The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity.

Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.

A latent profile analysis of resilience and their relation to differences in sleep quality in patients with lung cancer.

PURPOSE: Sleep problems are a significant issue in patients with lung cancer, and resilience is a closely related factor. However, few studies have identified subgroups of resilience and their relationship with sleep quality. This study aimed to investigate whether there are different profiles of resilience in patients with lung cancer, to determine the sociodemographic characteristics of each subgroup, and to determine the relationship between resilience and sleep quality in different subgroups. METHODS: A total of 303 patients with lung cancer from four tertiary hospitals in China completed the General Sociodemographic sheet, the Connor-Davidson Resilience Scale, and the Pittsburgh Sleep Quality Index. Latent profile analysis was applied to explore the latent profiles of resilience. Multivariate logistic regression was used to analyze the sociodemographic variables in each profile, and ANOVA was used to explore the relationships between resilience profiles and sleep quality. RESULTS: The following three latent profiles were identified: the "high-resilience group" (30.2%), the "moderate-resilience group" (46.0%), and the "low-resilience group" (23.8%). Gender, place of residence, and average monthly household income significantly influenced the distribution of resilience in patients with lung cancer. CONCLUSION: The resilience patterns of patients with lung cancer varied. It is suggested that health care providers screen out various types of patients with multiple levels of resilience and pay more attention to female, rural, and poor patients. Additionally, individual differences in resilience may provide an actionable means for addressing sleep problems.

Dual stress factors adaptive evolution for high EPA production in Schizochytrium sp. and metabolomics mechanism analysis.

Eicosapentaenoic acid (EPA) is a vital É·-3 polyunsaturated fatty acid (PUFA) for human body with various physiological functions. In this study, we proposed an adaptive evolutionary strategy based on high-temperature and high-oxygen two-factor stress to increase the EPA production capacity of Schizochytrium. High-temperature stress was used to increase EPA yield, and high oxygen was implemented to continuously stimulate cell growth and lipid accumulation. The biomass and EPA production of ALE-D50 reached 35.33 g/L and 1.54 g/L, which were 43.85% and 71.11% higher than that of the original strain, respectively. Lower in vivo reactive oxygen species levels indicated that the evolved strain possessed stronger antioxidant activity. Liquid chromatography-mass spectrometry metabolomics showed that enhanced glucose consumption and glycolysis metabolism, as well as a weakened tricarboxylic acid cycle and reduced amino acid metabolic tributaries in the evolved strain, might be associated with increased growth and EPA synthesis. Finally, the lipid production and EPA production in a fed-batch fermentation were further increased to 48.93 g/L and 3.55 g/L, improving by 54.30% and 90.86%, respectively. This study provides a novel pathway for promoting EPA biosynthesis in Schizochytrium.

Peripheral blood lymphocyte subsets in children with nephrotic syndrome: a retrospective analysis.

BACKGROUND: Nephrotic syndrome (NS) in children is widely believed to be associated with severe changes in the immune system. Based on lymphocyte subset analysis, we examined the pathogenesis of immune deficiencies in children with NS with varying steroid sensitivity. METHODS: Our study utilized flow cytometry to retrospectively analyze the ratios of lymphocyte subsets in 204 children with nephrotic syndrome and 19 healthy children. RESULTS: Compared with healthy children, the ratio of CD4 + /CD8 + in onset and remission was decreased in SRNS group (p < 0.05), and CD19 + B lymphocytes were increased in onset (p < 0.05). Compared with onset, the proportion of CD19 + B lymphocytes decreased in SRNS, while the proportion of CD19 + B lymphocytes increased in SDNS, p < (0.01). The ratio of CD8 + T/CD19 + B in onset in SDNS group was significantly higher than that in SSNS and SRNS groups (p < 0.01) and healthy control group (p < 0.05). Compared with onset, the ratio of CD8 + T/CD19 + B in SDNS group decreased significantly (p < 0.01), while the ratio of CD8 + T/CD19 + B in SRNS group increased significantly (p < 0.01). The proportion of CD56 + CD16 + NK cells was significantly reduced in children with INS (p < 0.01). CONCLUSION: CD8 + T lymphocytes may be involved in the mechanism of lymphocyte subsets disorder during onset of SDNS, while CD19 + B lymphocytes may be involved in the mechanism of lymphocyte subsets disorder during relapse of SDNS. The CD8 + T/CD19 + B ratio may predict the degree of frequent recurrence. There is a certain degree of lymphoid subsets disorder in children with NS.

Does "who I am" influence "how I feel"? Cultural identity and mental health among Hong Kong Chinese adolescents.

Securing a clear sense of identity is a critical issue in adolescence, yet the role that cultural identity plays in the well-being of youths remains unclear. This study aims to examine the relationship between cultural identity and mental health among three groups of adolescents in Hong Kong with different residential backgrounds. Data came from a cross-sectional survey with 2180 4th-9th grade students in Hong Kong. Cultural identity was assessed by whether the youths identify themselves as local Hong Kong people, mainland Chinese, both Hong Kong and mainland Chinese, or confused about which group to belong to. Mental health was assessed by self-esteem, mental well-being, happiness, social anxiety, and depression. Multiple linear regression was performed to examine the relationship between cultural identity and mental health, adjusting for sociodemographic variables. The regression results suggested adolescents with confused cultural identity scored lower in all positive indicators of mental health compared with those with a clear cultural identification. No significant association was found between cultural identity and social anxiety/depression. Uncertainty in cultural identification may be detrimental for the mental health of adolescents living in a multicultural society. Interventions may consider cultivating clear cultural identities among adolescents to promote their mental health.

A two-part, single-arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies.

This single-arm, multicentre, phase I study is the first study of zanubrutinib, a potent, specific, irreversible Bruton tyrosine kinase (BTK) inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies. The objectives were to evaluate safety and preliminary anti-tumour activity. Forty-four patients received zanubrutinib 320 mg once daily (QD) (n = 10) or 160 mg twice daily (BID) (n = 34) until disease progression or unacceptable toxicity. 29.5% of patients received zanubrutinib for at least two years. The most common adverse event (AE) and the most common grade 3 or higher AE was neutrophil count decreased (54.5% and 25.0% respectively). Two patients (4.5%) discontinued treatment due to AEs and one treatment-emergent AE led to death. All haemorrhagic events were grade 1-2 (except for one non-serious grade 3 purpura). No second primary malignancies, tumour lysis syndrome, or atrial fibrillation/flutter occurred. The overall response rate was 52.3% (complete response rate, 18.2%). Patients with all cancer subtypes benefited from treatment. BTK C481S/R or L528W mutations were found in zanubrutinib-progressive patients. The safety/efficacy profiles of patients treated with 320 mg QD and 160 mg BID were comparable and similar daily area under the curve (AUC) was achieved. Overall, zanubrutinib was well tolerated and either of these two regimens is clinically practical. Registered at ClinicalTrials.gov (NCT03189524, on 16 June 2017, https://clinicaltrials.gov/ct2/show/NCT03189524).

Autophagy and pressure overload-induced cardiac hypertrophy.

Autophagy plays an important role in the pathogenesis of cardiovascular diseases. Dysregulation of autophagy may have a huge effect on cardiac hypertrophy induced by overload pressure although reports on autophagy and cardiac hypertrophy have been contradictory. Some studies showed that autophagy activation attenuated cardiac hypertrophy. However, others suggested that inhibition of autophagy would be protective. Different research models or different pathways involved could be responsible for it. Cardiac hypertrophy may be alleviated through regulation of autophagy. This review aims to highlight the pathways and therapeutic targets identified in the prevention and treatment of cardiac hypertrophy by regulating autophagy.

Evaluation of drug interaction potential of zanubrutinib with cocktail probes representative of CYP3A4, CYP2C9, CYP2C19, P-gp and BCRP.

AIM: This study aims to assess the potential effects of zanubrutinib on the activity of cytochrome P450 (CYP) enzymes and drug transporter proteins using a cocktail probe approach. METHODS: Patients received single oral doses of probe drugs alone and after at least 8 days of treatment with zanubrutinib 160 mg twice daily in a single-sequence study in 18 healthy male volunteers. Simultaneous doses of 10 mg warfarin (CYP2C9) and 2 mg midazolam (CYP3A) were administered on Day 1 and Day 14, 0.25 mg digoxin (P-glycoprotein [P-gp]) and 10 mg rosuvastatin (breast cancer resistance protein [BCRP]) on Day 3 and Day 16, and 20 mg omeprazole (CYP2C19) on Day 5 and Day 18. Pharmacokinetic (PK) parameters were estimated from samples obtained up to 12 h post dose for zanubrutinib; 24 h for digoxin, omeprazole and midazolam; 48 h for rosuvastatin; and 144 h for warfarin. RESULTS: The ratios (%) of geometric least squares means (90% confidence intervals) for the area under the concentration-time curve from time zero to the last quantifiable concentration in the presence/absence of zanubrutinib were 99.80% (97.41-102.2%) for S-warfarin; 52.52% (48.49-56.88%) for midazolam; 111.3% (103.8-119.3%) for digoxin; 89.45% (78.73-101.6%) for rosuvastatin; and 63.52% (57.40-70.30%) for omeprazole. Similar effects were observed for maximum plasma concentrations. CONCLUSIONS: Zanubrutinib 320 mg total daily dose had minimal or no effect on the activity of CYP2C9, BCRP and P-gp, but decreased the systemic exposure of CYP3A and CYP2C19 substrates (mean reduction <50%).

Bone marrow-derived mesenchymal stem cells attenuate myocardial ischemia-reperfusion injury via upregulation of splenic regulatory T cells.

BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is the main pathological manifestation of cardiovascular diseases such as myocardial infarction. The potential therapeutic effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) and the participation of regulatory T cells (Tregs) in MIRI remains to be defined. METHODS: We used the experimental acute MIRI that was induced in mice by left ascending coronary ischemia, which were subsequently randomized to receive immunoglobulin G (IgG) or anti-CD25 antibody PC61 with or without intravenously injected BM-MSCs. The splenectomized mice underwent prior to experimental MIRI followed by intravenous administration of BM-MSCs. At 72 h post-MIRI, the hearts and spleens were harvested and subjected to cytometric and histologic analyses. RESULTS: CD25+Foxp3+ regulatory T cells were significantly elevated after MIRI in the hearts and spleens of mice receiving IgG + BM-MSCs and PC61 + BM-MSCs compared to the respective control mice (all p < 0.01). This was accompanied by upregulation of interleukin 10 and transforming growth factor ß1 and downregulation of creatinine kinase and lactate dehydrogenase in the serum. The post-MIRI mice receiving BM-MSCs showed attenuated inflammation and cellular apoptosis in the heart. Meanwhile, splenectomy compromised all therapeutic effects of BM-MSCs. CONCLUSION: Administration of BM-MSCs effectively alleviates MIRI in mice through inducing Treg activation, particularly in the spleen.

Transitory restless arms syndrome in a patient with antipsychotics and antidepressants: a case report.

BACKGROUND: Restless arms syndrome (RAS) is characterized by uncomfortable aching or burning sensations in the arms. RAS is regarded as an upper limb variant of restless legs syndrome (RLS). The lack of specific diagnostic criteria makes it difficult to recognize the RAS. Therefore, RAS is usually neglected in clinical practice. Moreover, when a patient was diagnosed with RAS, the adjustment of medications was the first choice for doctors, which may make the patient's condition unstable. CASE PRESENTATION: A 33-year-old woman was diagnosed with schizophrenia and major depressive disorder. Starting with 0.6 g/d amisulpride, 0.1 g/d quetiapine, 75 mg/d venlafaxine sustained-release tablets, the patient reported symptoms of RAS (itching arms) on the fourth day since the latest hospitalization. After ruling out other factors, her RAS was suspected to be induced by antidepressants or antipsychotics. Without medication adjustment, RAS spontaneously remitted. CONCLUSIONS: This case suggests that psychiatrists should pay attention to RAS when using antipsychotics and/or antidepressants. Moreover, RAS may be transitory. When a patient manifests RAS, observation may be one choice instead of an immediate medication adjustment.

Compliance with aspirin in paediatric CHD post-percutaneous transcatheter occlusion: a cross-sectional study.

BACKGROUND: Predictors of compliance with aspirin in children following cardiac catheterisation have not been identified. The aim of this study is to identify the caregivers' knowledge, compliance with aspirin medication, and predictors of compliance with aspirin in children with Congenital Heart Disease (CHD) post-percutaneous transcatheter occlusion. METHODS: A cross-sectional explorative design was adopted using a self-administered questionnaire and conducted between May 2017 and May 2018. Recruited were 220 caregivers of children with CHD post-percutaneous transcatheter occlusion. Questionnaires included child and caregivers' characteristics, a self-designed and tested knowledge about aspirin scale (scoring scale 0-2), and the 8-item Morisky Medication Adherence Scale (scoring scale 0-8). Data were analysed using multivariate binary logistic regression analysis to identify predictors of compliance with aspirin. RESULTS: Of the 220 eligible children and caregivers, 210 (95.5%) responded and 209 surveys were included in the analysis. The mean score of knowledge was 7.25 (standard deviation 2.27). The mean score of compliance was 5.65 (standard deviation 1.36). Child's age, length of aspirin use, health insurance policies, relationship to child, monthly income, and knowledge about aspirin of caregivers were independent predictors of compliance with aspirin (p < 0.05). CONCLUSION: Caregivers of children with CHD had an adequate level of knowledge about aspirin. Compliance to aspirin medication reported by caregivers was low. Predictors of medium to high compliance with aspirin were related to the child's age and socio-economic reasons. Further studies are needed to identify effective strategies to improve knowledge, compliance with medication, and long-term outcomes of children with CHD.

Quitting trajectories of Chinese women smokers following telephone smoking cessation counselling: A longitudinal study.

AIMS AND OBJECTIVES: This study mapped the quitting patterns (trajectories) of Hong Kong Chinese women smokers who had received counselling via a quitline service and examined factors correlated with different trajectories. BACKGROUND: Quitting smoking is always a gradual and progressive process. However, most existing studies on smoking cessation have adopted a cross-sectional approach to conduct evaluation. Little is known about the quitting trajectories of smokers, particularly those who are women after receiving smoking cessation counselling. METHODS: We used a retrospective longitudinal design and analysed 474 women smokers who had called the quitline. Quitting trajectories were mapped using latent growth modelling. Multinomial logistic regression was performed to identify factors associated with class membership. A STROBE checklist was completed. RESULTS: We identified three trajectory groups: 'quitters' who quit smoking at 6 months and abstained from cigarettes up to 6 years; 'reducers' who cut down cigarette consumption ≥50% at 3 years and maintained reduced levels up to 6 years; and 'increasers' who increased smoking ≥20% at 3 years and continued smoking up to 6 years. Participants who perceived more difficulties in quitting were more likely to be increasers. Those with higher daily cigarette consumption at baseline were more likely to be reducers. CONCLUSIONS: We clarified three trajectory groups of women smokers. The results indicate that existing cessation services need to be improved, especially for women smokers who do not quit after receiving telephone counselling. RELEVANCE TO CLINICAL PRACTICE: Existing cessation services need to be improved, especially for women smokers who do not quit after receiving telephone counselling. For those who reduce smoking but fail to quit, quit plans should be developed that provide step-by-step guidance in achieving abstinence through smoking reduction. Instant messages may complement telephone counselling to deliver cessation support for those who increase their cigarette consumption.

Visual detection of kanamycin with DNA-functionalized gold nanoparticles probe in aptamer-based strip biosensor.

Kanamycin has been widely used to treat human and animal diseases. The excessive use of kanamycin causes its accumulation in animal-derived foods, and eventually threats human health. In the present study, we develop a lateral flow strip biosensor for fast and sensitive detection of kanamycin. The strip biosensor combines the easy separation of magnetic microspheres (MMS) with target-mediated chain displacement of single-stranded DNA and the capture of the visible DNA-functionalized gold nanoparticles (AuNPs) probe. The presence of kanamycin can competitively bind to the aptamer and release cDNA to the supernatant. The concentration of free cDNA, which is the direct target of the strip, is proportional to the concentration of kanamycin. The capture of DNA-functionalized AuNPs on the test zone of the strip through cDNA-induced hybridization provides a visual detection signal. The assay can be completed within 20 min. The visual detection limit by naked eyes of the strip is 50 nM. A linear detection range of 5-500 nM is derived for quantitative determination, with the detection limit of 4.96 nM (S/N = 3). This lateral flow strip biosensor can quickly and sensitively detect kanamycin in different food samples, which holds great application potential in medicine and daily life.

Physiologically-based pharmacokinetic modelling to predict oprozomib CYP3A drug-drug interaction potential in patients with advanced malignancies.

AIMS: Oprozomib is an oral, second-generation, irreversible proteasome inhibitor currently in clinical development for haematologic malignancies, including multiple myeloma and other malignancies. Oprozomib is a rare example of a small molecule drug that demonstrates cytochrome P450 (CYP) mRNA suppression. This unusual property elicits uncertainty regarding the optimal approach for predicting its drug-drug interaction (DDI) risk. The current study aims to understand DDI potential during early clinical development of oprozomib. METHODS: To support early development of oprozomib (e.g. inclusion/exclusion criteria, combination study design), we used human hepatocyte data and physiologically-based pharmacokinetic (PBPK) modelling to predict its CYP3A4-mediated DDI potential. Subsequently, a clinical DDI study using midazolam as the substrate was conducted in patients with advanced malignancies. RESULTS: The clinical DDI study enrolled a total of 21 patients, 18 with advanced solid tumours. No patient discontinued oprozomib due to a treatment-related adverse event. The PBPK model prospectively predicted oprozomib 300 mg would not cause a clinically relevant change in exposure to CYP3A4 substrates (≤30%), which was confirmed by the results of this clinical DDI study. CONCLUSIONS: These results indicate oprozomib has a low potential to inhibit the metabolism of CYP3A4 substrates in humans. The study shows that cultured human hepatocytes are a more reliable system for DDI prediction than human liver microsomes for studying this class of compounds. Developing a PBPK model prior to a clinical DDI study has been valuable in supporting clinical development of oprozomib.

The influence of undetermined deaths on suicides in Shanghai, China.

PURPOSE: In global forensic practice, some suicides were misclassified as undetermined deaths, leading to suicide underreporting. In this study, we aimed to explore the influence of undetermined deaths on suicides in Shanghai, China. METHODS: The police records on suicide verdicts and undetermined deaths in Pudong, Shanghai, from 2004 to 2016 were used. In this study, undetermined deaths have been classified into three levels of suicide possibilities namely, probable, possible, and highly unlikely. Probable suicides were presumed as misclassified suicides. Poisson regression was used to calculate the rate ratio ("RR") of probable suicides compared to suicide verdicts. Poisson regression was also used to calculate the annual percentage change ("APC") of the original suicide rates (crude suicide rates based on the suicide verdicts) and adjusted suicide rates (crude suicide rates based on the suicide verdicts and probable suicides). RESULTS: Among the 1,318 underdetermine deaths, 560 (42.5%) were classified as probable suicides. The overall RR was 0.23 (95% CI 0.21-0.26): 0.15 (0.13-0.17) for the locals' RR and 0.22 (0.19-0.26) for the migrants' RR. The APCs of the original and adjusted suicide rates were - 2.0 (- 3.1 to - 0.9) and - 2.9 (- 3.8 to - 2.0), respectively, for the overall population. CONCLUSIONS: The number of suicides could be 23% higher than the reported cases. Suicides were more likely to be underreported in migrants than in the locals. Thus, it is important to improve suicide monitoring and the surveillance systems in China.

Identifying Reducing and Capping Sites of Protein-Encapsulated Gold Nanoclusters.

The reducing and capping sites along with their local structure impact photo properties of the red bovine serum albumin-capped Au nanocluster (BSA-AuNC), however, they are hard to identify. We developped a workflow and relevant techniques using mass spectrometry (MS) to identify the reducing and capping sites of BSA-AuNCs involved in their formation and fluorescence. Digestion without disulfide cleavages yielded an Au core fraction exhibiting red fluorescence and [AunSm] ion signals and a non-core fraction exhibiting neither of them. The core fraction was identified to mainly be comprised of peptides containing cysteine residues. The fluorescence and [AunSm] signals were quenched by tris(2-carboxyethyl)phosphine, confirming that disulfide groups were required for nanocluster stabilization and fluorescence. By MS sequencing, the disulfide pairs, C75-C91/C90-C101 in domain IA, C315-C360/C359-C368 in domain IIB, and C513-C558/C557-C566 in domain IIIB, were identified to be main capping sites of red AuNCs. Peptides containing oxidized cysteines (sulfinic or cysteic acid) were identified as reducing sites mainly in the non-core fraction, suggesting that disulfide cleavages by oxidization and conformational changes contributed to the subsequent growth of nanoclusters at nearby intact disulfide pairs. This is the first report on precise identification of the reducing and capping sites of BSA-AuNCs.

Liuweibuqi capsules improve pulmonary function in stable chronic obstructive pulmonary disease with lung-qi deficiency syndrome by regulating STAT4/STAT6 and MMP-9/TIMP-1.

Context: Liuweibuqi (LWBQ) capsule has been reported to influence symptoms of patients with chronic obstructive pulmonary disease (COPD); however, specific function of LWBQ capsules in COPD with lung-qi deficiency syndrome remains elusive.Objective: This study investigates effect of LWBQ capsules on STAT4/STAT6 and MMP-9/TIMP-1 expression and pulmonary function in stable COPD with lung-qi deficiency syndrome.Materials and methods: Totally, 429 patients diagnosed with stable COPD and lung-qi deficiency syndrome were treated with starch capsules (each time for 9 capsules), or different doses: low (each dose for 8 capsules and 1 LWBQ capsules), medium (each time for 6 capsules and 3 LWBQ capsules), or high (each time for 9 LWBQ capsules) of LWBQ capsules for 30 days, 3 times a day. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC% and DLco%pred were evaluated by pulmonary function meter. STAT4/STAT6 and MMP-9/TIMP-1 expression was assessed by RT-qPCR and western blot analysis, and serum concentrations of IL-4, IFN-γ and IL-6 by ELISA.Results: Spearman rank correlation analysis and ROC curve showed that STAT4/STAT6 and MMP-9/TIMP-1 affected pulmonary functions and curative effect of stable COPD with lung-qi deficiency syndrome. After LWBQ capsule treatment, FEV1, FVC, FEV1/FVC% and DLco%pred elevated; STAT4/STAT6, MMP-9/TIMP-1, IFN-γ and IL-6 expression declined whereas IL-4 expression increased (p < 0.05). Logistic regression analysis demonstrated that FEV1/FVC was negatively correlated with STAT4/STAT6 and MMP-9/TIMP-1 expression in COPD patients.Conclusions: LWBQ capsules play a beneficial role in pulmonary function of stable COPD with lung-qi deficiency syndrome via STAT4/STAT6 and MMP-9/TIMP-1.

CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma.

Carfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m(2) [cycle 1, days 1-2]; 27 mg/m(2) thereafter). This multicenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IV infusion) on days 1, 8, and 15 of 28-day cycles. The phase 1 portion used a 3 + 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at the MTD. Patients received dexamethasone (40 mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 9+. A total of 116 patients were enrolled. The MTD was 70 mg/m(2), and 104 patients (phase 1/2) received carfilzomib 70 mg/m(2) At 70 mg/m(2), the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m(2), the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m(2) was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials.gov as #NCT01677858.

Bisphosphonate use and the risk of breast cancer: a meta-analysis of observational studies.

PURPOSE: To summarize current evidence of the association of bisphosphonate use with breast cancer risk, we used a systematic review and meta-analysis of observational studies to explore this issue. METHODS: A comprehensive search was conducted on PubMed, EMBASE, and the Cochrane Library. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: Bisphosphonate use was associated with a 16% lower breast cancer risk (pool RR0.84, 95%CI 0.77-0.90, n = 8). A protective effect of bisphosphonate was found in cohort studies (RR 0.85, 95%CI 0.80-0.90, n = 4) and case-control studies (RR 0.78, 95%CI 0.64-0.96, n = 4).We also found that the use of bisphosphonate resulted in a statistically significant reduction in all breast cancer risk (RR 0.87, 95%CI 0.81-0.93) and greater reduction in invasive breast cancer risk (RR 0.78, 95%CI 0.68-0.91) and contralateral breast cancer risk (RR, 0.41; 95% CI, 0.20-0.84).With respect to the type of bisphosphonate, we found that alendronate and etidronate resulted significant reduction in breast cancer risk. The short-term use of bisphosphonate (<1 y) led to nonsignificant change (RR 0.93, 95%CI 0.86-1.00), but a significant 26% reduction of breast cancer risk was noted with long-term use (>1 y) (RR 0.74, 95%CI 0.66-0.83). CONCLUSIONS: Our results supported bisphosphonate as being effective in preventing breast cancer, including invasive and contralateral breast cancer. Furthermore, the long-term use (>1 y) of bisphosphonate was more significant in lowering breast cancer risk.

Bisphosphonate use and the risk of endometrial cancer: a meta-analysis of observational studies.

BACKGROUND: The association of bisphosphonate use and the risk of endometrial cancer is still unclear. No meta-analysis was conducted to review the evidence concerning this topic. METHODS: Relevant studies were identified through PubMed and EMBASE and the Cochrane Library databases. The adjusted relative risk (RR) or odds ratios were determined using a fixed effects or random effects model, depending on the overall heterogeneity. RESULTS: Seven studies, including four cohort studies and three case-control studies, met the method criteria and were included. The random effects model showed a significant reduction in the risk association between bisphosphonate use and endometrial cancer incidence (RR 0.75, 95%CI 0.60-0.94, p = 0.064, I2 = 49.6%). A significantly protective effect was observed with the use of bisphosphonate for more than 1 year, and we found a statistically significant risk reduction with the use of bisphosphonate for more than 1 to 3 years (RR 0.58, 95%CI 0.47-0.72) and for more than 3 years (RR 0.44, 95%CI 0.28-0.70). However, with the use of bisphosphonate for less than 1 year (RR 0.92, 95%CI 0.64-1.34), we found no protective effect against endometrial cancer. CONCLUSIONS: We found that the use of bisphosphonate was significantly associated with a 25% risk reduction in the incidence of endometrial cancer in the overall analysis. Furthermore, the use of bisphosphonate for more than 1 year but not less than 1 year may have a more beneficial effect on endometrial cancer risk. Copyright © 2016 John Wiley & Sons, Ltd.