Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools.

Exosomes are nano-sized vesicles that serve as mediators for intercellular communication through the delivery of cargo, including protein, lipids, nucleic acids or other cellular components, to neighboring or distant cells. Exosomal cargo may vary in response to different physiological or pathological conditions. The endosomal sorting complex required for transport (ESCRT) family has been widely accepted as a key mechanism in biogenesis and cargo sorting. On the other hand, accumulating evidence show that ESCRT-independent pathways exist. Due to the critical role of exosomes in intercellular communications in delivering cargo to recipient cells, exosomes have been investigated as a vector for the delivery of endogenous or exogenous cargo for therapeutic purposes. But the number of exosomes produced by cells is limited, which hampers their application. Synthetic exosome-mimics have been fabricated and investigated as a therapeutic tool for drug delivery. This review focuses on ESCRT-independent regulation of cargo loading into exosomes, including lipid raft and ceramide-mediated mechanisms, and reported exosomes or exosome-mimics with therapeutic effects.

Admission for osteoporotic pelvic fractures and predictors of length of hospital stay, mortality and loss of independence.

OBJECTIVE: To study the implications of osteoporotic pelvic fractures in older patients in terms of mortality, length of hospital stay and independent living. METHODS: The study included 110 consecutive patients, aged over 60 years, with osteoporotic pelvic fractures admitted to the Queen Elizabeth Hospital, Gateshead, between July 2009 and March 2011. Demographic and routine clinical data were collected prospectively until date of discharge, and vital status data were collected up to 3 months post-fracture. These data were analysed to assess associations with outcomes such as length of hospital stay, mortality and loss of independence (according to changes in residential housing status). RESULTS: Fourteen patients died either in hospital, or within 3 months of fracture. Length of hospital stay was associated with age (b=0.77 days per year, 95% CI 0.001, 1.54, P=0.05) and was significantly longer in those with acute medical problems on admission (b=21.2 days, 95% CI 8.72, 33.73, P=0.001). The odds of changing from independent to institutionalised accommodation were significantly associated with age (OR 1.08 per year, 95% CI 1.01, 1.04, P=0.007) and length of hospital stay (OR 1.12 per day, 95% CI 1.01, 1.04, P=0.007). CONCLUSION: In-hospital mortality rates in this patient group are similar to those seen for hip fractures, yet pelvic fractures in older people receive relatively little in the way of attention or funding. Guidelines to improve the management of such fractures in older people are important to improve care while in hospital, reduce time spent in hospital and reduce the impact on independent living.

Chemotherapy-Enabled Colorectal Cancer Immunotherapy of Self-Delivery Nano-PROTACs by Inhibiting Tumor Glycolysis and Avoiding Adaptive Immune Resistance.

The chemo-regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c-Myc, which also inhibits the expression of programmed death ligand 1 (PD-L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self-delivery nano-PROTACs (designated as DdLD NPs) are further fabricated by the self-assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE-PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo-regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD-L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo-regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self-delivery nano-PROTACs may provide a new insight for chemotherapy-enabled tumor immunotherapy.

Identification of miR-20b-5p as an inhibitory regulator in cardiac differentiation via TET2 and DNA hydroxymethylation.

BACKGROUND: Congenital heart disease (CHD) is a prevalent congenital cardiac malformation, which lacks effective early biological diagnosis and intervention. MicroRNAs, as epigenetic regulators of cardiac development, provide potential biomarkers for the diagnosis and treatment of CHD. However, the mechanisms underlying miRNAs-mediated regulation of cardiac development and CHD malformation remain to be further elucidated. This study aimed to explore the function of microRNA-20b-5p (miR-20b-5p) in cardiac development and CHD pathogenesis. METHODS AND RESULTS: miRNA expression profiling identified that miR-20b-5p was significantly downregulated during a 12-day cardiac differentiation of human embryonic stem cells (hESCs), whereas it was markedly upregulated in plasma samples of atrial septal defect (ASD) patients. Our results further revealed that miR-20b-5p suppressed hESCs-derived cardiac differentiation by targeting tet methylcytosine dioxygenase 2 (TET2) and 5-hydroxymethylcytosine, leading to a reduction in key cardiac transcription factors including GATA4, NKX2.5, TBX5, MYH6 and cTnT. Additionally, knockdown of TET2 significantly inhibited cardiac differentiation, which could be partially restored by miR-20b-5p inhibition. CONCLUSIONS: Collectively, this study provides compelling evidence that miR-20b-5p functions as an inhibitory regulator in hESCs-derived cardiac differentiation by targeting TET2, highlighting its potential as a biomarker for ASD.

Cardiopulmonary progenitors facilitate cardiac repair via exosomal transfer of miR-27b-3p targeting the SIK1-CREB1 axis.

Ischemic heart disease, especially myocardial infarction (MI), is one of the leading causes of death worldwide, and desperately needs effective treatments, such as cell therapy. Cardiopulmonary progenitors (CPPs) are stem cells for both heart and lung, but their repairing role in damaged heart is still unknown. Here, we obtained CPPs from E9.5 mouse embryos, maintained their stemness while expanding, and identified their characteristics by scRNA-seq, flow cytometry, quantitative reverse transcription-polymerase chain reaction, and differentiation assays. Moreover, we employed mouse MI model to investigate whether CPPs could repair the injured heart. Our data identified that CPPs exhibit hybrid fibroblastic, endothelial, and mesenchymal state, and they could differentiate into cell lineages within the cardiopulmonary system. Moreover, intramyocardial injection of CPPs improves cardiac function through CPPs exosomes (CPPs-Exo) by promotion of cardiomyocytic proliferation and vascularization. To uncover the underlying mechanism, we used miRNA-seq, bulk RNA-seq, and bioinformatic approaches, and found the highly expressed miR-27b-3p in CPPs-Exo and its target gene Sik1, which can influence the transcriptional activity of CREB1. Therefore, we postulate that CPPs facilitate cardiac repair partially through the SIK1-CREB1 axis via exosomal miR-27b-3p. Our study offers a novel insight into the role of CPPs-Exo in heart repair and highlights the potential of CPPs-Exo as a promising therapeutic strategy for MI.

Exploring brain glucose metabolic patterns in cognitively normal adults at risk of Alzheimer's disease: A cross-validation study with Chinese and ADNI cohorts.

OBJECTIVE: Disease-related metabolic brain patterns have been verified for a variety of neurodegenerative diseases including Alzheimer's disease (AD). This study aimed to explore and validate the pattern derived from cognitively normal controls (NCs) in the Alzheimer's continuum. METHODS: This study was based on two cohorts; one from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the other from the Sino Longitudinal Study on Cognitive Decline (SILCODE). Each subject underwent [18F]fluoro-2-deoxyglucose positron emission tomography (PET) and [18F]florbetapir-PET imaging. Participants were binary-grouped based on ß-amyloid (Aß) status, and the positivity was defined as Aß+. Voxel-based scaled subprofile model/principal component analysis (SSM/PCA) was used to generate the "at-risk AD-related metabolic pattern (ARADRP)" for NCs. The pattern expression score was obtained and compared between the groups, and receiver operating characteristic curves were drawn. Notably, we conducted cross-validation to verify the robustness and correlation analyses to explore the relationships between the score and AD-related pathological biomarkers. RESULTS: Forty-eight Aß+ NCs and 48 Aß- NCs were included in the ADNI cohort, and 25 Aß+ NCs and 30 Aß- NCs were included in the SILCODE cohort. The ARADRPs were identified from the combined cohorts and the two separate cohorts, characterized by relatively lower regional loadings in the posterior parts of the precuneus, posterior cingulate, and regions of the temporal gyrus, as well as relatively higher values in the superior/middle frontal gyrus and other areas. Patterns identified from the two separate cohorts showed some regional differences, including the temporal gyrus, basal ganglia regions, anterior parts of the precuneus, and middle cingulate. Cross-validation suggested that the pattern expression score was significantly higher in the Aß+ group of both cohorts (p < 0.01), and contributed to the diagnosis of Aß+ NCs (with area under the curve values of 0.696-0.815). The correlation analysis revealed that the score was related to tau pathology measured in cerebrospinal fluid (p-tau: p < 0.02; t-tau: p < 0.03), but not Aß pathology assessed with [18F]florbetapir-PET (p > 0.23). CONCLUSIONS: ARADRP exists for NCs, and the acquired pattern expression score shows a certain ability to discriminate Aß+ NCs from Aß- NCs. The SSM/PCA method is expected to be helpful in the ultra-early diagnosis of AD in clinical practice.

ß-Amyloid in blood neuronal-derived extracellular vesicles is elevated in cognitively normal adults at risk of Alzheimer's disease and predicts cerebral amyloidosis.

BACKGROUND: Blood biomarkers that can be used for preclinical Alzheimer's disease (AD) diagnosis would enable trial enrollment at a time when the disease is potentially reversible. Here, we investigated plasma neuronal-derived extracellular vesicle (nEV) cargo in patients along the Alzheimer's continuum, focusing on cognitively normal controls (NCs) with high brain ß-amyloid (Aß) loads (Aß+). METHODS: The study was based on the Sino Longitudinal Study on Cognitive Decline project. We enrolled 246 participants, including 156 NCs, 45 amnestic mild cognitive impairment (aMCI) patients, and 45 AD dementia (ADD) patients. Brain Aß loads were determined using positron emission tomography. NCs were classified into 84 Aß- NCs and 72 Aß+ NCs. Baseline plasma nEVs were isolated by immunoprecipitation with an anti-CD171 antibody. After verification, their cargos, including Aß, tau phosphorylated at threonine 181, and neurofilament light, were quantified using a single-molecule array. Concentrations of these cargos were compared among the groups, and their receiver operating characteristic (ROC) curves were constructed. A subset of participants underwent follow-up cognitive assessment and magnetic resonance imaging. The relationships of nEV cargo levels with amyloid deposition, longitudinal changes in cognition, and brain regional volume were explored using correlation analysis. Additionally, 458 subjects in the project had previously undergone plasma Aß quantification. RESULTS: Only nEV Aß was included in the subsequent analysis. We focused on Aß42 in the current study. After normalization of nEVs, the levels of Aß42 were found to increase gradually across the cognitive continuum, with the lowest in the Aß- NC group, an increase in the Aß+ NC group, a further increase in the aMCI group, and the highest in the ADD group, contributing to their diagnoses (Aß- NCs vs. Aß+ NCs, area under the ROC curve values of 0.663; vs. aMCI, 0.857; vs. ADD, 0.957). Furthermore, nEV Aß42 was significantly correlated with amyloid deposition, as well as longitudinal changes in cognition and entorhinal volume. There were no differences in plasma Aß levels among NCs, aMCI, and ADD individuals. CONCLUSIONS: Our findings suggest the potential use of plasma nEV Aß42 levels in diagnosing AD-induced cognitive impairment and Aß+ NCs. This biomarker reflects cortical amyloid deposition and predicts cognitive decline and entorhinal atrophy.

Glucose metabolism in the right middle temporal gyrus could be a potential biomarker for subjective cognitive decline: a study of a Han population.

INTRODUCTION: Subjective cognitive decline (SCD) represents a cognitively normal state but at an increased risk for developing Alzheimer's disease (AD). Recognizing the glucose metabolic biomarkers of SCD could facilitate the location of areas with metabolic changes at an ultra-early stage. The objective of this study was to explore glucose metabolic biomarkers of SCD at the region of interest (ROI) level. METHODS: This study was based on cohorts from two tertiary medical centers, and it was part of the SILCODE project (NCT03370744). Twenty-six normal control (NC) cases and 32 SCD cases were in cohort 1; 36 NCs, 23 cases of SCD, 32 cases of amnestic mild cognitive impairment (aMCIs), 32 cases of AD dementia (ADDs), and 22 cases of dementia with Lewy bodies (DLBs) were in cohort 2. Each subject underwent [18F]fluoro-2-deoxyglucose positron emission tomography (PET) imaging and magnetic resonance imaging (MRI), and subjects from cohort 1 additionally underwent amyloid-PET scanning. The ROI analysis was based on the Anatomical Automatic Labeling (AAL) template; multiple permutation tests and repeated cross-validations were conducted to determine the metabolic differences between NC and SCD cases. In addition, receiver operating characteristic curves were used to evaluate the capabilities of potential glucose metabolic biomarkers in distinguishing different groups. Pearson correlation analysis was also performed to explore the correlation between glucose metabolic biomarkers and neuropsychological scales or amyloid deposition. RESULTS: Only the right middle temporal gyrus (RMTG) passed the methodological verification, and its metabolic levels were correlated with the degrees of complaints (R = - 0.239, p = 0.009), depression (R = - 0.200, p = 0.030), and abilities of delayed memory (R = 0.207, p = 0.025), and were weakly correlated with cortical amyloid deposition (R = - 0.246, p = 0.066). Furthermore, RMTG metabolism gradually decreased across the cognitive continuum, and its diagnostic efficiency was comparable (NC vs. ADD, aMCI, or DLB) or even superior (NC vs. SCD) to that of the metabolism of the posterior cingulate cortex or precuneus. CONCLUSIONS: These findings suggest that the hypometabolism of RMTG could be a typical feature of SCD, and the large-scale hypometabolism in patients with symptomatic stages of AD may start from the RMTG, which gradually progresses starting in the preclinical stage. The specificity of identifying SCD from the perspective of self-perceived symptoms is likely to be increased by the detection of RMTG metabolism.

Self-delivery nanomedicine to overcome drug resistance for synergistic chemotherapy.

Multidrug resistance (MDR) is one of the prime reasons for the failure of cancer chemotherapy, which continues to be a great challenge to be solved. In this work, α-tocopherol succinate (α-TOS) and doxorubicin (DOX)-based self-delivery nanomedicine (designated as α-TD) is prepared to combat drug resistance for cancer synergistic chemotherapy. Carrier-free α-TD possesses a fairly high drug loading rate and improves the cellular uptake via the endocytosis pathway. More importantly, the apoptotic inducer α-TOS could elevate the reactive oxygen species (ROS) generation, disrupt mitochondrial function and reduce adenosine 5'-triphosphate (ATP) production, which facilitate the intracellular drug retention while decreasing its efflux. As a result, α-TD achieves a considerable synergistic chemotherapeutic effect against drug resistant cancer cells. Moreover, it also exhibits a preferable inhibitory effect on tumor growth with a low system toxicity in vivo. This synergistic drug self-delivery strategy would open a new window for developing carrier-free nanomedicine for overcoming drug resistance in cancer therapy.

BRD9 controls the oxytocin signaling pathway in gastric cancer via CANA2D4, CALML6, GNAO1, and KCNJ5.

BACKGROUND: First-line chemotherapeutic agents lead to remarkable activation treatment in cancers, but the side effects of these drugs also damage healthy cells. In some cases, drug resistance to chemotherapeutic agents is induced in cancer cells. The molecular mechanisms underlying such a side effect have been studied in a range of cancer types, yet little is known about how the adverse effects of chemotherapeutic drugs can be diminished by targeting bromodomain-containing protein 9 (BRD9) in gastric cancers. METHODS: We used two gastric cancer cell lines (MGC-803 and AGS) for comparison. We applied molecular and cellular techniques to measure cell survival and mRNA expression, investigated clinical data in the consensus of The Cancer Genome Atlas, and utilized high-throughput sequencing in MGC-803 cells and AGS cells for global gene expression analysis in inhibiting BRD9 conditions. RESULTS: Our studies showed that cancer cells with BRD9 overexpression, MGC-803 cells, were more sensitive to BRD9 inhibitors (i.e., BI9564 or BI7273) than AGS cells. The mechanism of BRD9 was related to the regulation of calcium voltage-gated channel auxiliary subunit alpha2 delta 4 (CANA2D4), calmodulin-like 6 (CALML6), guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O (GNAO1) and Potassium Inwardly Rectifying Channel Subfamily J, Member 5 (KCNJ5) oncogenes in the oxytocin signaling pathway. BRD9 inhibitors could enhance the sensitivity of gastric cancer MGC-803 cells to adriamycin and cisplatin, so we may reduce the dosage of chemotherapeutic agents in curing gastric cancers with BRD9 over expression by combining BI9564 or BI7273 with adriamycin or cisplatin. CONCLUSIONS: Our study elucidated the feasibility and effectiveness of inhibiting BRD9 to reduce the adverse effects of first-line chemotherapeutic agents in treating gastric cancer with BRD9 overexpression. This study provides a scientific theoretical basis for a chemotherapy regimen in gastric cancer with BRD9 overexpression.

Tumor targeted self-synergistic nanoplatforms for arsenic-sensitized photodynamic therapy.

Development of antitumor agents with high efficiency and low toxicity is one of the most important goals for biomedical research. However, most traditional therapeutic strategies were limited due to their non-specificity and abnormal tumor microenvironments, causing a poor therapeutic efficiency and severe side effects. In this paper, a tumor targeted self-synergistic nanoplatform (designated as PAO@PCN@HA) was developed for chemotherapy sensitized photodynamic therapy (PDT) against hypoxic tumors. The efficient drug loading of phenylarsine oxide (PAO) in porphyrinic metal organic framework of PCN-224 as well as the surface modification of hyaluronic acid (HA) improved the targeted drug delivery and reduced the side effects of PAO at the therapeutic dose. Particularly, PAO as an arsenical-based chemotherapeutic agent could not only induce cell apoptosis by generating reactive oxygen species (ROS), but also regulate tumor microenvironments to improve the PDT effect of PCN-224 by mitigating hypoxia and consuming cellular GSH. Both in vitro and in vivo investigations confirmed an effective self-synergy of PAO@PCN@HA in hypoxic tumor therapy with a low systemic toxicity. This integration of microenvironment adjustment with tumor targeted self-synergistic mechanism might provide a new insight for the development of arsenic-based antitumor strategy for clinical applications.

Mitochondria and plasma membrane dual-targeted chimeric peptide for single-agent synergistic photodynamic therapy.

Mitochondria and cell membrane play important roles in maintaining cellular activity and stability. Here, a single-agent self-delivery chimeric peptide based nanoparticle (designated as M-ChiP) was developed for mitochondria and plasma membrane dual-targeted photodynamic tumor therapy. Without additional carrier, M-ChiP possessed high drug loading efficacy as well as the excellent ability of producing reactive oxygen species (ROS). Moreover, the dual-targeting property facilitated the effective subcellular localization of photosensitizer protoporphyrin IX (PpIX) to generate ROS in situ for enhanced photodynamic therapy (PDT). Notably, plasma membrane-targeted PDT would enhance the membrane permeability to improve the cellular delivery of M-ChiP, and even directly disrupt the cell membrane to induce cell necrosis. Additionally, mitochondria-targeted PDT would decrease mitochondrial membrane potential and significantly promote the cell apoptosis. Both in vitro and in vivo investigations indicated that this combinatorial PDT in mitochondria and plasma membrane could achieve the therapeutic effect maximization with reduced side effects. The single-agent self-delivery system with dual-targeting strategy was demonstrated to be a promising nanoplatform for synergistic tumor therapy.

A biomimetic cascade nanoreactor for tumor targeted starvation therapy-amplified chemotherapy.

Targeted drug delivery with precisely controlled drug release and activation is highly demanding and challenging for tumor precision therapy. Herein, a biomimetic cascade nanoreactor (designated as Mem@GOx@ZIF-8@BDOX) is constructed for tumor targeted starvation therapy-amplified chemotherapy by assembling tumor cell membrane cloak and glucose oxidase (GOx) onto zeolitic imidazolate framework (ZIF-8) with the loading prodrug of hydrogen peroxide (H2O2)-sensitive BDOX. Biomimetic membrane camouflage affords superior immune evasion and homotypic binding capacities, which significantly enhance the tumor preferential accumulation and uptake for targeted drug delivery. Moreover, GOx-induced glycolysis would cut off glucose supply and metabolism pathways for tumor starvation therapy with the transformation of tumor microenvironments. Importantly, this artificial adjustment could trigger the site-specific BDOX release and activation for cascade amplified tumor chemotherapy regardless of the complexity and variability of tumor physiological environments. Both in vitro and in vivo investigations indicate that the biomimetic cascade nanoreactor could remarkably improve the therapeutic efficacy with minimized side effects through the synergistic starvation therapy and chemotherapy. This biomimetic cascade strategy would contribute to developing intelligent drug delivery systems for tumor precision therapy.

Stimulation of osteogenic differentiation in bone marrow stromal cells via Wnt/ß-catenin pathway by Qili Jiegu-containing serum.

A capsule of Qili Jiegu, a traditional Chinese medicine with numerous biological activities, may exert a protective eff ;ect against postmenopausal bone loss. However, it remains unclear whether Qili Jiegu-containing serum regulates the osteogenic diff ;erentiation of bone marrow stromal cells (BMSCs) in vitro. In this study, BMSCs were treated with medium and Qili Jiegu-containing serum over a 14-day period. We found that Qili Jiegu-containing serum promoted the BMSC proliferation and alkaline phosphatase (ALP) activities, as well as stimulated the expression of osteogenic markers and Wnt/ß-catenin pathway-related genes, i.e., runt-related transcription factor 2 (Runx2), osteocalcin (OCN), ß-catenin and Wnt4a, in BMSCs. Finally, we found that Qili Jiegu-containing serum activated the Wnt/ß-catenin pathway. An addition of Dickkopf-related protein-1 (an inhibitor of the Wnt/ß-catenin signaling pathway) to the Qili Jiegu-containing serum could decrease the stimulatory osteogenic effect of Qili Jiegu-containing serum on BMSCs. Therefore, Qili Jiegu-containing serum could promote the osteogenic diff ;erentiation of BMSCs, and the potential mechanism may involve regulation of Wnt/ß-catenin signaling.

[A cross-sectional case study of human immunodeficiency virus and tuberculosis co-infection in mainland China].

OBJECTIVE: In order to take an insight into the profile of HIV/AIDS and tuberculosis (TB) co-infection, we made a statistic survey in 9 hospitals in mainland China. With the purpose of guiding the prevention and treatment, 241 cases with such co-infection were enrolled and the data with respect to clinical manifestations, laboratory tests, therapy and prognosis were analysed. METHODS: All indices were collected with unified questionary. RESULTS: Young men (75.9%) took constituted the majority. HIV was transmitted mainly by intravenous drug use (IDU) in Xinjiang and Yunnan provinces, by blood transfusion or blood products in Shanghai, Henan and Wenxi county of Shanxi, and by sexual transmission in Fuzhou, Shanghai, Shenzhen and Dehong prefecture of Yunnan province. In this survey, pulmonary TB accounted for 59.3%, extra-pulmonary TB for 21.2%, and both for 19.5% of the patients. As for laboratory tests, only 9.5% was positive in sputum for acid-fast bacillus (AFB) and 2.9% in culture, 10.8% of the patients had AFB in pleural fluid or cerebrospinal fluid. Besides, PPD was negative or weakly positive in most of the cases. Overall, 76.8% of the 241 cases had a CD(4) cell count < 200/microl, and 58.5% < 100/microl. 80.5% of the patients was treated with anti-tuberculous medications and 69.7% with highly active antiretroviral therapy (HAART). 203 (84.2%) were still alive and 38 (15.8%) died. CONCLUSIONS: (1) The clinical manifestations of the 241 cases were varied because of prevailing pulmonary TB. (2) The immune function was depressed with reducing CD(4) counts in most of the patients. (3) Positivity rate of examination relevant to TB was too low to help the diagnosis. (4) The mortality (15.8%) was high even with HAART and/or chemotherapy.

Emerging treatment options for ovarian cancer: focus on rucaparib.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are an exciting class of anticancer drugs, which have revolutionized the management of BRCA mutant/homologous recombination-deficient recurrent high-grade serous ovarian cancer (HGSOC). With three PARPi now approved by the US Food and Drug Administration, olaparib (Lynparza™), niraparib (Zejula™), and rucaparib (Rubraca™) in 2014 (and 2017 for the tablet formulation), 2016, and 2017, respectively, these drugs have now entered routine clinical practice. The marked single-agent efficacy of PARPi either as maintenance following response to platinum-based chemotherapy or as up-front treatment in these indications is based on the well-known concept of synthetic lethality. PARPi themselves work by blocking the repair of single-strand DNA breaks by the base excision/single-strand break repair pathway and can also be directly cytotoxic by the mechanism of PARP trapping. The greatest benefit in terms of progression-free survival, in all three PARPi maintenance registration studies, was seen in women with platinum-sensitive BRCA mutation-associated HGSOC. However, it is clear that non-BRCA HGSOC can benefit from PARPi and the ongoing challenge of biomarker driven studies is how best to define these patients. PARPi are well tolerated, but more information is needed to assess the longer-term/later onset toxicities as these agents are investigated in the first-line setting. The future direction and challenges for PARPi will be to continue to expand beyond BRCA and ovarian cancer by identifying molecular or functional signatures of response; to see if the durable responses in ovarian cancer can be improved and efficacy can be achieved in other cancer sub-types by combining with novel targeted agents. This review summarizes the development of PARPi as a class in ovarian cancer with particular focus on the PARPi rucaparib.

A case of 18p deletion syndrome after blepharoplasty.

OBJECTIVE: The deletion of the short arm of chromosome 18 is thought to be one of the rare chromosomal aberrations. Here, we report a case to review this disease. CASE REPORT: The proband is a five-and-a-half-year-old girl who has had phenotypes manifested mainly by ptosis, broad face, broad neck with low posterior hairline, mental retardation, short stature, and other malformations. Chromosomal analysis for her mother showed a normal karyotype. Her father and younger brother were phenotypically normal. RESULT: Phenotypical features were quite similar throughout other cases and in accordance with the usual phenotype of del(18p) suggested within the same cases and among the del(18p) cases described. She underwent blepharoplasty, which improved her appearance. CONCLUSION: 18p deletion syndrome is diagnosed by gene analysis. Plastic surgeries for improving the appearance might be an option for these patients.

Inhibition of Gata4 and Tbx5 by Nicotine-Mediated DNA Methylation in Myocardial Differentiation.

Maternal nicotine exposure causes alteration of gene expression and cardiovascular programming. The discovery of nicotine-medicated regulation in cardiogenesis is of major importance for the study of cardiac defects. The present study investigated the effect of nicotine on cardiac gene expression and epigenetic regulation during myocardial differentiation. Persistent nicotine exposure selectively inhibited expression of two cardiac genes, Tbx5 and Gata4, by promoter DNA hypermethylation. The nicotine-induced suppression on cardiac differentiation was restored by general nicotinic acetylcholine receptor inhibition. Consistent results of Tbx5 and Gata4 gene suppression and cardiac function impairment with decreased left ventricular ejection fraction were obtained from in vivo studies in offspring. Our results present a direct repressive effect of nicotine on myocardial differentiation by regulating cardiac gene suppression via promoter DNA hypermethylation, contributing to the etiology of smoking-associated cardiac defects.

Susceptibility of lung cancer with polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 genotypes in the population of Inner Mongolia region.

BACKGROUND: To study the relationship of susceptibility to lung cancer with the gene polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1, GSTP1 and smoking status in Han and Mongolian populations of Inner Mongolia, an autonomous region of China. MATERIALS AND METHODS: PCR-RFLP, allele-specific and multiplex PCR were employed to identify the genotypes of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 in a case-control study of 322 lung cancer patients diagnosed by bronchoscopy and 456 controls free of malignancy. RESULTS: There is a significant difference in genotypic frequency of GSTT1 of healthy Mongolian and Han subjects. A statistically prominent association was found between CYP1A1 Msp1 (vt/vt) (OR=4.055, 95%CI:2.107-7.578, p=0.000), GSTM1 (-) (OR=2.290, 95%CI:1.467-3.573, p=0.000) and lung cancer in Mongolians. Similarly, in the Han population, CYP1A1 Msp1 (vt/vt) (OR=3.194, 95%CI:1.893-5.390, p=0.000) and GSTM1 (-) (OR=1.884, 95%CI:1.284-2.762, p=0.001) carriers also had an elevated risk of lung cancer. The smokers were more susceptible to lung cancer 2.144 fold and 1.631 fold than non-smokers in Mongolian and Han populations, respectively. The smokers who carried with CYP1A1 Msp1 (wt/vt+vt/vt), exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) respectively were found all to have a high risk of lung cancer. CONCLUSIONS: CYP1A1 Msp1 (vt/ vt) and GSTM1 (-) are risk factors of lung cancer in Han and Mongolian population in the Inner Mongolia region. The smokers with CYP1A1 Msp1 (wt/vt+vt/vt), CYP1A1 exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) genotypes, respectively, are at elevated risk of lung cancer.

Invasive fungal infections among inpatients with acquired immune deficiency syndrome at a Chinese university hospital.

Invasive fungal infections (IFIs) have become a major cause of morbidity and mortality among people with acquired immune deficiency syndrome (AIDS), however, little is known about the clinical features and prognosis of IFI in AIDS in China. This study aimed to characterise the clinical features and prognosis of IFI in AIDS patients in China. We retrospectively reviewed the records of all HIV-infected patients at a Chinese university hospital between December 2004 and May 2006. We identified 35 patients with IFI. IFIs included thrush, oesophageal candidiasis, fungal pneumonia, cryptococcosis, penicilliosis and fungaemia, 44.4% of IFIs occurred in the digestive tract, 71.8% of IFIs occurred in patients with CD4(+)T-lymphocyte counts <100 cells mm(-3). Candida albicans accounted for 57.4% of fungal pathogens isolated. All the patients received both antiretroviral and antifungal therapy; 27 patients were cured and eight died. IFI is one of the most common opportunistic infections in AIDS patients in China. IFIs mainly occur in patients with low CD4(+)T-lymphocyte counts. The majority of IFIs occur in the digestive tract. The most common pathogen causing IFI is C. albicans. The mortality rate remains high although antiretroviral therapy and many newer antifungals are available in China.