Deep neural network uncertainty estimation for early oral cancer diagnosis.

BACKGROUND: Early diagnosis in oral cancer is essential to reduce both morbidity and mortality. This study explores the use of uncertainty estimation in deep learning for early oral cancer diagnosis. METHODS: We develop a Bayesian deep learning model termed 'Probabilistic HRNet', which utilizes the ensemble MC dropout method on HRNet. Additionally, two oral lesion datasets with distinct distributions are created. We conduct a retrospective study to assess the predictive performance and uncertainty of Probabilistic HRNet across these datasets. RESULTS: Probabilistic HRNet performs optimally on the In-domain test set, achieving an F1 score of 95.3% and an AUC of 96.9% by excluding the top 30% high-uncertainty samples. For evaluations on the Domain-shift test set, the results show an F1 score of 64.9% and an AUC of 80.3%. After excluding 30% of the high-uncertainty samples, these metrics improve to an F1 score of 74.4% and an AUC of 85.6%. CONCLUSION: Redirecting samples with high uncertainty to experts for subsequent diagnosis significantly decreases the rates of misdiagnosis, which highlights that uncertainty estimation is vital to ensure safe decision making for computer-aided early oral cancer diagnosis.

Circadian Rhythm Disruption in Hepatocellular Carcinoma Investigated by Integrated Analysis of Bulk and Single-Cell RNA Sequencing Data.

Circadian rhythms are essential regulators of a multitude of physiological and behavioral processes, such as the metabolism and function of the liver. Circadian rhythms are crucial to liver homeostasis, as the liver is a key metabolic organ accountable for the systemic equilibrium of the body. Circadian rhythm disruption alone is sufficient to cause liver cancer through the maintenance of hepatic metabolic disorder. Although there is evidence linking CRD to hepatocarcinogenesis, the precise cellular and molecular mechanisms that underlie the circadian crosstalk that leads to hepatocellular carcinoma remain unknown. The expression of CRD-related genes in HCC was investigated in this study via bulk RNA transcriptomic analysis and single-cell sequencing. Dysregulated CRD-related genes are predominantly found in hepatocytes and fibroblasts, according to the findings. By using a combination of single-cell RNA sequencing and bulk RNA sequencing analyses, the dysregulated CRD-related genes ADAMTS13, BIRC5, IGFBP3, MARCO, MT2A, NNMT, and PGLYRP2 were identified. The survival analysis using the Kaplan-Meier method revealed a significant correlation between the expression levels of BIRC5 and IGFBP3 and the survival of patients diagnosed with HCC.

In vitro antifungal susceptibility profile and genotypic characterization of clinical Aspergillus isolates in Eastern China on behalf of Eastern China Invasive Fungi Infection Group.

Aspergillus species is a widespread environmental mould that can cause aspergillosis. The purpose of this study was to investigate the antifungal susceptibility profile and genotypic characterization of clinical Aspergillus isolates from different provinces in Eastern China. The data included the antifungal susceptibility distributions with eight common antifungal drugs, cyp51A gene mutations of triazole-resistant Aspergillus fumigatus sensu stricto, and the genotypic relationships among the A. fumigatus sensu stricto isolates based on microsatellite typing. A. fumigatus sensu lato was the most common clinical Aspergillus species (n = 252), followed by A. flavus (n = 169), A. terreus (n = 37), A. niger (n = 29), and A. nidulans (n = 4). The modal minimum effective concentration values of micafungin and anidulafungin were lower than those of caspofungin for all Aspergillus species. The in vitro efficacy of isavuconazole was similar to that of voriconazole against most Aspergillus species. Sequencing revealed cyp51A gene mutations TR34/L98H, TR34/L98H/S297T/F495I, and TR46/Y121F/T289A in four triazole-resistant A. fumigatus sensu stricto. Phylogenetic analyses using microsatellite markers of A. fumigatus sensu stricto revealed that 211 unique genotypes clustered into two clades. The data demonstrate the diversity of clinically relevant Aspergillus species in Eastern China. Routine antifungal susceptibility testing should be performed to monitor the antifungal resistance and guide clinical therapy.

The 6-year multicenter study collected a total of 491 Aspergillus isolates from Eastern China to investigate the in vitro antifungal susceptibility to eight antifungal drugs, the cyp51A gene mutations of triazole-resistant A. fumigatus sensu stricto, and the genetic relatedness through microsatellite typing.

Mutation of aspartic acid 262 on estrogen receptor abrogates estradiol signaling pathway.

OBJECTIVE: ERα (estrogen receptor alpha) exerts nuclear genomic actions and membrane-initiated non-genomic effects. The mutation of aspartic acid into alanine in vitro revealed the critical role of aspartic acid 258 (corresponding to mouse amino acid site 262) of ERα for non-nuclear function. Our previous in vitro study revealed that this mutation blocked estrogen's non-genomic effects on vascular endothelial H2S release. Here, we studied the in vivo role of the aspartic acid 262 of ERα in the reproductive system and in the vascular tissue. APPROACH AND RESULTS: We generated a mouse model harboring a point mutation of the murine counterpart of this aspartic acid into alanine (ERαD262A). Our results showed that the ERαD262A females are fertile with standard hormonal serum levels, but the uterine development and responded with estrogen and follicular development are disrupted. In line with our previous study, we found that the rapid dilation of the aorta was abrogated in ERαD262A mice. In contrast to the previously reported R264-ERα mice, the classical estrogen genomic effector SP1/NOS3/AP1 and the nongenomic effectors p-eNOs, p-AKT, and p-ERK were disturbed in the ERαD262A aorta. Besides, the serum H2S concentration was decreased in ERαD262A mice. Together, ERαD262A mice showed compromised both genomic and non-genomic actions in response to E2. CONCLUSIONS: These data showed that aspartic acid 262 of ERα are important for both genomic and non-genomic effects of E2. Our data provide a theoretical basis for further selecting an effective non-genomic mouse model and provide a new direction for developing estrogen non-genomic effect inhibitors.

Cathelicidin Antimicrobial Peptide Acts as a Tumor Suppressor in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is associated with high rates of metastasis and recurrence, and is one of the most common causes of cancer-associated death worldwide. This study examined the protein changes within circulating exosomes in patients with HCC against those in healthy people using isobaric tags for a relative or absolute quantitation (iTRAQ)-based quantitative proteomics analysis. The protein levels of von Willebrand factor (VWF), cathelicidin antimicrobial peptide (CAMP), and proteasome subunit beta type-2 (PSMB2) were altered in HCC. The increased levels of VWF and PSMB2 but decreased CAMP levels in the serum of patients with HCC were validated by enzyme-linked immunosorbent assays. The level of CAMP (the only cathelicidin found in humans) also decreased in the circulating exosomes and buffy coat of the HCC patients. The serum with reduced levels of CAMP protein in the HCC patients increased the cell proliferation of Huh-7 cells; this effect was reduced following the addition of CAMP protein. The depletion of CAMP proteins in the serum of healthy people enhances the cell proliferation of Huh-7 cells. In addition, supplementation with synthetic CAMP reduces cell proliferation in a dose-dependent manner and significantly delays G1-S transition in Huh-7 cells. This implies that CAMP may act as a tumor suppressor in HCC.

Perturbative Quantum Simulation.

Approximation based on perturbation theory is the foundation for most of the quantitative predictions of quantum mechanics, whether in quantum many-body physics, chemistry, quantum field theory, or other domains. Quantum computing provides an alternative to the perturbation paradigm, yet state-of-the-art quantum processors with tens of noisy qubits are of limited practical utility. Here, we introduce perturbative quantum simulation, which combines the complementary strengths of the two approaches, enabling the solution of large practical quantum problems using limited noisy intermediate-scale quantum hardware. The use of a quantum processor eliminates the need to identify a solvable unperturbed Hamiltonian, while the introduction of perturbative coupling permits the quantum processor to simulate systems larger than the available number of physical qubits. We present an explicit perturbative expansion that mimics the Dyson series expansion and involves only local unitary operations, and show its optimality over other expansions under certain conditions. We numerically benchmark the method for interacting bosons, fermions, and quantum spins in different topologies, and study different physical phenomena, such as information propagation, charge-spin separation, and magnetism, on systems of up to 48 qubits only using an 8+1 qubit quantum hardware. We demonstrate our scheme on the IBM quantum cloud, verifying its noise robustness and illustrating its potential for benchmarking large quantum processors with smaller ones.

Exercise effects on fatigue in breast cancer survivors after treatments: A systematic review and meta-analysis.

AIM: The aim of this study is to explore the effects of exercise interventions by type, duration and intensity of exercise for fatigue in breast cancer survivors who had completed their treatment. BACKGROUND: Most studies found that exercise has valuable outcomes for cancer survivors. This meta-analysis comprehensively summarizes the benefits of exercise intervention for fatigue in breast cancer patients who had completed their adjuvant treatments. METHODS: We conducted a meta-analysis on randomized control trials published during 1 January 2000 through 31 December 2019, from PubMed, Cochrane Library databases, EMBASE, Medline (ProQuest), CINAHL, PsycINFO, Chinese Electronic Periodical Service and Wan Fan Data with prespecified searching criteria. Breast cancer patients earlier than stage IIIc and completing adjuvant treatments were included, and the effects of exercise on fatigue were investigated. RESULTS: Nine randomized controlled trials (RCTs) were included (N = 581). Patients receiving exercise interventions showed reduced fatigue comparing with those without exercise. Exercise with low-moderate intensity, 20 min/day, three times per week and lasting up to 12 weeks had a significant effect on reducing fatigue for breast cancer survivors. CONCLUSION: Our study suggested that exercise interventions can reduce fatigue for this group of cancer survivors. The duration and intensity of exercise intervention could be prescribed for this specific group of cancer patients as a basic requirement to handle their reported fatigue.

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics.

With the widespread clinical use of drug combinations, the incidence of drug-drug interactions (DDI) has significantly increased, accompanied by a variety of adverse reactions. Drug transporters play an important role in the development of DDI by affecting the elimination process of drugs in vivo, especially in the pathological state. Tubulointerstitial fibrosis (TIF) is an inevitable pathway in the progression of chronic kidney disease (CKD) to end-stage renal disease. Here, the dynamic expression changes of eleven drug transporters in TIF kidney have been systematically investigated. Among them, the mRNA expressions of Oat1, Oat2, Oct1, Oct2, Oatp4C1 and Mate1 were down-regulated, while Oat3, Mrp2, Mrp4, Mdr1-α, Bcrp were up-regulated. Pearson correlation analysis was used to analyze the correlation between transporters and Creatinine (Cr), OCT2 and MATE1 showed a strong negative correlation with Cr. In contrast, Mdr1-α exhibited a strong positive correlation with Cr. In addition, the pharmacokinetics of cimetidine, ganciclovir, and digoxin, which were the classical substrates for OCT2, MATE1 and P-glycoprotein (P-gp), respectively, have been studied. These results reveal that changes in serum creatinine can indicate changes in drug transporters in the kidney, and thus affect the pharmacokinetics of its substrates, providing useful information for clinical use.

Investigate the improvement of facial skin texture with the VISIA system after total thyroidectomy.

BACKGROUND: During clinical practice we have noticed that some patients with hyperthyroidism have finer skin with less wrinkles, pores, and spots after thyroidectomy, and the improvement can be observed within a few weeks after the operation. However, there is no evidence or study in the literature to proof this finding. AIM AND OBJECTIVE: This study was designed to evaluate and quantify the skin characters of patients with hyperthyroidism before and after thyroidectomy. MATERIAL AND METHODS: This is a prospective study to include patients with hyperthyroidism who received total thyroidectomy between March 1st, 2018 and February 28th, 2019. The patients received blood test for T4 and TSH analysis and VISIA measurements for skin texture quantification, at the preoperative stage, three, and six months postoperatively. A total of 8 patients were included. Repeated measurement was used to determine the lab data and VISIA measurement changes before and after the operation. Mauchly's sphericity test was performed to determine whether the violation of sphericity occurs, and the Greenhouse-Geisser correction was used when the violation of sphericity occurs. RESULTS: All the patients were female and generally healthy without systemic medical disease except the hyperthyroidism. The T4 and TSH levels were not significantly different before and after the thyroidectomy. In terms of the skin character measurements, the wrinkles, texture, pores, UV spots, and brown spots were not improved after thyroidectomy. A trend of improvement in spots, red area, and porphyrin was noted, although not statistically significant. CONCLUSIONS: Surgical removal of the thyroid gland in patients with hyperthyroidism does not improve the skin quality and texture in examinations via the VISIA system.

Caffeic acid phenethyl ester suppresses androgen receptor signaling and stability via inhibition of phosphorylation on Ser81 and Ser213.

BACKGROUND: Androgen receptor (AR) plays important role in the development, progression, and metastasis of prostate cancer (PCa). Caffeic acid phenethyl ester (CAPE) is the main component of honey bee propolis. We determined if CAPE affects the signaling and stability of AR in PCa cells. METHODS: Effects of CAPE on AR transcriptional activity and localization were determined by reporter gene assay and immunofluorescent microscopy. Western blotting, fluorescent polarization, computer simulation, and animal experiment were performed to investigate the molecular mechanism how CAPE reduces the stability of AR. RESULTS: CAPE treatment dose-dependently suppressed the transcriptional activity of AR as well as the protein levels of AR and its target gene PSA. Cyclohexamide treatment revealed that androgen stabilized AR protein, but AR stability was diminished by CAPE. Fluorescence microscopy demonstrated that androgen promoted the nucleus translocation of AR in PCa cells, while treatment with CAPE reduced protein level of AR in both nucleus and cytoplasm. CAPE treatment suppressed the phosphorylation of Ser81 and Ser213 on AR, which regulates the stability of AR. CDK1 and AKT are the kinases phosphorylating Ser81 and Ser213 on AR, respectively. CAPE treatment significantly reduced the protein level and activity of CDK1 and AKT in PCa cells. Overexpression of CDK1 or AKT rescued the AR protein level under CAPE treatment. CONCLUSIONS: Our results suggested that CAPE treatment reduced AR stability and AR transcriptional activity in PCa cells, implying the possibility of using CAPE as a treatment for advanced PCa.

Caffeic Acid phenethyl ester is a potential therapeutic agent for oral cancer.

Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% of oral cancers are oral and oropharyngeal squamous cell carcinoma (OSCC). The overall five-year survival rate of OSCC patients is approximately 63%, which is due to the low response rate to current therapeutic drugs. In this review we discuss the possibility of using caffeic acid phenethyl ester (CAPE) as an alternative treatment for oral cancer. CAPE is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment can effectively suppress the proliferation, survival, and metastasis of oral cancer cells. CAPE treatment inhibits Akt signaling, cell cycle regulatory proteins, NF-κB function, as well as activity of matrix metalloproteinase (MMPs), epidermal growth factor receptor (EGFR), and Cyclooxygenase-2 (COX-2). Therefore, CAPE treatment induces cell cycle arrest and apoptosis in oral cancer cells. According to the evidence that aberrations in the EGFR/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling, NF-κB function, COX-2 activity, and MMPs activity are frequently found in oral cancers, and that the phosphorylation of Akt, EGFR, and COX-2 correlates to oral cancer patient survival and clinical progression, we believe that CAPE treatment will be useful for treatment of advanced oral cancer patients.

Micro- and nano-hybrid cellulose fibers prepared by straightforward and high-efficiency hot water soaking-assisted colloid grinding for high-performance cellulose paper.

Micro- and nano-hybrid cellulose fiber (MNCF) stands out as a versatile cellulosic nanomaterial with promising applications in various fields owing to its excellent intrinsic nature and outstanding characteristics. However, the inefficiency in preparing MNCF, attributed to a complex multi-step processing, hinders its widespread adoption. In this study, a straightforward and highly efficient method for MNCF preparation was developed via a hot water soaking-assisted colloid grinding strategy. Active water molecules in hot water facilitating stronger transverse shrinkage and longitudinal expansion in fiber crystallized region, and thus improving the fibrillation degree of cellulose fibers. As a result, MNCFs with a mean diameter of 37.5 ± 22.2 nm and high concentration (2 wt%) were successfully achieved though pure mechanical method. The micro and nano-hybrid structure leads to the corresponding resulting cellulose paper with micro- and nano-hybrid structure possesses a compact stacking and fewer defects, leading to extraordinary mechanical properties including tensile strength of 204.5 MPa, Young's modulus of 6.3 GPa and elongation of 10.1 %. This work achieves significant progress towards straightforward and highly efficient production of MNCFs, offering an appreciable prospect for the development of multifunctional MNCF-based materials.

Mechanically strong micro-nano fibrillated cellulose paper with improved barrier and water-resistant properties for replacing plastic.

Replacing nonbiodegradable plastics with environmentally friendly cellulose materials has emerged as a key trend in environmental protection. This study highlights the development of a strong and hydrophobic micro-nano fibrillated cellulose paper (MNP) through the incorporation of micro-nano fibrillated cellulose fiber (MNF) and chitin nanocrystal (Ch), followed by the impregnation of polymethylsiloxane (PMHS). A low-acid, heat-assisted colloidal grinding strategy was employed to prepare MNF with a high aspect ratio effectively. Ch was incorporated as a reinforcing matrix into the cellulose fiber scaffold through straightforward mechanical mixing and mechanical hot-pressing treatments. Compared to pure MNP, the 5Ch-MNP exhibited a 25 % improvement in tensile strength, reaching 170 MPa, and showed enhanced barrier properties against oxygen and water vapor. The impregnation of PMHS rapidly confers environmentally resistant hydrophobic properties to 1 % PMHS-5Ch-MNP, leading to a water contact angle exceeding 112°, and a 290 % increase in tensile strength under wet conditions. Additionally, the paper demonstrated excellent antibacterial adhesion properties, with the adhesion rates for E. coli and S. aureus exceeding 98 %. This study successfully produced functional cellulose paper with remarkable mechanical properties and barrier properties, as well as hydrophobicity, using a simple, efficient, and environmentally friendly method, making it a promising substitute for petroleum-based plastics.

In Vitro Activitiy of Rezafungin in Comparison with Anidulafungin and Caspofungin against Invasive Fungal Isolates (2017 to 2022) in China.

The efficacy of different echinocandins is assessed by evaluating the in vitro activity of a novel antifungal, rezafungin, against invasive fungal isolates in comparison with anidulafungin and caspofungin. Using the broth microdilution (BMD) method, the susceptibility of 1000 clinical Candida isolates (including 400 C. albicans, 200 C. glabrata, 200 C. parapsilosis, 150 C. tropicalis and 50 C. krusei) and 150 Aspergillus isolates (100 A. fumigatus and 50 A. flavus) from the Eastern China Invasive Fungi Infection Group (ECIFIG) was tested for the antifungals including anidulafungin, rezafungin, caspofungin and fluconazole. The echinocandins showed strong activity against C. albicans that was maintained against fluconazole-resistant isolates. The GM MIC (geometric mean minimum inhibitory concentration) value of rezafungin was found to be comparable to that of anidulafungin or caspofungin against the five tested common Candida species. C. tropicalis exhibited higher resistance rates (about 8.67-40.67% in different antifungals) than the other four Candida species. Through the sequencing of FKS genes, we searched for mutations in echinocandin-resistant C. tropicalis isolates and found that all displayed alterations in FKS1 S654P. The determined MEC (minimal effective concentration) values against A. fumigatus and A. flavus for rezafungin (0.116 µg/mL, 0.110 µg/mL) are comparable to those of caspofungin (0.122 µg/mL, 0.142 µg/mL) but higher than for anidulafungin (0.064 µg/mL, 0.059 µg/mL). Thus, the in vitro activity of rezafungin appears comparable to anidulafungin and caspofungin against most common Candida and Aspergillus species. Rezafungin showed higher susceptibility rates against C. glabrata. Rezafungin indicates its potent activity for potential clinical application.

Design, Synthesis and Anti-cancer Evaluation of Nitrogen-containing Derivatives of 30-Carboxyl of Gambogic Acid.

BACKGROUND: Gambogic acid (GA) is a natural product from the resin of the Garcinia species, which showed significant activity in the induction of apoptosis. .t can be one promising lead compound for the design and synthesis of new anticancer drugs. OBJECTIVE: The objective of the current study is to design novel nitrogen-contained GA derivatives with better anti-cancer activities and study the effect of the introduction of different nitrogen-contained groups on the activity of GA. METHODS: The designed 15 derivatives were synthesized via esterification or amidation of 30-carboxylate. The synthetic compounds were characterized via different spectroscopic techniques, including X-ray single crystal diffraction, MS and NMR. The cytotoxic activity of the designed derivatives was evaluated in vitro against A549, HepG-2, and MCF-7 cell lines using methyl thiazolyl tetrazolium (MTT) test. RESULTS: 15 nitrogen-contained GA derivatives were successfully synthesized and established. Based on the IC50 values, compounds 9, 10, 11 and 13 showed stronger inhibitory effects on A549, HepG-2, MCF-7 cell lines than GA, while 9 is the most active compound with IC50 value of 0.64-1.49 µM. Most derivatives of GA with esterification of C-30 including cyano-benzene ring were generally weaker than those of pyrimidinyl-substituted derivatives. In addition, length of alkyl linkers between C-30 of GA and nitrogen-contained group produced different effects on A549, HepG-2 and MCF-7 cell lines. CONCLUSION: The structure-activity relationship results show that aromatic substituent and linker length play important roles to improve the anticancer activities, while compound 9 with pyrimidine substituent and C-C-C linkers is the most active derivative against tested cell lines, and is a promising anti-cancer agent for further development.

Variability in competitive fitness among environmental and clinical azole-resistant Aspergillus fumigatus isolates.

Azoles are the primary antifungal drugs used to treat infections caused by Aspergillus fumigatus. However, the emergence of azole resistance in A. fumigatus has become a global health concern despite the low proportion of resistant isolates in natural populations. In bacteria, antibiotic resistance incurs a fitness cost that renders strains less competitive in the absence of antibiotics. Consequently, fitness cost is a key determinant of the spread of resistant mutations. However, the cost of azole resistance and its underlying causes in A. fumigatus remain poorly understood. In this observation, we revealed that the 10 out of 15 screened azole-resistant isolates, which possessed the most common azole-targeted cyp51A mutations, particularly the presence of tandem repeats in the promoter region, exhibit fitness cost when competing with the susceptible isolates in azole-free environments. These results suggest that fitness cost may significantly influence the dynamics of azole resistance, which ultimately contributes to the low prevalence of azole-resistant A. fumigatus isolates in the environment and clinic. By constructing in situ cyp51A mutations in a parental azole-susceptible strain and reintroducing the wild-type cyp51A gene into the azole-resistant strains, we demonstrated that fitness cost is not directly dependent on cyp51A mutations but is instead associated with the evolution of variable mutations related to conidial germination or other unknown development-related processes. Importantly, our observations unexpectedly revealed that some azole-resistant isolates showed no detectable fitness cost, and some even exhibited significantly increased competitive fitness in azole-free environments, highlighting the potential risk associated with the prevalence of these isolates. IMPORTANCE: Azole resistance in the human fungal pathogen Aspergillus fumigatus presents a global public health challenge. Understanding the epidemic trends and evolutionary patterns of azole resistance is critical to prevent and control the spread of azole-resistant isolates. The primary cause is the mutation of the drug target 14α-sterol-demethylase Cyp51A, yet its impact on competitive ability remains uncertain. Our competition assays revealed a diverse range of fitness outcomes for environmental and clinical cyp51A-mutated isolates. We have shown that this fitness cost is not reliant on cyp51A mutations but might be linked to unknown mutations induced by stress conditions. Among these isolates, the majority displayed fitness costs, while a few displayed enhanced competitive ability, which may have a potential risk of spread and the need to closely monitor these isolates. Our observation reveals the variation in fitness costs among azole-resistant isolates of A. fumigatus, highlighting the significant role of fitness cost in the spread of resistant strains.

Follicle-stimulating hormone accelerates osteoclast migration by enhancing methyltransferase-like 3-mediated m6A methylation of cathepsin K.

Follicle-stimulating hormone (FSH) accelerates osteoporosis in postmenopausal women, while the underlying mechanism remains uncharacterized. N6-methyladenosine (m6A) is one of the most important regulations in the development of osteoporosis. In this study, we aimed to investigate the role of FSH in m6A modification and osteoclast function. Here, we showed that FSH upregulated m6A levels in osteoclasts via stimulating methyltransferase-like 3 (METTL3) protein expression. FSH enhanced osteoclast migration, while the knockdown of METTL3 eliminated this enhancement. Both MeRIP-seq and RNA sequencing identified that cathepsin K (CTSK) is the potential downstream target of METTL3. Knockdown of CTSK reduced FSH-upregulated osteoclast migration. Furthermore, silencing METTL3 decreased CTSK mRNA stability. Finally, FSH induced phosphorylation of cyclic-AMP response element-binding protein (CREB), while silencing of CREB attenuated the effects of FSH on the promoter transcriptional activity of Mettl3 and CTSK/METTL3 protein. Taken together, these findings indicate that FSH promotes osteoclast migration via the CREB/METTL3/CTSK signaling pathway, which may provide a potential target for suppressing osteoclast mobility and postmenopausal osteoporosis therapy.

Analytical and clinical validation of multiplex droplet digital PCR assay for detecting pathogenic fungal infection in lungs.

Pulmonary invasive fungal infection in immunocompromised hosts is difficult to diagnose, and current tools for diagnosis or monitoring of response to antifungal treatments have inherent limitations. Droplet digital PCR (ddPCR) has emerged as a promising tool for pulmonary pathogen detection with high sensitivity. This study presents a novel ddPCR panel for rapid and sensitive identification of pulmonary fungal pathogens. First, a ddPCR method for detecting three fungal genera, including Pneumocystis, Aspergillus, and Cryptococcus, was established and evaluated. Then, the clinical validation performance of ddPCR was compared with that of qPCR using 170 specimens, and the 6 specimens with inconsistent results were further verified by metagenomics next-generation sequencing, which yielded results consistent with the ddPCR findings. Finally, the area under the ROC curve (AUC) was used to evaluate the efficiency of ddPCR. While the qPCR identified 16 (9.41%) cases of Aspergillus and 6 (3.53%) cases of Pneumocystis, ddPCR detected 20 (11.76%) Aspergillus cases and 8 (4.71%) Pneumocystis cases. The AUC for Aspergillus, Cryptococcus, and Pneumocystis was 0.974, 0.998, and 0.975, respectively. These findings demonstrated that the ddPCR assay is a highly sensitive method for identifying pathogens responsible for invasive fungal pulmonary infections, and is a promising tool for early diagnosis. .

FSH induces EMT in ovarian cancer via ALKBH5-regulated Snail m6A demethylation.

Background: The therapeutic benefits of targeting follicle-stimulating hormone (FSH) receptor in treatment of ovarian cancer are significant, whereas the role of FSH in ovarian cancer progresses and the underlying mechanism remains to be developed. Methods: Tissue microarray of human ovarian cancer, tumor xenograft mouse model, and in vitro cell culture were used to investigate the role of FSH in ovarian carcinogenesis. siRNA, lentivirus and inhibitors were used to trigger the inactivation of genes, and plasmids were used to increase transcription of genes. Specifically, pathological characteristic was assessed by histology and immunohistochemistry (IHC), while signaling pathway was studied using western blot, quantitative RT-PCR, and immunofluorescence. Results: Histology and IHC of human normal ovarian and tumor tissue confirmed the association between FSH and Snail in ovarian cancer metastasis. Moreover, in epithelial ovarian cancer cells and xenograft mice, FSH was showed to promote epithelial mesenchymal transition (EMT) progress and metastasis of ovarian cancer via prolonging the half-life of Snail mRNA in a N6-methyladenine methylation (m6A) dependent manner, which was mechanistically through the CREB/ALKBH5 signaling pathway. Conclusions: These findings indicated that FSH induces EMT progression and ovarian cancer metastasis via CREB/ALKBH5/Snail pathway. Thus, this study provided new insight into the therapeutic strategy of ovarian cancer patients with high level of FSH.

Caffeic Acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling.

Prostate cancer is the fifth most common cancer overall in the world. Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, most prostate cancer patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant tumors within 1-3 years after treatment. The median overall survival time is 1-2 years after tumor relapse. Chemotherapy shows little effect on prolonging survival for patients with metastatic hormone-refractory prostate cancer. More than 80% of prostate tumors acquire mutation or deletion of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling, indicating that inhibition of PI3K/Akt might be a potential therapy for advanced prostate tumors. Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honeybee hive propolis. CAPE is a well-known NF-κB inhibitor. CAPE has been used in folk medicine as a potent anti-inflammatory agent. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells. We discuss the potential of using CAPE as a treatment for patients with advanced prostate cancer targeting Akt signaling pathway in this review article.