed by the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in migraine days per month, migraine days per month, and adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB 2.0 tool and the certainty of evidence by using the GRADE approach. RESULTS: Our search yielded 10.826 unique records, of which three trials (n = 622) were eligible for data synthesis and analysis. We found moderate certainty evidence that amitriptyline increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo (relative risk: 1.60 (95% CI 1.17 to 2.19); absolute risk difference: 165 more per 1,000 (95% CI 47 more to 327 more). We found moderate certainty evidence that amitriptyline increases the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.05 (95% CI 0.01 to 0.10); absolute risk difference: 50 more per 1,000 (95% CI 10 more to 100 more). CONCLUSIONS: Our meta-analysis showed that amitriptyline may have a prophylactic role in migraine patients, however these results are far from robust. This warrants further large-scale research to evaluate the role of amitriptyline in migraine prevention.

TPX2 enhances the transcription factor activation of PXR and enhances the resistance of hepatocellular carcinoma cells to antitumor drugs.

The pregnane X receptor (PXR) is an important regulator of hepatocellular carcinoma cellular resistance to antitumor drugs. Activation of PXR was modulated by the co-regulators. The target protein for the Xenopus plus end-directed kinesin-like protein (Xklp2) known as TPX2 that was previously considered as a tubulin regulator, also functions as the regulator of some transcription factors and pro-oncogenes in human malignances. However, the actions of TPX2 on PXR and HCC cells are still unclear. In the present study, our results demonstrate that the high expression of endogenous mRNA level of TPX2 not only correlated with the poor prognosis of advanced HCC patients who received sorafenib treatment but also with expression of PXR's downstream genes, cyp3a4 and/or mdr-1. Results from luciferase and real-time polymerase chain reaction (qPCR) showed that TPX2 leads to enhancement of the transcription factor activation of PXR. Protein-protein interactions between PXR and TPX2 were identified using co-immunoprecipitation. Mechanically, overexpression of TPX2 led to enhancement of PXR recruitment to its downstream gene cyp3a4's promoter region (the PXRE region) or enhancer region (the XREM region). Treatment of HCC cells with paclitaxel, a microtubule promoter, led to enhancement of the effects of TPX2, whereas vincristine, a microtubule depolymerizing agent caused a decrease in TPX2-associated effects. TPX2 was found to cause acceleration of the metabolism or clearance of sorafenib, a typical tyrosine kinase inhibitor (TKI) in HCC cells and in turn led to the resistance to sorafenib by HCC cells. By establishing novel actions of TXP2 on PXR in HCC cells, the results indicate that TPX2 could be considered a promising therapeutic target to enhance HCC cells sensitivity to antitumor drugs.

Potential therapeutic targets for age-related macular degeneration: The nuclear option.

The functions and activities of nuclear receptors, the largest family of transcription factors in the human genome, have classically focused on their ability to act as steroid and hormone sensors in endocrine organs. However, they are responsible for a diverse array of physiological functions, including cellular homeostasis and metabolism, during development and aging. Though the eye is not a traditional endocrine organ, recent studies have revealed high expression levels of nuclear receptors in cells throughout the posterior pole. These findings have precipitated an interest in investigating the role of these transcription factors in the eye as a function of age and ocular disease, in particular age-related macular degeneration (AMD). As the leading cause of vision impairment in the elderly, identifying signaling pathways that may be targeted for AMD therapy is of great importance, given the lack of therapeutic options for over 85% of patients with this disease. Herein we review this relatively new field and recent findings supporting the hypothesis that the eye is a secondary endocrine organ, in which nuclear receptors serve as the bedrock for biological processes in cells vulnerable in AMD, including retinal pigment epithelial and choroidal endothelial cells, and discuss the therapeutic potential of targeting these receptors for AMD.

Dihydroartemisinin inhibited the Warburg effect through YAP1/SLC2A1 pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) was the third most common cause of cancer death. But it has only limited therapeutic options, aggressive nature, and very low overall survival. Dihydroartemisinin (DHA), an anti-malarial drug approved by the Food and Drug Administration (FDA), inhibited cell growth in HCC. The Warburg effect was one of the ten new hallmarks of cancer. Solute carrier family 2 member 1 (SLC2A1) was a crucial carrier for glucose to enter target cells in the Warburg effect. Yes-associated transcriptional regulator 1 (YAP1), an effector molecule of the hippo pathway, played a crucial role in promoting the development of HCC. This study sought to determine the role of DHA in the SLC2A1 mediated Warburg effect in HCC. In this study, DHA inhibited the Warburg effect and SLC2A1 in HepG2215 cells and mice with liver tumors in situ. Meanwhile, DHA inhibited YAP1 expression by inhibiting YAP1 promoter binding protein GA binding protein transcription factor subunit beta 1 (GABPB1) and cAMP responsive element binding protein 1 (CREB1). Further, YAP1 knockdown/knockout reduced the Warburg effect and SLC2A1 expression by shYAP1-HepG2215 cells and Yap1LKO mice with liver tumors. Taken together, our data indicated that YAP1 knockdown/knockout reduced the SLC2A1 mediated Warburg effect by shYAP1-HepG2215 cells and Yap1LKO mice with liver tumors induced by DEN/TCPOBOP. DHA, as a potential YAP1 inhibitor, suppressed the SLC2A1 mediated Warburg effect in HCC.

Hypoxia-induced factor and its role in liver fibrosis.

Liver fibrosis develops as a result of severe liver damage and is considered a major clinical concern throughout the world. Many factors are crucial for liver fibrosis progression. While advancements have been made to understand this disease, no effective pharmacological drug and treatment strategies have been established that can effectively prevent liver fibrosis or even could halt the fibrotic process. Most of those advances in curing liver fibrosis have been aimed towards mitigating the causes of fibrosis, including the development of potent antivirals to inhibit the hepatitis virus. It is not practicable for many individuals; however, a liver transplant becomes the only suitable alternative. A liver transplant is an expensive procedure. Thus, there is a significant need to identify potential targets of liver fibrosis and the development of such agents that can effectively treat or reverse liver fibrosis by targeting them. Researchers have identified hypoxia-inducible factors (HIFs) in the last 16 years as important transcription factors driving several facets of liver fibrosis, making them possible therapeutic targets. The latest knowledge on HIFs and their possible role in liver fibrosis, along with the cell-specific activities of such transcription factors that how they play role in liver fibrosis progression, is discussed in this review.

Regulation of programmed cell death by Brd4.

Epigenetic factor Brd4 has emerged as a key regulator of cancer cell proliferation. Targeted inhibition of Brd4 suppresses growth and induces apoptosis of various cancer cells. In addition to apoptosis, Brd4 has also been shown to regulate several other forms of programmed cell death (PCD), including autophagy, necroptosis, pyroptosis, and ferroptosis, with different biological outcomes. PCD plays key roles in development and tissue homeostasis by eliminating unnecessary or detrimental cells. Dysregulation of PCD is associated with various human diseases, including cancer, neurodegenerative and infectious diseases. In this review, we discussed some recent findings on how Brd4 actively regulates different forms of PCD and the therapeutic potentials of targeting Brd4 in PCD-related human diseases. A better understanding of PCD regulation would provide not only new insights into pathophysiological functions of PCD but also provide new avenues for therapy by targeting Brd4-regulated PCD.

EGFR-induced suppression of HPV E6/E7 is mediated by microRNA-9-5p silencing of BRD4 protein in HPV-positive head and neck squamous cell carcinoma.

EGFR upregulation is an established biomarker of treatment resistance and aggressiveness in head and neck cancers (HNSCC). EGFR-targeted therapies have shown benefits for HPV-negative HNSCC; surprisingly, inhibiting EGFR in HPV-associated HNSCC led to inferior therapeutic outcomes suggesting opposing roles for EGFR in the two HNSCC subtypes. The current study aimed to understand the link between EGFR and HPV-infected HNSCC particularly the regulation of HPV oncoproteins E6 and E7. We demonstrate that EGFR overexpression suppresses cellular proliferation and increases radiosensitivity of HPV-positive HNSCC cell lines. EGFR overexpression inhibited protein expression of BRD4, a known cellular transcriptional regulator of HPV E6/E7 expression and DNA damage repair facilitator. Inhibition of EGFR by cetuximab restored the expression of BRD4 leading to increased HPV E6 and E7 transcription. Concordantly, pharmacological inhibition of BRD4 led to suppression of HPV E6 and E7 transcription, delayed cellular proliferation and sensitised HPV-positive HNSCC cells to ionising radiation. This effect was shown to be mediated through EGFR-induced upregulation of microRNA-9-5p and consequent silencing of its target BRD4 at protein translational level, repressing HPV E6 and E7 transcription and restoring p53 tumour suppressor functions. These results suggest a novel mechanism for EGFR inhibition of HPV E6/E7 oncoprotein expression through an epigenetic pathway, independent of MAPK, but mediated through microRNA-9-5p/BRD4 regulation. Therefore, targeting EGFR may not be the best course of therapy for certain cancer types including HPV-positive HNSCC, while targeting specific signalling pathways such as BRD4 could provide a better and potentially new treatment to improve HNSCC therapeutic outcome.