Selective blockade of nociceptive neurons can be achieved by the delivery of permanently charged sodium channel blockers through the pores of nociceptive ion channels. To assess the feasibility of ...this application in the dental area, we investigated the electrophysiological and neurochemical characteristics of nociceptive dental primary afferent (DPA) neurons. DPA neurons were identified within trigeminal ganglia labeling with a retrograde fluorescent dye applied to the upper molars of adult rats. Electrophysiological studies revealed that the majority of dental primary afferent neurons showed characteristics of nociceptive neurons, such as sensitivity to capsaicin and the presence of a hump in action potential. Immunohistochemical analysis revealed a large proportion of DPA neurons to be IB4-positive and to express TRPV1 and P2X3. Single-cell RT-PCR revealed mRNA expression of various nociceptive channels, including the temperature-sensitive TRPV1, TRPA1, TRPM8 channels, the extracellular ATP receptor channels P2X2 and P2X3, as well as the nociceptor-specific sodium channel, NaV1.8. In conclusion, DPA neurons have the electrophysiological characteristics of nociceptors and express several nociceptor-specific ion channels. Analysis of these data may assist in the search for a new route of entry for the delivery of membrane-impermeant local anesthetics. Abbreviations: AP, action potential; DiI, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate; DPA, dental primary afferent; FITC, fluorescein 5(6)-isothiocyanate; IB4, isolectin-B4; RT-PCR, reverse-transcription polymerase chain-reaction; TRP, transient receptor potential.
The use of imatinib combined with chemotherapy has demonstrated improved outcome in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, a substantial ...proportion of patients continue to die as a result of disease progression.
We assessed the minimal residual disease (MRD)-based effect and long-term outcome of first-line incorporation of dasatinib (100 mg once daily) into chemotherapy alternatively for adults with Ph-positive ALL. The primary end point was the major molecular response (MMR) rate by the end of the second dasatinib cycle. Patients with a donor proceeded to allogeneic stem cell transplantation (SCT) as early as possible. MRD monitoring was centrally evaluated by real-time quantitative polymerase chain reaction (4.5-log sensitivity) using bone marrow samples.
Fifty-one patients (median age, 46 years) were enrolled and treated with this strategy. After the first dasatinib cycle, 50 patients (98.0%) achieved complete remission (CR). By the end of the second dasatinib cycle, 46 (93.9%) of 49 assessable patients had persistent CR, and 38 (77.6%) had MMR (32.7%) or undetectable MRD (44.9%). On the basis of the MRD kinetics by this time point, the numbers of early-stable, late, and poor molecular responders were 23 (46.9%), 15 (30.7%), and 11 (22.4%), respectively. Thirty-nine patients (76.5%) underwent allogeneic SCT in CR1. After a median follow-up of 54 months, the 4-year cumulative incidence of relapse and disease-free survival (DFS) rate for all patients were 30.0% and 52.0%, respectively, and the corresponding outcomes among those receiving allogeneic SCT in CR1 were 20.5% and 64.1%, respectively. Poor molecular responders had a higher risk of relapse and DFS than those of early-stable molecular responders.
This dasatinib-based protocol was effective for achieving a good quality molecular response and durable DFS in adults with Ph-positive ALL.
clinicaltrials.gov, NCT01004497.
Curcumin has diverse therapeutic effects, such as anti-inflammatory, anti-oxidant, anti-cancer, and antimicrobial activities. The vanilloid moiety of curcumin is considered important for activation ...of the transient receptor potential vanilloid 1 (TRPV1), which plays an important role in nociception. However, very little is known about the effects of curcumin on nociception. In the present study, we investigated whether the anti-nociceptive effects of curcumin are mediated via TRPV1 by using nociceptive behavioral studies and in vitro whole-cell patch-clamp recordings in the trigeminal system. Subcutaneous injection of capsaicin in the vibrissa pad area of rats induced thermal hyperalgesia. Intraperitoneally administered curcumin blocked capsaicin-induced thermal hyperalgesia in a dose-dependent manner. Whereas curcumin reduced capsaicin-induced currents in a dose-dependent manner in both trigeminal ganglion neurons and TRPV1-expressing HEK 293 cells, curcumin did not affect heat-induced TRPV1 currents. Taken together, our results indicate that curcumin blocks capsaicin-induced TRPV1 activation and thereby inhibits TRPV1-mediated pain hypersensitivity.
The annual modulation signal observed by the DAMA experiment is a long-standing question in the community of dark matter direct detection. This necessitates an independent verification of its ...existence using the same detection technique. The COSINE-100 experiment has been operating with 106 kg of low-background NaI(Tl) detectors providing interesting checks on the DAMA signal. However, due to higher backgrounds in the NaI(Tl) crystals used in COSINE-100 relative to those used for DAMA, it was difficult to reach final conclusions. Since the start of COSINE-100 data taking in 2016, we also have initiated a program to develop ultra-pure NaI(Tl) crystals for COSINE-200, the next phase of the experiment. The program includes efforts of raw powder purification, ultra-pure NaI(Tl) crystal growth, and detector assembly techniques. After extensive research and development of NaI(Tl) crystal growth, we have successfully grown a few small-size (0.61–0.78 kg) thallium-doped crystals with high radio-purity. A high light yield has been achieved by improvements of our detector assembly technique. Here we report the ultra-pure NaI(Tl) detector developments at the Institute for Basic Science, Korea. The technique developed here will be applied to the production of NaI(Tl) detectors for the COSINE-200 experiment.
This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic ...myeloid leukemia (CML).
In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy.
The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR.
The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.
Abstract Non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation shows good and rapid response to EGFR tyrosine kinase inhibitors (TKIs). We ...prospectively evaluated the efficacy of EGFR TKI for metastatic brain tumors in NSCLC patients harboring EGFR mutation. This was an open-label, single-institution, phase II study. Patients diagnosed with NSCLC harboring EGFR mutation and measurable metastatic brain tumors were eligible. They received either erlotinib or gefitinib once a day. Out of total 28 patients enrolled, 23 patients (83%) showed a partial response (PR) and 3 patients (11%) did stable disease (SD), giving a disease control rate of 93%. Median progression free survival (PFS) and overall survival (OS) were 6.6 months (95% CI, 3.8–9.3 months) and 15.9 months (95% CI, 7.2–24.6 months), respectively. There was no difference in PFS and OS according to EGFR TKIs used. After discontinuation of the treatment, 14 patients (50%) received local therapy for metastatic brain tumors during their disease course, either whole brain radiotherapy or radiosurgery, giving a local therapy-free interval of 12.6 months (95% CI, 7.6–17.6 months). EGFR TKI therapy might be the treatment of choice for metastatic brain tumors in NSCLC patients harboring an activating EGFR mutation.
Summary Objective Hypoxia-inducible factor-2α (HIF-2α) transcriptionally upregulates Nampt in articular chondrocytes. NAMPT, which exhibits nicotinamide phosphoribosyltransferase activity, in turn ...causes osteoarthritis (OA) in mice by stimulating the expression of matrix-degrading enzymes. Here, we sought to elucidate whether HIF-2α activates the NAMPT-NAD+ -SIRT axis in chondrocytes and thereby contributes to the pathogenesis of OA. Methods Assays of NAD levels, SIRT activity, reporter gene activity, mRNA, and protein levels were conducted in primary cultured mouse articular chondrocytes. Experimental OA in mice was induced by intra-articular (IA) injection of adenovirus expressing HIF-2α (Ad- Epas1 ) or NAMPT (Ad- Nampt ). The functions of SIRT in OA were examined by IA co-injection of SIRT inhibitors or adenovirus expressing individual SIRT isoforms or shRNA targeting specific SIRT isoforms. Results HIF-2α activated the NAMPT-NAD+ -SIRT axis in chondrocytes by upregulating NAMPT, which stimulated NAD+ synthesis and thereby activated SIRT family members. The activated NAMPT-SIRT pathway, in turn, promoted HIF-2α protein stability by negatively regulating its hydroxylation and 26S proteasome-mediated degradation, resulting in increased HIF-2α transcriptional activity. Among SIRT family members (SIRT1–7), SIRT2 and SIRT4 were positively associated with HIF-2α stability and transcriptional activity in chondrocytes. This reciprocal regulation was required for the expression of catabolic matrix metalloproteinases (MMP3, MMP12, and MMP13) and OA cartilage destruction caused by IA injection of Ad- Epas1 Ad- Nampt. Conclusion The reciprocal regulation of HIF-2α and the NAMPT-NAD+ -SIRT axis in articular chondrocytes is involved in OA cartilage destruction caused by HIF-2α or NAMPT.
Scedosporium spp. is the most common mold infection in pneumonia resulting from near‐drowning. Three fatal scedosporiosis cases developed after solid organ transplantation, probably transmitted from ...the nearly‐drowned donor. One heart transplant recipient and two kidney transplant recipients developed fatal scedosporiosis following deceased donor transplantation from the same donor, a nearly‐drowned victim of a suicide attempt. Genotypically, indistinguishable strains of Scedosporium auratiacum were recovered from the three recipients. Two liver transplant recipients from the same donor received prophylactic voriconazole without any subsequent signs of infection. To determine the safety of donation from nearly‐drowned donors, a national traceback investigation was also performed of the causes of deaths in all transplant recipients who received organs from drowned donors between 2001 and 2013. Over 13 years, 2600 deceased donor transplants were performed in Korea. Among these 2600 deceased donor transplants, 27 (1%) victims of drowning donated their organs. From these 27 donors, 84 patients received organ transplants and 18 died, including the above three. We found no microbiologic evidence of invasive mold transmission from the nearly‐drowned donors to the other 15 recipients. Although disseminated infection in the donor could not be demonstrated by culture, undiagnosed disseminated donor infection and transmission of Scedosporium spp. should be considered in near‐drowning events.
The authors describe their experience of one heart recipient and two kidney recipients with fatal scedosporiosis following deceased donor transplantation from the same donor, a nearly drowned victim of a suicide attempt.
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