Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial.

BACKGROUND: The autologous anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up. METHODS: Participants received an average dose of 0.5 × 106 cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated. RESULTS: Seventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes. CONCLUSIONS: These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma. TRIAL REGISTRATION: LEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.

Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

Chlorin e6 (Ce6)-loaded plaque-specific liposome with enhanced photodynamic therapy effect for atherosclerosis treatment.

Recently, photodynamic therapy (PDT) has been considered as a new strategy for atherosclerosis treatment. Targeted delivery of photosensitizer could significantly reduce its toxicity and enhance its phototherapeutic efficiency. CD68 is an antibody that can be conjugated to nano-drug delivery systems to actively target plaque sites, owing to its specific binding to CD68 receptors that are highly expressed on the surfaces of macrophage-derived foam cells. Liposomes are very popular nanocarriers due to their ability to encapsulate a wide range of therapeutic compounds including drugs, microRNAs and photosensitizers, and their ability to be surface-modified with targeting moieties leading to the development of nanocarriers with an improved targeted ability. Hence, we designed a Ce6-loaded liposomes using the film dispersion method, followed by the conjugation of CD68 antibody on the liposomal surface through a covalent crosslinking reaction, forming CD68-modified Ce6-loaded liposomes (CD68-Ce6-mediated liposomes). Flow cytometry results indicated that Ce6-containing liposomes were more effective in promoting intracellular uptake after laser irradiation. Furthermore, CD68-modified liposomes significantly strengthened the cellular recognization and thus internalization. Different cell lines have been incubated with the liposomes, and the results showed that CD68-Ce6-mediated liposomes had no significant cytotoxicity to coronary artery endothelial cells (HCAEC) under selected conditions. Interestingly, they promoted autophagy in foam cells through the increase in LC3-Ⅰ, LC3-Ⅱ expression and the decrease in p62 expression, and restrained the migration of mouse aortic vascular smooth muscle cells (MOVAS) in vitro. Moreover, the enhancement of atherosclerotic plaque stability and the reduction in the cholesterol content by CD68-Ce6-mediated liposomes were dependent on transient reactive oxygen species (ROS) generated under laser irradiation. In summary, we demonstrated that CD68-Ce6-mediated liposomes, as a photosensitizer nano-drug delivery system, have an inhibitory effect on MOVAS migration and a promotion of cholesterol efflux in foam cells, and thereby, represent promising nanocarriers for atherosclerosis photodynamic therapy.

[The Risk and Survival Analysis of Multiple Malignancies in Hematologic Malignancy Patients: A Single Chinese Center Retrospective Study, 2009 through 2017].

OBJECTIVE: To explore the risk and location of multiple malignancies in patients with hematologic malignancies who were followed up for 9 years in Jiangsu Province Hospital and to evaluate the impact of the second primary malignancy on survival of patients. METHODS: The incidence and survival of multiple malignancies in 7 921 patients with hematologic malignancies from 2009 to 2017 were analyzed retrospectively. RESULTS: A total of 180 (2.3%, 180/7 921) patients developed second malignancy, of whom 58 patients were diagnosed with hematologic malignancies as the first primary malignancy, and 98 patients developed hematologic malignancies as second primary malignancy, and the other 24 cases were diagnosed with the second malignancy within 6 months after the first primary malignancy was diagnosed, which was difined as multiple malignancies occurring simultaneously. In 180 patients, 18 cases developed two hematologic malignancies successively, and 11 patients developed more than 3 primary cancers (among them, 2 female patients were diagnosed with 4 primary cancers). Patients with lymphoma and multiple myeloma (MM) as the second primary malignancy had poorer survival than patients with lymphoma and MM as the first primary malignancy. Patients with chronic myeloid leukemia as the second primary malignancy were also associated with inferior overall survival. CONCLUSION: In this study, 2.3% of hematologic malignancy patients had multiple mali-gnancies, lymphoma and MM as the second primary malignancy had poor survival.

The role of lysine-specific demethylase 6A (KDM6A) in tumorigenesis and its therapeutic potentials in cancer therapy.

Histone demethylation is a key post-translational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Lysine specific demethylase 6A (KDM6A, also known as UTX) is an Fe2+- and α-ketoglutarate- dependent oxidase which belongs to KDM6 Jumonji histone demethylase subfamily, and it can remove mono-, di- and tri-methyl groups from methylated lysine 27 of histone H3 (H3K27me1/2/3). Mounting studies indicate that KDM6A is responsible for driving multiple human diseases, particularly cancers and pharmacological inhibition of KDM6A is an effective strategy to treat varieties of KDM6A-amplified cancers in cellulo and in vivo. Although there are several reviews on the roles of KDM6 subfamily in cancer development and therapy, all of them only simply introduce the roles of KDM6A in cancer without systematically summarizing the specific mechanisms of KDM6A in tumorigenesis, which greatly limits the advances on the understanding of roles KDM6A in varieties of cancers, discovering targeting selective KDM6A inhibitors, and exploring the adaptive profiles of KDM6A antagonists. Herein, we present the structure and functions of KDM6A, simply outline the functions of KDM6A in homeostasis and non-cancer diseases, summarize the role of KDM6A and its distinct target genes/ligand proteins in development of varieties of cancers, systematically classify KDM6A inhibitors, sum up the difficulties encountered in the research of KDM6A and the discovery of related drugs, and provide the corresponding solutions, which will contribute to understanding the roles of KDM6A in carcinogenesis and advancing the progression of KDM6A as a drug target in cancer therapy.

Sequential 2.5 mg letrozole/FSH therapy is more effective for promoting pregnancy in infertile women with PCOS: a pragmatic randomized controlled trial.

Study question: In infertile women with polycystic ovary syndrome (PCOS), is the sequential use of letrozole 2.5 mg/follicle stimulating hormone(FSH) more effective than letrozole 5 mg/FSH in stimulating ovulation and promoting pregnancy? Research design and methods: The study was designed as a prospective, single-center, randomized, controlled pragmatic clinical trial. 220 infertile women between the ages of 20 and 40, who matched the Rotterdam criteria for PCOS and had no other identified reasons for infertility were enrolled from April 2023 to July 2023.The participants were randomly assigned to two groups in a 1:1 ratio. One group received 2.5 mg of letrozole on cycle days 3-7 with a sequential injection of 75 IU FSH on cycle days 8-10 (n = 110), while the other group received 5 mg of letrozole on cycle days 3-7 with a sequential injection of 75 IU FSH on cycle days 8-10 (n = 110). The duration of FSH treatment varied depending on the follicular development stage. Each participant underwent one to three treatment cycles until achieving pregnancy.The primary outcome was the cumulative pregnancy rate of all the participants. Secondary outcomes included characteristics and clinical pregnancy rates of all the intervention cycles. Results: For all 220 participants, the sequential letrozole 2.5 mg/FSH treatment group had a significantly higher cumulative pregnancy rate compared to the letrozole 5 mg/FSH treatment group (72.7% versus 59.1%, RR (95%CI) = 1.23 (1.02, 1.49), P-value = 0.033). For all 468 intervention cycles, letrozole 2.5 mg/FSH group had a significantly higher clinical pregnancy rate than the letrozole 5 mg/FSH group (36.2% versus 26.3%, P-value = 0.021), no statistically significant differences were observed in ovulation rates or adverse effects. Conclusions: The data indicate that the sequential letrozole 2.5mg/FSH protocol may be more effective than the sequential letrozole 5mg/FSH protocol for promoting pregnancy in infertile women with PCOS. Clinical trial registration: www.chictr.org.cn, identifier ChiCTR2300069638.

Berberine as a potential agent for breast cancer therapy.

Breast cancer (BC) is a common malignancy that mainly occurred in women and it has become the most diagnosed cancer annually since 2020. Berberine (BBR), an alkaloid extracted from the Berberidacea family, has been found with broad pharmacological bioactivities including anti-inflammatory, anti-diabetic, anti-hypertensive, anti-obesity, antidepressant, and anticancer effects. Mounting evidence shows that BBR is a safe and effective agent with good anticancer activity against BC. However, its detailed underlying mechanism in BC treatment remains unclear. Here, we will provide the evidence for BBR in BC therapy and summarize its potential mechanisms. This review briefly introduces the source, metabolism, and biological function of BBR and emphasizes the therapeutic effects of BBR against BC via directly interacting with effector proteins, transcriptional regulatory elements, miRNA, and several BBR-mediated signaling pathways. Moreover, the novel BBR-based therapeutic strategies against BC improve biocompatibility and water solubility, and the efficacies of BBR are also briefly discussed. Finally, the status of BBR in BC treatment and future research directions is also prospected.

[Clinical Characteristics of Multiple Myeloma Patients with Early Relapse].

OBJECTIVE: To analyze the clinical characteristics of multiple myeloma(MM) patients with early relapse. METHODS: A total of 50 MM patients with early relapse (≤12 months) and 50 matched controls with late relapse (>12 months) were selected. The time from diagnosis to relapse and related clinical data of the 100 patients were retrospectively analyzed, and the factors associated with early relapse were identified. Kaplan-Meier curve was used to analyze the overall survival (OS) time of the whole cohort. Area under the curve (AUC) was used to evaluate the effect of circulating plasma cells on early recurrence of the patients. RESULTS: The results showed that high-risk cytogenetics (FISH) (P=0.005), and ISS stage III (P=0.008) were associated with early recurrence of the patients. For patients with early relapse, high-risk FISH showed poor survival. Compared with the patients with late relapse, most of the chromosome karyotype of patients with early relapse showed quantitative and structural abnormalities. The expression of circulating plasma cells was significantly increased in patients with early recurrence group (P=0.0318). The response to initial treatment was poor in the early recurrence group (P=0.001), and the prognosis was significantly worse than those in the late recurrence group (median OS: 38 vs 81 months, P=0.002). CONCLUSION: Early relapse is a marker poor prognostic in MM patients, and such patients should be focused on the improving their prognosis.

Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2).

BACKGROUND: LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. METHODS: LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. RESULTS: As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. CONCLUSIONS: The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.

Three novel MOFs constructed from 1,3,5-tris(1-imidazolyl)benzene and dicarboxylate ligands with selective adsorption for C2H2/C2H4 and C2H6/CH4.

The urothermal reactions of Co(II)/Zn(II) salts with the diverse carboxylic acid and 1,3,5,-tris(1-imidazolyl)benzene(tib) ligands afforded three novel MOFs, namely, [Co3(tib)2(abdc)2(ox)]2·6H2O (1), [Co3O(tib)(abdc)2(DMI)]·2DMI·2H2O (2) and [Zn3I2(tib)2(napdc)2]·2DMI·2H2O (3), (H2abdc = 5-amino-1,3-benzenedicarboxylate, H2napdc = 1,4-naphthalene dicarboxylic acid and DMI = 1,3-dimethyl-2-imidazolidinone). In compounds 1 and 2, the Co(II) atoms are connected by polycarboxylate ligands to form two-dimensional (2D) layers that are pillared by tib ligands leading to the formation of 3D porous frameworks. In compound 3, the Zn(II) atoms are linked by tib ligands to form one-dimensional ribbon-like chains which are further connected by polycarboxylate ligands, making a 3D framework possible. Compound 1 can selectively adsorb unsaturated hydrocarbon molecules (C2H2 and C2H4) and saturated hydrocarbon molecules (C2H6 and CH4). Specifically, compound 1 has high IAST selectivity for acetylene and methane (0.50 : 0.50, v/v) at 273 K and 1 bar. DFT calculations reveal that the π-conjugated hexagonal carbon ring may be the primary adsorption site because there are π-π interactions between the unsaturated hydrocarbon molecules (C2H2 and C2H4) and the π-conjugated hexagonal carbon ring in the framework of compound 1.

Comprehensive geriatric assessment in newly diagnosed older myeloma patients: a multicentre, prospective, non-interventional study.

BACKGROUND: Multiple myeloma is a disease of the older people, whose prognoses are highly heterogeneous. The International Myeloma Working Group (IMWG) proposed a geriatric assessment (GA) based on age, functional status and comorbidities to discriminate between fit and frail patients. Given the multidimensional nature of frailty and the relatively recent exploration of frailty in the field of MM, reaching a consensus on the measurement of frailty in MM patients remains challenging. OBJECTIVE: We sought to assess the feasibility of performing a comprehensive GA (CGA) in older MM patients in a real-world and multicentre setting and to evaluate their baseline CGA profiles. RESULTS: We studied 349 older patients with newly diagnosed MM (age range, 65-86 years). Our results showed that a CGA is feasible for older MM patients. Using the IMWG-GA criteria, we identified significantly more frail patients in our cohort comparing to in the IMWG cohort (43% vs 30%, P = 0.002). In the IMWG-GA 'fit' group, risk of malnutrition, depression and cognitive impairment remains. The median follow-up time was 26 months (range 1-38). The median overall survival (OS) was 34.7 months, and the estimated 3-year OS rate was 50%. A high MNA-SF score (MNA-SF ≥ 12), low GDS score (GDS ≤ 5) and high CCI score (CCI ≥ 2) can be used to predict the OS of older patients with newly diagnosed MM. This study is registered at www.clinicaltrials.gov (NCT03122327). CONCLUSIONS: Our study justifies the need for a CGA in older patients with newly diagnosed MM.

Hepatocellular carcinoma with indocyanine green excretory defect: a case report and review of the literature.

Constitutional indocyanine green (ICG) excretory defect is rare. However, ICG excretory defect concomitant with hepatocellular carcinoma (HCC) is extremely rare, and only six reports of hepatectomy in patients with constitutional ICG excretory defect have been published in the English language literature through 2020. In this study, we report a case of combined HCC and ICG excretory defect and discuss its clinicopathological features and outcomes. The case featured a 68-year-old man who was admitted to the hospital with a diagnosis of resectable HCC. The preoperative ICG retention rate at 15 minutes was 82.9%. Despite this finding, the Child-Pugh assessment and hepatobiliary-specific magnetic resonance imaging (MRI) did not reveal any abnormal findings. Therefore, we diagnosed the patient with constitutional ICG excretory defect and performed partial hepatectomy. For patients requiring hepatectomy, the indications and procedure for surgery should be considered. These should be based on liver function tests such as gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced MRI.

[Retracted] Bergamottin isolated from Citrus bergamia exerts in vitro and in vivo antitumor activity in lung adenocarcinoma through the induction of apoptosis, cell cycle arrest, mitochondrial membrane potential loss and inhibition of cell migration and invasion.

Following the publication of the above paper, a concerned reader drew to the Editor's attention that a number of figures (specifically, Figs. 6, 8, 9, 10 and 12) contained apparent anomalies, including repeated patternings of data within the same figure panels. After having conducted an independent investigation in the Editorial Office, the Editor of Oncology Reports has determined that this paper should be retracted from the Journal on account of a lack of confidence concerning the originality and the authenticity of the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal. [the original article was published in Oncology Reports 36: 324­332, 2016; DOI: 10.3892/or.2016.4833].

Multicomponent Self-Assembly of a Giant Heterometallic Polyoxotungstate Supercluster with Antitumor Activity.

The hierarchical aggregation of molecular nanostructures from multiple components is a grand synthetic challenge, which requires highly selective linkage control. We demonstrate how two orthogonal linkage groups, that is, organotin and lanthanide cations, can be used to drive the aggregation of a giant molecular metal oxide superstructure. The title compound {[(Sn(CH3 )2 )2 O]4 {[CeW5 O18 ] [TeW4 O16 ][CeSn(CH3 )2 ]4 [TeW8 O31 ]4 }2 }46- (1 a) features dimensions of ca. 2.2×2.3×3.4 nm3 and a molecular weight of ca. 25 kDa. Structural analysis shows the hierarchical aggregation from several independent subunits. Initial biomedical tests show that 1 features an inhibitory effect on the proliferation of HeLa cells based on an apoptosis pathway. In vivo experiments in mice reveal the antiproliferative activity of 1 and open new paths for further development of this new compound class.

Repression of FBXW7 by HES5 contributes to inactivation of the TGF-ß signaling pathway and alleviation of endometriosis.

Endometriosis (EMS) is a gynecologic disorder associated with infertility and characterized by the endometrial-type mucosa outside the uterine cavity. Currently available treatment modalities are limited to undesirable effects. Thus, in the present study, we sought to study the pathogenesis mechanism of EMS. For this purpose, the ectopic and eutopic endometrial tissues were resected from 86 patients with EMS and 54 infertile patients without EMS, respectively. The regulatory mechanism among HES family bHLH transcription factor 5 (HES5), transforming growth factor-beta (TGF-ß)-induced factor 1 (TGIF1), F-box, and WD repeat domain containing 7 (FBXW7) was studied by performing co-immunoprecipitation, dual-luciferase reporter gene assay, and chromatin immunoprecipitation, respectively. A mouse model of EMS was established to verify the aforementioned regulatory mechanism in vivo. Upregulation of HES5 and TGIF1, as well as downregulation of FBXW7, was observed in EMS endometrial tissues and human endometrial stromal cells (hESCs), respectively. The overexpression of HES5 was found to suppress the FBXW7 transcription and TGIF1 degradation, resulting in the inactivation of the TGF-ß signaling pathway, as well as inhibition of hESC proliferation and invasion, thereby enhancing apoptosis. Results from a mouse model of EMS showed that the presence of HES5 contributed to the alleviation of EMS. Collectively, we attempted to provide a mechanistic insight into the unrecognized roles of the HES5/FBXW7 in EMS progression.

Synthesis and evaluation of new compounds bearing 3-(4-aminopiperidin-1-yl)methyl magnolol scaffold as anticancer agents for the treatment of non-small cell lung cancer via targeting autophagy.

Magnolol and honokiol are the two major active ingredients with similar structure and anticancer activity from traditional Chinese medicine Magnolia officinalis, and honokiol is now in a phase I clinical trial (CTR20170822) for advanced non-small cell lung cancer (NSCLC). In search of potent lead compounds with better activity, our previous study has demonstrated that magnolol derivative C2, 3-(4-aminopiperidin-1-yl)methyl magnolol, has better activity than honokiol. Here, based on the core of 3-(4-aminopiperidin-1-yl)methyl magnolol, we synthesized fifty-one magnolol derivatives. Among them, compound 30 exhibited the most potent antiproliferative activities on H460, HCC827, H1975 cell lines with the IC50 values of 0.63-0.93 µM, which were approximately 10- and 100-fold more potent than those of C2 and magnolol, respectively. Besides, oral administration of 30 and C2 on an H460 xenograft model also demonstrated that 30 has better activity than C2. Mechanism study revealed that 30 induced G0/G1 phase cell cycle arrest, apoptosis and autophagy in cancer cells. Moreover, blocking autophagy by the autophagic inhibitor enhanced the anticancer activity of 30in vitro and in vivo, suggesting autophagy played a cytoprotective role on 30-induced cancer cell death. Taken together, our study implied that compound 30 combined with autophagic inhibitor could be another choice for NSCLC treatment in further investigation.

The Potential Role of N6-Methyladenosine (m6A) Demethylase Fat Mass and Obesity-Associated Gene (FTO) in Human Cancers.

N6-methyladenosine (m6A) demethylase fat mass and obesity-associated gene(FTO), previously recognized to be related with obesity and diabetes, was gradually discovered to be dysregulated in multiple cancers and plays an oncogenic or tumor-suppressive role. However, the specific expression and pro- or anti-cancer role of FTO in various cancers remained controversial. In this review, through summarizing the available literature, we found that FTO single nucleotide polymorphisms (SNPs) were closely related with cancer risk. Additionally, the dysregulation of FTO was implicated in multiple biological processes, such as cancer cell apoptosis, proliferation, migration, invasion, metastasis, cell-cycle, differentiation, stem cell self-renewal and so on. These modulations mostly relied on the communications between FTO and specific signaling pathways, including PI3K/AKT, MAPK and mTOR signaling pathways. Furthermore, FTO had great potential for clinical application by serving as a prognostic biomarker.

Two types of lung cancer with situs inversus totalis: a case report and review of the literature.

Situs inversus totalis (SIT) is a rare congenital anatomical variation. However, patients with SIT combined with cancer are rare and these patients with two types of lung cancer have not been reported. We report here a case of combined lung adenocarcinoma and solitary fibrous tumor of the pleura with SIT and discuss its clinicopathological features and outcomes. A 68-year-old asymptomatic woman was referred to the Affiliated Hospital of Qingdao University because of an abnormal shadow on chest radiography. Computed tomography showed SIT and an irregularly shaped nodule (measuring 38 × 27 mm in diameter) in the pleural area of the left lower lobe and a 5-mm nodule in the dorsal segment of the lower lobe of the left lung. Surgery was then performed. For such patients, we should eliminate anxiety in patients, perform regular reexaminations, focus on the individual features of these patients, and avoid misdiagnosis because of habitual thinking. At the same time, the lymph nodes should be completely removed and different parts of the tumor with different properties should be treated differently according to the situation.

Flavonoids with Inhibitory Effects on NLRP3 Inflammasome Activation from Millettia velutina.

Eight new flavonoids, including two ß-hydroxy/methoxychalcones, velutones A and B (1 and 2), two 1,3-diarylpropan-1-ols, velutols C and D (3 and 4), a dihydroxychalcone, velutone E (5), a chalcone, velutone F (6), a furanoflavanone, velutone G (7), and a furanoflavonol, velutone H (8), and 14 known compounds were isolated from Millettia velutina. Their structures were determined by high-resolution electrospray ionisation mass spectrometry (HR-ESIMS) and spectroscopic data analyses and time-dependent density functional theory electronic circular dichroism (TD-DFT-ECD) calculations. Among the isolated constituents, compound 6 exhibited the most potent inhibitory effect (IC50: 1.3 µM) against nigericin-induced IL-1ß release in THP-1 cells. The initial mechanism of action study revealed that compound 6 suppressed NLRP3 inflammasome activation via blocking ASC oligomerization without affecting the priming step, which subsequently inhibited caspase-1 activation and IL-1ß secretion. Most importantly, compound 6 exerted potent protective effects in the LPS-induced septic shock mice model by improving the survival rate of mice and suppressing serum IL-1ß release. These results demonstrated that compound 6 had the potential to be developed as a broad-spectrum NLRP3 inflammasome inhibitor for the treatment of NLRP3-related disease.

Modulation of LPS-induced inflammation in RAW264.7 murine cells by novel isoflavonoids from Millettia pulchra.

Millettia pulchra is a renowned anti-inflammatory herbal medicine in southeast provinces of China. However, the underlying anti-inflammation mechanism remained incompletely understood. Herein, four new isoflavones, pulvones A-D and eleven reported constituents were isolated from the stems of Millettia pulchra with their structures being elucidated by HRMS and NMR analysis. The anti-inflammatory activities of pulvones A and C were further evaluated due to the better inhibitory activity on nitric oxide production in LPS-stimulated RAW264.7 cells and no obvious cytotoxicity to RAW264.7 cells. Western blot showed that pulvones A significantly decreased the levels of iNOS and COX-2 proteins and pulvones C only decreased the level of iNOS protein. ELISA analysis demonstrated that pulvones A inhibited the production of both interleukin-6 (IL-6) and IL-1ß while pulvones C showed better suppression effect on IL-1ß production in LPS-stimulated RAW264.7 cells. Then, their potential inhibitory effects on NF-κB pathway were tested in LPS-stimulated RAW264.7 cells. Immunofluorescence and western blot assay showed that pulvones A and C reduced the nuclear translocation of NF-κB(p65) and interrupted IκB phosphorylation. The ADP-Glo™ kinase assay showed pulvones A and C could directedly inhibit the IKKß kinase activity with the inhibitory rate of 40%, which were also verified by docking study. Collectively, these results suggested that pulvones A and C's anti-inflammatory effects were relevant to the interruption of NF-κB activation by inhibiting IKKß kinase.