Explore the vast range of titles available.

Amyotrophic lateral sclerosis (ALS) is the most common adult onset motoneuron disease. The etiology and precise pathogenic mechanisms of the disease remain unknown, and there is no effective treatment. Vascular endothelial growth factor (VEGF) has recently been shown to exert direct neurotrophic and neuroprotective effects in animal models of ALS. Here we show that intrathecal transplantation of immortalized human neural stem cells (NSCs) overexpressing human VEGF gene (HB1.F3.VEGF) significantly delayed disease onset and prolonged the survival of the SOD1G93A mouse model of ALS. At 4 weeks, post-transplantation grafted cells were found within the gray matter of the spinal cord. Furthermore, transplanted F3.VEGF cells that express neuronal phenotype (MAP2+) were found in the anterior horn of the spinal cord gray matter indicating that the transplanted human NSCs migrated into the gray matter, took the correct structural position, integrated into the spinal cord anterior horn and differentiated into motoneurons. Intrathecal transplantation of F3.VEGF cells provides a neuroprotective effect in the diseased spinal cord by concomitant downregulation of proapoptotic proteins and upregulation of antiapoptotic proteins. Our results suggest that this treatment modality of intrathecal transplantation of human NSCs genetically modified to overexpress neurotrophic factor(s) might be of value in the treatment of ALS patients without significant adverse effects.

Background:Although electrophysiological tests and brain MRI provide information about the site of the lesion in Bell’s palsy, clinicians usually depend on clinical data. However, the accuracy of clinical findings in identifying lesions has never been evaluated.Method:A total of 57 patients with idiopathic peripheral facial palsy were included in this study. We determined the sites of the lesions based on associated symptoms and by brain MRI. We then compared the two to assess the value of clinical findings in determining lesion sites.Results:Of the 57 patients, 27 were men. The mean age of all patients was 50.6±16.7 years. The lesion sites determined from clinical findings were as follows: the infrageniculate-suprastapedial segment, 13 (23%); the infrastapedial-suprachordal segment, 9 (16%); and the mastoid segment, 35 (61%). No sites were classified as involving the suprageniculate segment. On brain MRI, 51 (89%) of the 57 patients showed abnormal enhancement of the facial nerve, with the most common area being the suprageniculate segment, including the distal intrameatal, labyrinthine and geniculate ganglion.Conclusions:We demonstrate that clinical history is not helpful in determining the site of a lesion in Bell’s palsy. The segment most frequently involved in Bell’s palsy is the suprageniculate segment.

To determine the immediate and short-term efficacies of mastoid oscillation vs. Gufoni maneuver in treating the apogeotropic type of horizontal canal benign paroxysmal positional vertigo (HC-BPPV), we designed a randomized, prospective, sham-controlled study. In eight dizziness clinics in Korea, 209 consecutive patients with apogeotropic HC-BPPV were enrolled. The patients were randomly assigned to receive a single application of Gufoni ( n  = 70), mastoid oscillation ( n  = 67), or sham maneuver ( n  = 72). Immediate and second-day responses were determined based on the results within 1 h after a single trial of each maneuver and the following day, respectively. Second-day response was assessed in patients who were non-responders on the first day. The short-term response was determined based on the cumulative response for 2 days. Successful treatment was defined as a resolution of positional nystagmus or as a transition into geotropic horizontal nystagmus (not requires vertigo symptom resolution). The immediate responses of the Gufoni maneuver (33/70, 47.1%) and mastoid oscillation (32/67, 47.8%) were better than the sham maneuver (14/72, 19.4%) ( p  = 0.00). The second-day results did not differ among the three groups ( p  = 0.76). The short-term responses showed better efficacies with the Gufoni maneuver (51/70, 76.1%) and mastoid oscillation (46/67, 71.9%) than with the sham maneuver (38/72, 53.5%) ( p  = 0.02). Therapeutic efficacies did not differ between the Gufoni and mastoid oscillation groups in terms of both immediate and short-term outcomes ( p  = 0.94, 0.57). Both the Gufoni maneuver and mastoid oscillation are valid methods for treating apogeotropic HC-BPPV, with a success rate of approximately 70% for a single maneuver during the short-term follow-up. Trial registration: clinicaltrials.gov identifier number: NCT02046980.

This study is the first to examine the increased apoptosis in the adult rat ovary after lactational exposure to coumestrol (COU), a potent phytoestrogen. Lactating dams were gavaged at doses of 0.01, 0.1, 1, and 10 mg/kg COU during the lactation period and the reproductive effects of female pups were investigated in young adults. Rats were sacrificed at postnatal days (PND) 81-84. Ovarian weights were reduced significantly at 0.1 and 1.0 mg/kg COU. The reduction in the ovarian weight occurred in parallel with an increase in the apoptosis at PND 135-140. A marked dose-dependent increase in the expressions of active caspase-3 and -7 was observed in ovarian granulosa cells. Immunostaining for active caspase-3 and the TUNEL staining of apoptotic cells were also increased in ovaries exposed to COU in a dose-dependent manner. These results suggest new sights into the effect of lactational exposure to COU on the female reproductive health.

Mitochondrial dysfunction is associated with aging‐mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress‐induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro‐inflammatory cytokines in elderly subjects. Circulating levels of cell‐free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20‐month‐old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15‐deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL‐17 production in Th17 cells, GDF15 contributes to regulatory T‐cell‐mediated suppression of conventional T‐cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging‐mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice. Aging‐induced GDF15 production is observed in humans and mice, which is positively correlated with systemic inflammation and mitochondrial stress. GDF15 deficiency promotes glucose intolerance as well as hepatic and adipose inflammation in old mice. GDF15 contributes to regulatory T cells‐mediated suppression of conventional T cell activation, but senescent T cells were resistant to regulatory T cells‐mediated suppression compared to conventional T cells.

Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival. Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 [95% CI 0·437–0·994], one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 [75%] of 92 vs 14 [16%] of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred. Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen. Pfizer, Shinpoong, and Daewoong Korea and Takeda.

In a trial of adjuvant treatment for patients with resected ALK -positive non–small-cell lung cancer, disease-free survival at 2 years was 93.6% with the ALK inhibitor alectinib and 63.7% with standard chemotherapy.

Apigenin, an aromatic compound, exhibits antioxidant, anti-inflammatory and anti-viral effects. The present study aimed to investigate the effects of apigenin on cell proliferation and apoptosis of human melanoma cells A375P and A375SM. Therefore, melanoma cells were treated with apigenin to determine its anti-proliferative and survival effects, using wound healing and MTT assays. The results revealed that melanoma cell viability was decreased in a dose-dependent manner. Furthermore, chromatin condensation, indicating apoptosis, was significantly increased in a dose-dependent manner, as demonstrated by DAPI staining. In addition, increased apoptosis rate following treatment with apigenin was confirmed by Annexin V-propidium iodide staining. The changes in the expression levels of apoptosis-related proteins in A375P and A375SM melanoma cells were subsequently detected using western blot analysis. The results demonstrated that the protein expression levels of Bcl-2 were decreased, whereas those of Bax, cleaved poly ADP-ribose polymerase, cleaved caspase-9 and p53 were upregulated in a dose-dependent manner in apigenin-treated cells compared with those noted in untreated cells. In addition, in apigenin-treated A375P cells, phosphorylated (p)-p38 was upregulated and p-extracellular signal-regulated kinase (ERK), p-c-Jun N-terminal kinase (JNK) and p-protein kinase B (Akt) were downregulated. However, in A375SM cells, apigenin treatment increased p-ERK and p-JNK and decreased p-p38 and p-Akt protein expression levels. Subsequently, the inhibitory effect of apigenin on tumor growth was investigated in vivo. Tumor volume was significantly reduced in the 25 and 50 mg/kg apigenin-treated groups compared with the control group. Additionally, a TUNEL assay was performed to detect apoptotic cells. Immunohistochemical staining also revealed elevated p-ERK expression in the apigenin-treated group compared with the control group. Overall, the findings of the present study indicated that apigenin attenuated the growth of A375SM melanoma cells by inducing apoptosis via regulating the Akt and mitogen-activated protein kinase signaling pathways.

The human equilibrative nucleoside transporter 1 (hENT1), a member of the SLC29 family, plays crucial roles in adenosine signaling, cellular uptake of nucleoside for DNA and RNA synthesis, and nucleoside-derived anticancer and antiviral drug transport in humans. Because of its central role in adenosine signaling, it is the target of adenosine reuptake inhibitors (AdoRI), several of which are used clinically. Despite its importance in human physiology and pharmacology, the molecular basis of hENT1-mediated adenosine transport and its inhibition by AdoRIs are limited, owing to the absence of structural information on hENT1. Here, we present crystal structures of hENT1 in complex with two chemically distinct AdoRIs: dilazep and S-(4-nitrobenzyl)-6-thioinosine (NBMPR). Combined with mutagenesis study, our structural analyses elucidate two distinct inhibitory mechanisms exhibited on hENT1 and provide insight into adenosine recognition and transport. Our studies provide a platform for improved pharmacological intervention of adenosine and nucleoside analog drug transport by hENT1.

In humans, cold is primarily sensed by transient receptor potential melastatin member 8 (TRPM8), a calcium channel. Yin et al. present cryo–electron microscopy structures of TRPM8 with cooling agents, membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2), and calcium. Structural and functional analyses showed that the PIP2 binding site in TRPM8 is completely different from PIP2 sites in other TRP channels. The binding of PIP2 and cooling agents allosterically enhance each other and activate the channel opening. Thus, the activation mechanism of TRPM8 is distinct from that used by other TRP channels. Science , this issue p. eaav9334 Cryo-EM structures elucidate the molecular basis for cold and menthol sensing and reveal the distinctive PIP2 dependence in the TRPM8 calcium channel. Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca 2+ )–permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo–electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP 2 , and Ca 2+ , as well as in complex with the menthol analog WS-12 and PIP 2 . Our structures reveal the binding sites for cooling agonists and PIP 2 in TRPM8. Notably, PIP 2 binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP 2 and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.