Thyroid Metastases from Triple-Negative Breast Cancer with High PD-L1 Expression - A Rare Presentation.

Thyroid metastases secondary to triple-negative breast cancer are sporadic. Diagnosis usually requires fine needle aspiration biopsy (FNAB) and immunohistochemistry. There are no treatment guidelines for this type of cancer, and to date, reports of chemotherapy combined with immunotherapy in thyroid metastases are very rare. Here, we first report the effectiveness of anti-PD-1 inhibitor in combination with chemotherapy for the treatment of metastatic thyroid cancer secondary to advanced triple-negative breast cancer with high expression of programmed cell death ligand 1 (PD-L1). Following six cycles of albumin paclitaxel (400mg d1/21 days) plus PD-1 antibody inhibitor (Sindilizumab 200mg d1/21 days), the patient experienced significant relief of neck swelling and obstructive feeding, both the thyroid metastases and the right breast lesion regressed completely following six cycles of treatment. Chemotherapy combined with immunotherapy may provide a new direction for unresectable advanced thyroid metastases.

Novel chlorin e6-based conjugates of tyrosine kinase inhibitors: Synthesis and photobiological evaluation as potent photosensitizers for photodynamic therapy.

Since tyrosine kinase inhibitor (TKI) could reverse ABCG2-mediated drug-resistance, novel chlorin e6-based conjugates of Dasatinib and Imatinib as photosensitizer (PS) were designed and synthesized. The results demonstrated that conjugate 10b showed strongest phototoxicity against HepG2 and B16-F10 cells, which was more phototoxic than chlorin e6 and Talaporfin. It could reduce efflux of intracellular PS by inhibiting ABCG2 in HepG2 cells, and localize in mitochondria, lysosomes, golgi and ER, resulting in higher cell apoptosis rate and ROS production than Talaporfin. Moreover, it could induce cell autophagy and block cell cycle in S phase, and significantly inhibit tumor growth and prolong survival time on BALB/c nude mice bearing HepG2 xenograft tumor to a greater extent than chlorin e6. Consequently, compound 10b could be applied as a promising candidate PS due to its good water-solubility and stability, low drug-resistance, high quantum yield of 1O2 and excellent antitumor efficacy in vitro and in vivo.

Correlation between serum Dickkopf-1 (DKK1) levels and coronary artery stenosis.

BACKGROUND AND AIMS: To study the correlation between the level of serum Dickkopf-1 (DKK1) and the degree of coronary artery stenosis in patients with coronary atherosclerotic heart disease. METHODS AND RESULTS: In 2018, general data and biochemical indexes of 311 patients who underwent coronary angiography were recorded. Before procedure, arterial blood was drawn and the concentrations of DKK1, retinol binding protein 4 (RBP4), plasminogen activator inhibitor (PAI-1) were measured. Based on coronary angiography results, subjects were divided into a coronary heart disease (CHD) group; and a non-coronary heart disease (non-CHD)group. The CHD group was divided into three subgroups: the low Gensini score; the middle Gensini score; and the high Gensini score subgroups. Compared with those of the non-CHD group, DKK1, RBP4 and PAI-1 of the CHD group were significantly higher, while the OC was lower. DKK1,RBP4 and PAI-1 levels of the middle and high Gensini subgroups were significantly higher, compared with that of the low Gensini subgroup. Differences between osteocalcin (OC), beta-isomerized C-terminal telopeptidase (ß-CTX), and 25(OH)2D3 of the three subgroups were not significant. Correlation between DKK1 and the inflammatory factors, RBP4 and PAI-1, was positive. Correlation between DKK1 and ß - CTX, 25(OH)2D3 and OC was not significant. DKK1 was a risk factor for CHD. The degree of coronary artery stenosis was related to DKK1 concentration. CONCLUSIONS: Serum DKK1 levels in coronary heart disease patients were significantly higher, and positively correlated with the degree of coronary artery stenosis. DKK1 level is an independent risk factor for coronary heart disease.

25-hydroxyvitamin D levels are inversely related to metabolic syndrome risk profile in northern Chinese subjects without vitamin D supplementation.

BACKGROUND: The comparatively low 25 hydroxyvitamin D [25(OH)D] levels have been reported in patients with metabolic syndrome (MetS). Herein we investigated the cross-sectional and longitudinal relationships between serum 25(OH)D levels and MetS risk profile in northern middle-aged Chinese subjects without vitamin D supplementation. METHODS: A cohort of 211 participants including 151 MetS patients and 60 controls at 20-69 years of age were enrolled from suburban Beijing, China. The recruited MetS patients were subjected to diet and exercise counselling for 1-year. All subjects at baseline and MetS patients after intervention underwent clinical evaluations. RESULTS: Serum 25(OH)D levels were significantly decreased in MetS patients. 25(OH)D levels were inversely related to MetS score, fasting blood glucose (FBG) and triglyceride-glucose index (TyG) after adjusting for cofounders (all P < 0.05). Participants in the lowest tertile of 25(OH)D levels had increased odds for MetS (P = 0.045), elevated FBG (P = 0.004) in all subjects, and one MetS score gain in MetS patients (P = 0.005). Longitudinally, the metabolic statuses as well as 25(OH)D levels of MetS patients were significantly improved (all P < 0.05), and the increase of 25(OH)D levels were inversely related to MetS scores, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), FBG, and TyG, while positively related to high-density lipoprotein cholesterol (HDL-C) after adjusting for confounders. CONCLUSIONS: 25(OH)D levels were significantly decreased in MetS patients, and it was negatively associated with metabolic dysfunctions at baseline and 1-year after. Metabolic aberrations of MetS patients were significantly ameliorated with 1-year follow-up counselling accompanying by notably elevated 25(OH)D levels.

Heat shock protein 90 (Hsp90)/Histone deacetylase (HDAC) dual inhibitors for the treatment of azoles-resistant Candida albicans.

Clinical treatment of candidiasis has suffered from increasingly severe drug resistance and limited efficacy. Thus, novel strategies to deal with drug resistance are highly desired to develop effective therapeutic agents. Herein, dual inhibition of heat shock protein 90 (Hsp90) and histone deacetylase (HDAC) was validated as a new strategy to potentiate efficacy of fluconazole against resistant Candida albicans infections. The first generation of Hsp90/HDAC dual inhibitors were designed as synergistic enhancers to treat azoles-resistant candidiasis. In particular, compound J5 exhibited fungal-selective inhibitory effects on Hsp90 and HDACs, leading to low toxicity and excellent in vitro (FICI = 0.266) and in vivo synergistic antifungal potency to treat fluconazole resistant candidiasis. Antifungal-mechanistic investigation revealed that compound J5 suppressed important virulence factors and down-regulated expression of resistance-associated genes. Therefore, Hsp90/HDAC dual inhibitors represent a new strategy for the development of novel antifungal therapeutics to combat azole-resistant candidiasis.

Bone Metastases of Glioblastoma: A Case Report and Review of the Literature.

BACKGROUND: Glioblastoma (GBM) is the most common primary intracranial tumor and originates from the small pool of adult neural stem and progenitor cells (NSPCs). According to the World Health Organization (WHO) classification of brain tumors, gliomas are classified into grades I-IV, and GBM is defined as the highest grade (IV). GBM can be disseminated by cerebrospinal fluid (CSF), but extracranial metastasis is rare. Additionally, the pathway and mechanism involved remain unclear. CASE PRESENTATION: We report a rare case of left temporal lobe GBM with multiple bone metastases and soft tissue metastasis. This 49-year-old right-handed man who was diagnosed with GBM underwent surgery on May 9, 2017, followed by radiochemotherapy in June 2017. On August 13, 2019, local relapse was found. Then, the patient received a second surgery but not radiochemotherapy. In November 2019, the patient was reported to be suffering from low back pain for nearly 1 month. On December 6, 2019, magnetic resonance imaging (MRI) of the thoracolumbar vertebrae and abdominal computed tomography (CT) confirmed metastases on the ninth posterior rib on the right, the third anterior rib on the left, and the T7 and T10 vertebrae and their appendages. CT-guided rib space-occupying puncture biopsy was performed, and GBM was identified by pathology. CONCLUSION: We should pay attention to extracranial metastasis of GBM. Timely detection and early treatment improve overall quality of patients' life. The extracranial metastasis in this patient may have occurred through the spinal nerve root or intercostal nerve. Further clinical observations are required to clarify the pathway and mechanism involved.

Dural and Multiple Brain Metastases From Basaloid Nasopharyngeal Carcinoma: Case Report and Literature Review.

BACKGROUND: Nasopharyngeal carcinoma is an endemic head and neck cancer in Southern China. The common metastases organs involve bone, lung, and liver. Metastases in the dura and at multiple locations in the brain after a diagnosis of nasopharyngeal carcinoma are extremely rare. CASE PRESENTATION: We present a case of a 66-year-old man who initially complained of nasal congestion, epistaxis, and hearing impairment. The biopsy of the nasopharynx lesion showed basaloid squamous cell carcinoma. Eight months after conventional therapy, the patient was admitted to our hospital again with the complaint of a headache. A PET/CT scan was performed, revealing multiple metastases. A biopsy of subcutaneous soft tissue from the right upper arm was consistent with the previous biopsy. Palliative chemotherapy was administered. Thereafter, the patient had sudden dysfunction of the right side of the body. MRI demonstrated dural and multiple brain metastases. The therapeutic regimen then consisted of whole-brain radiotherapy, anti-angiogenesis therapy, and immunotherapy. CONCLUSIONS: This case highlights the diagnosis and treatment of uncommon metastases of nasopharyngeal carcinoma. Clinicians should remain vigilant for metastases during the treatment and follow-up periods.

Novel dual-mode antitumor chlorin-based derivatives as potent photosensitizers and histone deacetylase inhibitors for photodynamic therapy and chemotherapy.

The combination of photodynamic therapy (PDT) and chemotherapy is a prospective strategy to improve antitumor efficacy. Herein, a series of novel cytotoxic chlorin-based derivatives as dual photosensitizers (PSs) and histone deacetylase inhibitors (HDACIs) were synthesized and investigated for biological activity. Among them, compound 15e showed definite HDAC2 and 10 inhibitory activities by up-regulating expression of acetyl-H4 and highest phototoxicity and dark-toxicity, which was more phototoxic than Talaporfin as a PS while with stronger dark-toxicity compared to vorinostat (SAHA) as a HDACI. The biological assays demonstrated that 15e was liable to enter A549 cells and localized in mitochondria, lysosomes, golgi and endoplasmic reticulum (ER) etc. multiple organelles, resulting in higher cell apoptosis rate and ROS production compared to Talaporfin. Moreover, it could induce tumor cell autophagy as a dual PS and HDACI. All results suggested that compound 15e could be applied as a potential dual cytotoxic drug for PDT and chemotherapy.

Discovery of Piperidol Derivatives for Combinational Treatment of Azole-Resistant Candidiasis.

Effective strategies are needed to deal with invasive fungal infections caused by drug-resistant fungi. Previously, we designed a series of antifungal benzocyclane derivatives based on the drug repurposing of haloperidol. Herein, further structural optimization and antifungal mechanism studies were performed, leading to the discovery of new piperidol derivative B2 with improved synergistic antifungal potency, selectivity, and water solubility. In particular, the combination of compound B2 and fluconazole showed potent in vitro and in vivo antifungal activity against azole-resistant Candida albicans. Compound B2 inhibited important virulence factors by regulating virulence-associated genes and improved the efficacy of fluconazole by down-regulating the CYP51-coding gene and efflux pump gene. Taken together, the piperidol derivative B2 represents a promising lead compound for the combinational treatment of azole-resistant candidiasis.

Novel Carboline Fungal Histone Deacetylase (HDAC) Inhibitors for Combinational Treatment of Azole-Resistant Candidiasis.

Due to the evolution and development of antifungal drug resistance, limited efficacy of existing drugs has led to high mortality in patients with serious fungal infections. To develop novel antifungal therapeutic strategies, herein a series of carboline fungal histone deacetylase (HDAC) inhibitors were designed and synthesized, which had potent synergistic effects with fluconazole against resistant Candida albicans infection. In particular, compound D12 showed excellent in vitro and in vivo synergistic antifungal efficacy with fluconazole to treat azole-resistant candidiasis. It cooperated with fluconazole in reducing the virulence of C. albicans by blocking morphological mutual transformation and inhibiting biofilm formation. Mechanism studies revealed that the reversion of drug resistance was due to downregulation of the expression of the azole target gene ERG11 and efflux gene CDR1. Taken together, fungal HDAC inhibitor D12 offered a promising lead compound for combinational treatment of azole-resistant candidiasis.

A Potential Predictive Biomarker for Miller/Payne Grading: PD-L1 Expression before Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the value of programmed death ligand 1 (PD-L1) expression as a predictive biomarker for Miller/Payne grading before neoadjuvant chemotherapy (NACT) in breast cancer. PATIENTS AND METHODS: The expression of PD-L1 in pretreatment biopsies of breast cancer was assessed by immunohistochemistry in tissue microarrays. The results were analyzed using SPSS 22.0 statistical software. RESULTS: Of 53 female patients, 10 (18.9%) patients had a grade 5 (G5) response, and 12 (22.6%) patients showed PD-L1 expression, including 7 (13.2%) patients with staining in tumor cells (TCs) and 8 (15.1%) patients with staining in peritumoral lymphocytes (PTLCs). Logistic regression analysis revealed that G5 response to NACT was significantly associated with TCs or PTLCs PD-L1 positivity, whether with univariate analysis (TCs PD-L1: p = 0.00, OR 20.50, 95% CI 3.11-134.94; PTLCs PD-L1: p = 0.02, OR 6.50, 95% CI 1.27-33.20) or with multivariate analysis (TCs PD-L1: p = 0.00, OR 42.23, 95% CI 3.36-530.90; PTLCs PD-L1: p = 0.02, OR 9.07, 95% CI 1.37-60.02). The same trend was found in the luminal subgroup analysis (TCs PD-L1: p = 0.02, OR 23.43, 95% CI 1.66-331.58; PTLCs PD-L1: p = 0.01, OR 47.89, 95% CI 2.47-927.41). CONCLUSION: G5 response to NACT in breast cancer was significantly associated with TCs or PTLCs PD-L1-positive expression in pretreatment biopsies; it can be expected that PD-L1 will become a new independent biomarker of response to NACT in breast cancer.

Design, synthesis and biological evaluation of novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives as potent photosensitizers for photodynamic therapy.

This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e6, a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives 3a, 3b, 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16-F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16-F10 cells. Apparently, simultaneous introduction of amino acid residue and n-hexyloxy chain in chlorin e6 made a significant improvement in photophysical properties, ROS production, in vitro and in vivo PDT efficacy. Encouragingly, all target compounds showed higher in vitro phototoxicity than Talaporfin, and that 3c (152-Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (131-Asp), 3a (152-Asp) and 3b (152-Glu). Moreover, in vivo PDT antitumor efficacy of 3a, 3c and 8 was all better than that of Talaporfin, and that both 3c and 8 had stronger PDT antitumor efficiency than 3a. The overall results suggested that these novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives, especially 3c and 8, might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT.

Targeting fungal virulence factor by small molecules: Structure-based discovery of novel secreted aspartic protease 2 (SAP2) inhibitors.

Secreted aspartic protease 2 (SAP2), a kind of virulence factor, is an emerging new antifungal target. Using docking-based virtual screening and structure-based inhibitor design, a series of novel SAP2 inhibitors were successfully identified. Among them, indolone derivative 24a showed potent SAP2 inhibitory activity (IC50 = 0.92 µM). It blocked fungi biofilm and hypha formation by down-regulating the expression of genes SAP2, ECE1, ALS3 and EFG1. As a virulence factor inhibitor, compound 24a was inactive in vitro and showed potent in vivo efficacy in a murine model of invasive candidiasis. It represents a promising lead compound for the discovery of novel antifungal agents.

Discovery of Novel Fungal Lanosterol 14α-Demethylase (CYP51)/Histone Deacetylase Dual Inhibitors to Treat Azole-Resistant Candidiasis.

Invasive fungal infections (particularly candidiasis) are emerging as severe infectious diseases worldwide. Because of serious antifungal drug resistance, therapeutic efficacy of the current treatment for candidiasis is limited and associated with high mortality. However, it is highly challenging to develop novel strategies and effective therapeutic agents to combat drug resistance. Herein, the first generation of lanosterol 14α-demethylase (CYP51)-histone deacetylase (HDAC) dual inhibitors was designed, which exhibited potent antifungal activity against azole-resistant clinical isolates. In particular, compounds 12h and 15j were highly active both in vitro and in vivo to treat azole-resistant candidiasis. Antifungal mechanism studies revealed that they acted by blocking ergosterol biosynthesis and HDAC catalytic activity in fungus, suppressing the function of efflux pump, yeast-to-hypha morphological transition, and biofilm formation. Therefore, CYP51-HDAC dual inhibitors represent a promising strategy to develop novel antifungal agents against azole-resistant candidiasis.

Overexpression of LncRNA BM466146 Predicts Better Prognosis of Breast Cancer.

This study analyzes the expression and clinical significance of long non-coding RNA (lncRNA) BM466146 in breast cancer, and explores the role of BM466146 in immune regulation. The expression of BM466146 in 89 cases of breast cancer and their corresponding non-cancerous breast tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis was applied to evaluate patient survival. EDU and CCK-8 experiments on breast cancer cells were performed to verify the function of BM466146 in vitro. The target genes of BM466146 were screened by informatics analysis to predict associated miRNAs and their corresponding mRNAs, immune genes associated with lncRNAs and chemokines associated with CD8. Immunohistochemistry was used to detect the expression of CD8, Ki-67, and CXCL-13 in the 89 breast cancer tissues. It was found that the expression of lncRNA BM466146 in breast cancer tissues was significantly lower than that in normal breast tissues (P < 0.001). In breast cancer, tissues that overexpressed BM466146 exhibited a lower Ki-67 index compared with that of low BM466146 expression (P = 0.048). Kaplan-Meier survival analysis showed that breast cancer patients with overexpression of BM466146 had longer overall survival. EDU and CCK8 experiments showed that overexpression of BM466146 inhibited the proliferation of breast cancer cells. The hsa-miR-224-3p is associated with BM466146, and its target gene might be CXCL-13. The positive CD8 cells in the BM466146 overexpression group was higher than that in the low BM466146 expression group (P=0.027), and the positive CD8 cells in the CXCL-13 positive group was higher (P=0.023) than that of the negative group. Our results indicate that the lncRNA BM466146 has the function of tumor suppressor gene. Overexpression of BM466146 is associated with better prognosis. BM466146 could regulate CXCL-13 by adsorbing hsa-miR-224-3p and inducing CD8+ T cells to accumulate in the tumor area which regulate immune response. Therefore, BM466146 could be a prognostic biomarker and a molecular immune target of breast cancer.

Huidouba Improved Podocyte Injury by Down-Regulating Nox4 Expression in Rats With Diabetic Nephropathy.

Diabetic nephropathy (DN), as the most common microvascular complication of diabetes mellitus (DM), has become one of the leading causes of end-stage renal disease (ESRD). Numerous studies have indicated that podocyte loss plays an important role in the development of DN and can even cause proteinuria in the early stage of DN. In the study, we found that Huidouba (HDB) significantly decreased the level of fasting blood glucose (FBG), the ratio of microalbumin to urine creatine (mAlb/Ucr), serum creatine (Scr), serum urea nitrogen (BUN), and malondialdehyde (MDA) in the kidney and downregulated the expression of Nox4 predominantly located in glomerular tissue while upregulating nephrin and WT1 expression in DN rats. In addition, HDB could also reduce podocyte damage and glomerular basement membrane (GBM) pathologic changes, as shown by transmission electron microscopy (TEM). In vitro study showed that HDB could inhibit high glucose (HG)-induced Reactive Oxygen Species (ROS) production and protect against podocyte apoptosis by downregulated Nox4 expression in podocytes. These results may provide a scientific basis for developing HDB as a potential folk medicine for the treatment of DN.

Drug Repurposing of Haloperidol: Discovery of New Benzocyclane Derivatives as Potent Antifungal Agents against Cryptococcosis and Candidiasis.

Despite the high morbidity and mortality of invasive fungal infections (IFIs), effective and safe antifungal agents are rather limited. Starting from antifungal lead compound haloperidol that was identified by drug repurposing, a series of novel benzocyclane derivatives were designed, synthesized, and assayed. Several compounds showed improved antifungal potency and broader antifungal spectra. Particularly, compound B10 showed good inhibitory activities against a variety of fungal pathogens and was proven to be an inhibitor of several virulence factors important for drug resistance. In the in vivo cryptococcosis and candidiasis models, compound B10 could effectively reduce the brain fungal burden of Cryptococcus neoformans and synergize with fluconazole to treat resistant Candida albicans infections. Preliminary antifungal mechanism studies revealed that compound B10 regained cell membrane damage and down-regulated the overexpression of ERG11 and MDR1 genes when used in combination with fluconazole. Taken together, haloperidol derivative B10 represents a promising lead compound for the development of a new generation of antifungal agents.

Discovery of Simplified Sampangine Derivatives with Potent Antifungal Activities against Cryptococcal Meningitis.

Cryptococcal meningitis (CM) is associated with high morbidity and mortality. Current antifungal drug therapy for CM has the following challenges: limited efficacy, significant side effects, emerging drug resistance, and unavailability in highly needed countries. There is an urgent need to develop novel CM therapeutic agents with a new mode of action. On the basis of the antifungal natural product sampangine, herein, novel simplified isoxazole derivatives were identified to possess excellent inhibitory activity against Cryptococcus neoformans (C. neoformans). Particularly, compound 9a was highly active (the minimum inhibitory concentration of 80% inhibition, MIC80 = 0.031 µg/mL) and significantly inhibited biofilm formation, melanin, and urease production of C. neoformans. 9a had good blood-brain barrier (BBB) permeability and effectively reduced the brain fungal burden in a murine model of cryptococcosis. The antifungal mechanism of compound 9a was preliminarily investigated by transmission electron microscopy and flow cytometry. It was able to cause necrocytosis of C. neoformans cells and cell cycle arrest in the G1/S phase. Isoxazole compound 9a represents a promising lead compound for the development of novel CM therapeutic agents.

Discovery of Carboline Derivatives as Potent Antifungal Agents for the Treatment of Cryptococcal Meningitis.

Clinical treatment of cryptococcal meningitis (CM) remains a significant challenge because of the lack of effective and safe drug therapies. Developing novel CM therapeutic agents with novel chemical scaffolds and new modes of action is of great importance. Herein, new ß-hexahydrocarboline derivatives are shown to possess potent anticryptococcal activities. In particular, compound A4 showed potent in vitro and in vivo anticryptococcal activity with good metabolic stability and blood-brain barrier permeability. Compound A4 was orally active and could significantly reduce brain fungal burdens in a murine model of CM. Moreover, compound A4 could inhibit several virulence factors of Cryptococcus neoformans and might act by a new mode of action. Preliminary mechanistic studies revealed that compound A4 induced DNA double-stranded breaks and cell cycle arrest at the G2 phase by acting on the Cdc25c/CDK1/cyclin B pathway. Taken together, ß-hexahydrocarboline A4 represents a promising lead compound for the development of next-generation CM therapeutic agents.