Real-world experience quantifying access to JAK inhibitor care for alopecia areata patients: a patient-centered survey study.

Background: Janus kinase inhibitor (JAKi) therapy has revolutionized the treatment landscape for alopecia areata (AA); however, access may be limited by a lack of insurance coverage and high out-of-pocket costs. Objective: We aimed to evaluate real-world patient experiences regarding access to JAKi therapy. Methods: We conducted an online patient-centered survey using the National Alopecia Areata Foundation listserv. Results: In total 784 individuals initiated our survey, and 600 completed it in full (76.5%). While more non-White patients considered obtaining JAKi therapy, more White patients reported the use of this medication class. In total, 74.2% lacked insurance coverage or had partial coverage for JAKi, and 52% expressed dissatisfaction with available coverage. However, 52.9% reported delays in starting medication due to insurance approval processes, contributing to worsened AA and related stress. In total, 35% of patients did not try to obtain JAKi therapy due to concerns about costs, and 18.2% discontinued therapy due to financial barriers. Also, 19.8% of patients reported utilizing financial savings to pay for medication, and 55.2% reported using a copay assistance card. Further, 12.2% reported forgoing other necessities to pay for AA expenses. Limitations: Our results are limited by the subjective nature of survey studies. The recency of FDA approval for JAKi therapy may also influence patients' perceptions of access to care. Conclusion: Patients with AA face significant barriers when trying to obtain JAKi therapy, and existing racial inequities may be exacerbated by these barriers. Further advocacy work is needed to improve access to care.

Patient-Defined Goals and Preferences Among Adults With Advanced Neuroendocrine Tumors.

BACKGROUND: Patient preferences (quantity vs quality of life; present vs future health) have not been investigated in patients with neuroendocrine tumors (NETs). The goal of this cross-sectional study was to evaluate patient values toward treatment goals and competing health outcomes among adults with NETs. PATIENTS AND METHODS: Patients with well-differentiated, grade 1 or 2, advanced NETs starting a new systemic therapy completed 4 tools: (1) Health Outcomes Tool, which ranks the importance of 4 outcomes (survival, function/independence, freedom from pain, freedom from symptoms); (2) Attitude Scale, which identifies the extent to which patients agree with statements related to health outcomes; (3) Now versus Later Tool, which ranks the relative importance of quality of life (QoL) now versus 1 and 5 years from now; and (4) Prognosis and Treatment Perceptions Questionnaire, which identifies the amount of information the patient prefers to receive about their disease and treatment, the patient's treatment goal, the patient's perception of the physician's treatment goal, and self-reported health status. RESULTS: We recruited 60 patients with NETs (50.0% aged ≥65 years; 96.7% with stage IV disease). Primary tumor locations included the gastrointestinal tract (41.7%), pancreas (30.0%), and lung (21.7%). A plurality of patients reported maintaining independence as their most important health outcome (46.7%), followed by survival (30.0%), freedom from pain (11.7%), and freedom from symptoms (11.7%). A total of 67% of patients agreed with the statement, "I would rather live a shorter life than lose my ability to take care of myself"; 85.0% agreed with the statement, "It is more important to me to maintain my thinking ability than to live as long as possible." When asked to choose between current QoL versus QoL 1 year or 5 years in the future as more important, 48.3% and 40.0% of patients valued their QoL 1 year and 5 years in the future, respectively, more than their current QoL. Only 51.7% of patients believed their physician's treatment goals aligned with their own. CONCLUSIONS: Adult patients with NETs strongly value independence over survival. More communication between patients with NETs and their physicians is needed to ensure that patient preferences are incorporated into treatment plans.

Feasibility and Satisfaction of Using NET VITALS Self-assessment Tool Among Patients With Neuroendocrine Tumors.

OBJECTIVES: There is a lack of effective patient education regarding diagnosis/treatment of neuroendocrine tumors (NETs), possibly related to their rare incidence. METHODS: In this cross-sectional survey study, NET patients attending the 2019 Annual Los Angeles NET Education Conference were approached to complete NET VITALS, a self-assessment tool gauging patients' perception/awareness of their NET diagnosis/treatment, and a satisfaction survey. Feasibility of NET VITALS, patient satisfaction with NET VITALS, and patients' perception/awareness of their NET diagnosis/treatment were evaluated. RESULTS: This analysis included 68 patients (median age, 63 years; 47.1% gastrointestinal NETs; 88.2% metastatic disease). Participation was 88.3% (68/77), with a median of 85.7% of items completed (range, 61.9%-100.0%). More than 30% of the patients answered "Don't know/Not familiar"/left blank questions related to tumor characteristics, years of symptoms, and liver-directed therapies. In addition, 69.5% of the patients did not feel sufficient information about NETs was provided at diagnosis. Overall, 67.8% of the patients felt that NET VITALS provides topics to discuss with providers and 76.3% would recommend NET VITALS to others. CONCLUSIONS: NET VITALS is a feasible and acceptable self-assessment tool to potentially help patients improve communication about their NET diagnosis/treatment with their physician. Further studies will examine NET VITALS' generalizability and discuss its incorporation into clinical care.

Updates in Biliary Tract Cancers.

Biliary tract cancers (BTCs) are a heterogeneous group of malignancies arising from the epithelium of the biliary tree [...].

Pharmacotherapeutic Management of Well-Differentiated Neuroendocrine Tumors in Older Patients: Current Status and Potential Therapies.

Neuroendocrine tumors are a rare and heterogenous group of neoplasms that arise from hormone-producing cells throughout the body, with the greatest increase in incidence occurring among older adults aged ≥ 65 years. Despite this, there is currently a lack of data regarding the safety and efficacy of systemic treatment for older adults with neuroendocrine tumors. In this review, we provide a synopsis of the current standard-of-care pharmacotherapeutic treatments for neuroendocrine tumors, with an emphasis on available data in older adults. The benefits of various systemic options such as somatostatin analogs, tryptophan hydroxylase inhibition, molecular targeted agents, peptide receptor radionuclide therapy, and chemotherapy were similar between older adults compared to younger patients. However, real-world data regarding tolerance in the older adult population with neuroendocrine tumors are needed. Future development of novel systemic therapies in the neuroendocrine tumor treatment landscape and their inclusion of and potential impact on older adults living with neuroendocrine tumors is warranted.

Case Report: Pulmonary Metastases From Epithelioid Sarcoma in Extremity Favourably Responding to Immunotherapy With Camrelizumab.

Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS), with limited therapies available for metastatic disease. Here, we describe a case of a 30-year-old male with ES of the left knee and underwent surgery and radiation therapy for the primary disease. After 2 years, he had local recurrence and underwent extensive resection surgery; however, adjuvant chemotherapies were delayed due to recurrent wound infection. Nine months after the second surgery, progressive disease was confirmed after detection of metastases to the lungs and inguinal lymph nodes. Amputation was performed for the local recurrence, followed by inguinal lymph nodes dissection. Pazopanib was transiently administered but discontinued as a result of wound dehiscence. The tumour specimens were detected with unexpected high level of PD-L1 expression and tumoural infiltrating lymphocytes. Subsequently, he received camrelizumab 2.0 mg/kg every 21 days for 18 cycles with rapid remission of the pulmonary metastases. This promising response to camrelizumab indicates that immunotherapies may be an alternative choice for patients with metastatic ES in lung based on analysing the tumour immune microenvironment.

Three-dimensional-printed custom-made patellar endoprosthesis for recurrent giant cell tumor of the patella: A case report and review of the literature.

BACKGROUND: Giant cell tumor (GCT) is a benign lesion and rarely involves the patella. This disease is characterized by a relatively high recurrence rate after primary treatment. En bloc resection has been a predominant option for recurrent GCT. However, total patellectomy can lead to disruption of the knee. Therefore, exploration of functional reconstruction of the extensor mechanism is worthwhile. CASE SUMMARY: A 54-year-old woman presented with right knee pain and swelling, and was diagnosed as having a GCT in the patella following curettage and autograft. Medical imaging revealed a lytic and expanded lesion involving the whole patella with focal cortical breaches and pathological fracture. Based on the combination of histological, radiological, and clinical features, a diagnosis of recurrent GCT in the patella was made (Campanacci grade III). After a multidisciplinary team discussion, three-dimensional (3D)-printed custom-made patellar endoprosthesis was performed following en bloc resection for reconstructing the extensor mechanism. The patient was followed for 35 mo postoperatively. No evidence of local recurrence, pulmonary metastasis, or osteoarthritis of the right knee was observed. The active flexion arc was 0°-120°, and no extension lag was detected. A favorable patellar tracking and height (Insall-Salvati ratio 0.93) were detected by radiography. CONCLUSION: We depict a case of a GCT at the right patella, which was successfully treated by patellectomy and 3D-printed custom-made endoprosthetic replacement. The patella normal reconstruction, the precise-fit articular design, and gastrocnemius flap augmentation could lead to satisfactory knee function and a low rate of complications in the short-term follow-up.

Fungal liver infection mimicking hepatic malignant tumor on contrast enhanced ultrasound: A case report.

RATIONAL: Fungal liver infection mostly occurs in immunocompromised patients, and is often associated with delayed diagnosis and high mortality rates. Dynamic contrast enhanced imaging is crucial for the diagnosis of fungal liver infection and has been reported having variable manifestations. PATIENT CONCERNS: A 38-year-old Chinese man, with a history of diabetes and chronic hepatitis B, was admitted to our hospital due to prolonged fever of unknown cause. He had a medical history of receiving broad-spectrum antibiotic treatment for pulmonary inflammation at the local hospital. The blood test results showed that the white cell count (14.0 × 109/L) and neutrophil count ratio (77.0%) were subtly elevated. C-reactive protein (92.0 mg/l) and cancer antigen (CA)-125 (904.50 U/ml) were elevated. Non-small cell lung cancer antigen was within the normal limit. Hepatitis B virus DNA load was 3.28 × 103 IU/ml. Sputum and blood cultures were normal. Abdominal ultrasonography (US) found a large heterogeneous mass, with diffused echogenic foci without infiltrating the surrounding vascular, which exhibiting "rapid wash in and out" on contrast-enhanced ultrasound (CEUS). DIAGNOSIS: The diagnosis of liver fungal infection was confirmed pathologically via ultrasound-guided biopsy. INTERVENTIONS: Antibiotic and antifungal therapy with imipenem and voriconazole. OUTCOMES: The patient's body temperature had been controlled and the huge mass disappeared on follow-up ultrasound 1-year later. LESSONS: This case highlights the unusual imaging features of fungal liver infection, presenting as huge heterogeneous mass with diffusive echogenic foci without infiltrating the surrounding vascular on grayscale US and the enhancement pattern of "rapid wash in and out" on CEUS. Additionally, ultrasound-guided biopsy is necessary for the correct diagnosis of suspected liver lesions.

New secondary metabolite with cytotoxicity from spawning soft coral Asterospicularia laurae in Taiwan.

We have conducted a long-term research on the Taiwanese soft coral Asterospicularia laurae, which resulted in many xenicane-type diterpenoids such as asterolaurins A-M from A. laurae coral tissues during the non-spawning period were isolated. Here, we report a new xenicane diterpenoid, asterolaurin N (1), along with three known xenicane-type monocarbocyclic diterpenes [13-epi-9-desacetylxenicin (2), xeniolide-B 9-acetate (3) and asterolaurin I (4)] from A. laurae during the spawning period. The structures of the new secondary metabolite were established with an extensive spectroscopic analysis. The 1D and 2D nuclear magnetic resonance (NMR) data of the compounds were discussed. We discovered that the C-15 of 1 contains two methyl groups on a carbon bearing an acetyl group, which has not been reported previously. In addition, Compounds 1, 3, and 4 showed selective cytotoxic activity against Molt 4, while 2 exhibited significant cytotoxicity against Molt 4, K562, Sup-T1 and U937 cell lines.

Sevoflurane Post-Conditioning Ameliorates Neuronal Deficits and Axon Demyelination After Neonatal Hypoxic Ischemic Brain Injury: Role of Microglia/Macrophage.

Microglia/macrophages have been identified to be highly polarized after ischemia. Interestingly, the polarization of these microglia/macrophages varies immensely under differing disease conditions. Post-conditioning using sevoflurane, a volatile anesthetic, could provide long-term neuroprotection to neonatal rats after hypoxic-ischemic brain injury (HIBI). Thus, the current study aimed at investigating the effects of sevoflurane post-conditioning (SPC) on microglia/macrophage polarization after HIBI induction in neonatal rats. Additionally, we aimed at identifying the underpinning mechanisms specifically related to autophagy and lysosomal protease enzyme, cathepsin B. To develop a HIBI model, 7-day-old Sprague-Dawley rats underwent left common carotid artery ligation followed by 2 h of hypoxia. The role of microglia/macrophages in the neuroprotection conferred by SPC was examined by left-side intra-cerebroventricular injection with adenovirus vector carrying catB-GFP or rapamycin. The number of interleukin (IL)-1ß+ cells, cathepsin B+ cells, light chain 3B positive (LC3B+) cells among ionized calcium binding adaptor molecule 1(Iba1+)cells to investigate microglia polarization, neuronal apoptosis to assess neuronal death in the acute phase were tested at 24 h after HIBI. Behavioral tests including suspension test, Morris water maze tests were performed to investigate the long-term effects of SPC, at 21 to 34 days post HIBI. Nissl staining and myelin basic protein (MBP) immunostaining to assess the long-term neuronal and myelin damage were performed at 34 days after HIBI. Based on the obtained results post HIBI, we observed the cells that were positive for IL-1ß, cathepsin B, and LC3B among Iba1 positive cell population in the hippocampus were significantly decreased after SPC treatment. SPC significantly attenuated the HIBI-induced increase in neuronal apoptosis, improved long-term cognitive function, and attenuated HI-induced decrease of Nissl-positive cells and MBP expression. However, these trends were reversed by injection of adenovirus vector carrying catB-GFP and rapamycin. SPC attenuated microglia polarization towards neurotoxic phenotypes, alleviates neuronal death and axon demyelination after HIBI in neonatal rats by regulating microglia autophagy and cathepsin B expression, and therefore provided long-term cognitive, learning and memory protection.

Brief inhalation of sevoflurane can reduce glial scar formation after hypoxic-ischemic brain injury in neonatal rats.

Previous studies have demonstrated that sevoflurane postconditioning can provide neuroprotection after hypoxic-ischemic injury and improve learning and memory function in developing rodent brains. The classical Rice-Vannucci model was used to induce hypoxic-ischemic injury, and newborn (postnatal day 7) rats were treated with 2.4% sevoflurane for 30 minutes after hypoxic-ischemic injury. Our results showed that sevoflurane postconditioning significantly improved the learning and memory function of rats, decreased astrogliosis and glial scar formation, increased numbers of dendritic spines, and protected the histomorphology of the hippocampus. Mechanistically, sevoflurane postconditioning decreased expression of von Hippel-Lindau of hypoxia-inducible factor-1α and increased expression of DJ-1. Injection of 1.52 µg of the hypoxia-inducible factor-1α inhibitor YC-1 (Lificiguat) into the left lateral ventricle 30 minutes before hypoxic-ischemic injury reversed the neuroprotection induced by sevoflurane. This finding suggests that sevoflurane can effectively alleviate astrogliosis in the hippocampus and reduce learning and memory impairments caused by glial scar formation after hypoxic-ischemic injury. The underlying mechanism may be related to upregulated DJ-1 expression, reduced ubiquitination of hypoxia-inducible factor-1α, and stabilized hypoxia-inducible factor-1α expression. This study was approved by the Laboratory Animal Care Committee of China Medical University, China (approval No. 2016PS337K) on November 9, 2016.

Contrast-enhanced ultrasound in association with serum biomarkers for differentiating combined hepatocellular-cholangiocarcinoma from hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (CHC) is a rare type of primary liver cancer. Due to its complex histopathological characteristics, the imaging features of CHC can overlap with those of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). AIM: To investigate the possibility and efficacy of differentiating CHC from HCC and ICC by using contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) and tumor biomarkers. METHODS: Between January 2016 and December 2019, patients with histologically confirmed CHC, ICC and HCC with chronic liver disease were enrolled. The diagnostic formula for CHC was as follows: (1) LR-5 or LR-M with elevated alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9); (2) LR-M with elevated AFP and normal CA19-9; or (3) LR-5 with elevated CA19-9 and normal AFP. The sensitivity, specificity, accuracy and area under the receiver operating characteristic curve were calculated to determine the diagnostic value of the criteria. RESULTS: After propensity score matching, 134 patients (mean age of 51.4 ± 9.4 years, 108 men) were enrolled, including 35 CHC, 29 ICC and 70 HCC patients. Based on CEUS LI-RADS classification, 74.3% (26/35) and 25.7% (9/35) of CHC lesions were assessed as LR-M and LR-5, respectively. The rates of elevated AFP and CA19-9 in CHC patients were 51.4% and 11.4%, respectively, and simultaneous elevations of AFP and CA19-9 were found in 8.6% (3/35) of CHC patients. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy and area under the receiver operating characteristic curve of the aforementioned diagnostic criteria for discriminating CHC from HCC and ICC were 40.0%, 89.9%, 58.3%, 80.9%, 76.9% and 0.649, respectively. When considering the reported prevalence of CHC (0.4%-14.2%), the positive predictive value and NPV were revised to 1.6%-39.6% and 90.1%-99.7%, respectively. CONCLUSION: CHCs are more likely to be classified as LR-M than LR-5 by CEUS LI-RADS. The combination of the CEUS LI-RADS classification with serum tumor markers shows high specificity but low sensitivity for the diagnosis of CHC. Moreover, CHC could be confidently excluded with high NPV.

Quercetin is protective against short-term dietary advanced glycation end products intake induced cognitive dysfunction in aged ICR mice.

Dietary advanced glycation end products (dAGEs) might be potential toxins involved in the pathogenesis of Alzheimer's disease (AD). Quercetin is a flavonoid possessing neuroprotective effects. We aimed to explore whether a 21 days of dAGEs intake would result in cognitive dysfunction in aged ICR mice, and the protective effects of quercetin, with potential mechanisms explored. Fourteen-month old ICR mice were randomly assigned into four groups, that is, Control, AGEs, quercetin, and AGE diet supplemented with quercetin. Key markers involved in Aß, tau, and neuroinflammation from hippocampus and cortex were measured via western blot. Gut microbiota and short chain fatty acids profiles from intestinal contents were measured via 16S rRNA gene sequencing and gas chromatography (GC), respectively. Quercetin alleviated cognitive impairment induced by dAGEs in aged mice. This might be associated with that quercetin reduced cathepsin B, tau phosphorylation, and neuroinflammation, and elevated α-diversity index (ACE, Chao1, and Shannon index), and reduced phylum Verrucomicrobia of gut microbiota. PRACTICAL APPLICATIONS: Alzheimer's disease (AD) has been regarded as the commonest cause of progressive dementia for the elderly. This study is the very first to demonstrate that even a short-term dietary advanced glycation end product (dAGEs) intake induced impaired cognitive function in aged ICR mice, and querectin is capable of reversing dAGEs-induced cognitive dysfunction. Reduced tau phosphorylation, neuroinflammation, and altered gut microbiota profiles may be involved in querectin's protective effects against dAGEs-induced cognitive impairment. Our study suggested that quercetin supplementation might be beneficial for improving cognitive function in elderly subjects with high consumption of dAGEs such as grilling, frying, and broiling of food.

DietaryAdvancedGlycationEnd Products-InducedCognitive Impairment in Aged ICR Mice: Protective Role of Quercetin.

SCOPE: Dietary advanced glycation products (dAGEs) have been reported to induce cognitive impairment while quercetin possesses potential neuroprotective effects. The aim is to explore whether dAGEs would induce similar cognitive impairment from both young and aged ICR mice, and the protective effects of quercetin. METHODS AND RESULTS: A total of 32 aged ICR mice (15-month-old) and 16 young ICR mice (3-month-old) are randomly assigned into the following six groups: Young mice control group, young mice fed with AGEs diet group, old mice control group, old mice fed with AGEs diet group, old mice with quercetin supplemented diet group, old mice fed with AGE diet supplemented with quercetin group. Dietary AGEs induced cognitive impairment only in aged, but not in young, ICR mice, while quercetin intervention is capable of reversing dAGEs-induced cognitive dysfunction. This may be since quercetin 1) increased miR-219, miR-15a, and miR-132 expression, inhibited p-ERK1/2, and tau phosphorylation; and 2) improved gut microbiota richness and diversity, inhibited phylum Tenericutes and Proteobacteria, and elevated butyric acid from cecum. CONCLUSION: Prolonged application of quercetin may be beneficial in the elderly, especially for those with high consumption of dAGEs.

Sevoflurane post-conditioning alleviates neonatal rat hypoxic-ischemic cerebral injury via Ezh2-regulated autophagy.

Background: When neonatal rats suffer hypoxic-ischemic brain injury (HIBI), autophagy is over-activated in the hippocampus, and inhibition of autophagy provides neuroprotection. The aim of this study was to investigate the possible roles of autophagy and Ezh2-regulated Pten/Akt/mTOR pathway in sevoflurane post-conditioning (SPC)-mediated neuroprotection against HIBI in neonatal rats. Methods: Seven-day-old Sprague-Dawley rats underwent left common artery ligation followed by 2 h hypoxia as described in the Rice-Vannucci model. The roles of autophagy and the Ezh2-regulated Pten/Akt/mTOR signaling pathway in the neuroprotection conferred by SPC were examined by left-side intracerebroventricular injection with the autophagy activator rapamycin and the Ezh2 inhibitor GSK126. Results: SPC was neuroprotective against HIBI through the inhibition of over-activated autophagy in the hippocampus as characterized by the rapamycin-induced reversal of neuronal density, neuronal morphology, cerebral morphology, and the expression of the autophagy markers, LC3B-II and Beclin1. SPC significantly increased the expression of Ezh2, H3K27me3, pAkt, and mTOR and decreased the expression of Pten induced by HI. The Ezh2 inhibitor, GSK126, significantly reversed the SPC-induced changes in expression of H3K27me3, Pten, pAkt, mTOR, LC3B-II, and Beclin1. Ezh2 inhibition also reversed SPC-mediated attenuation of neuronal loss and behavioral improvement in the Morris water maze. Conclusion: These results indicate that SPC inhibits excessive autophagy via the regulation of Pten/Akt/mTOR signaling by Ezh2 to confer neuroprotection against HIBI in neonatal rats.

Concise synthesis of 2-methoxyestradiol from 17ß-estradiol through the C(sp2)-H hydroxylation.

A four-step route for the synthesis of 2-methoxyestradiol (5) starting from 17ß-estradiol (1) has been achieved with a 51% overall yield. The key step was the ruthenium-catalyzed ortho-C(sp2)-H bond hydroxylation of aryl carbamates. Using dimethyl carbamate as the directing group, [RuCl2(p-cymene)]2 as the catalyst, PhI(OAc)2 as the oxidant and trifluoroacetate/trifluoroacetic anhydride (1:1) as the co-solvent, the hydroxyl group could be singly installed at the 2-position of 3-dimethylcarbamoyloxyestradiol (2) with 65% yield. Subsequent methylation of hydroxy and removal of dimethyl carbamate afforded 2-methoxyestradiol (5).

Identification of new shikonin derivatives as STAT3 inhibitors.

The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells, especially for the MDA-MB-231 cells. For the cellular mechanisms research, PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells, associated with the reduction of mitochondrial membrane potential, production of ROS and alteration of the levels of apoptosis-related proteins. Furthermore, PMMB-187 inhibited constitutive/inducible STAT3 activation, transcriptional activity, nuclear translocation and downstream target genes expression in STAT3-dependent breast cancer cells MDA-MB-231. Besides, no obvious inhibitory effect on activation of STAT1 and STAT5 was observed with PMMB-187 treatment. Most notably, the in vivo studies further revealed that PMMB-187 could dramatically suppress the MDA-MB-231 cells xenografted tumor growth. The in vitro and in vivo results collectively suggest that PMMB-187 may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents.

Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin-dioxazole combination as tubulin targeting anticancer agents.

The advancement of cancer-fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin-derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC50  = 2.54 ± 0.82 µm against MCF-7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF-7 in a way depending on the dosage. The time- and dose-dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D-QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics.