Factors associated with changes in tacrolimus blood concentration after food initiation in patients with ulcerative colitis.

The therapeutic effect of tacrolimus against ulcerative colitis (UC) is correlated with its trough blood concentration. Conventionally, oral tacrolimus for the treatment of UC is initiated under fasting conditions; once the symptoms improve, food intake is resumed. Tacrolimus blood concentration decreases with food intake compared with that under fasting conditions. The aim of this study was to explore the characteristics of patients with UC whose tacrolimus blood concentrations tended to decrease after food initiation. Medical data of 13 patients with UC and treated with tacrolimus were retrospectively obtained. The participant characteristics associated with the changes in tacrolimus blood concentrations after food initiation were analyzed using regression analysis based on the rate of decrease in the concentration/dose (C/D) ratio after food initiation. Single regression analysis showed that the number of days required from tacrolimus initiation to food resumption (P = 0.0071) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0247) were significantly associated with the rate of decrease in the C/D ratio after food initiation. Furthermore, multiple regression analysis showed a significant effect of the number of days to food resumption (P = 0.0004) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0012). The results suggest that the degree of change in blood tacrolimus concentration after food initiation may be related to the severity of the symptoms and pathology of UC. Early identification of participant characteristics may help control tacrolimus blood concentration fluctuations after food initiation.

Entrapment partly participates in the longitudinal progression of neuropathy with anti-MAG antibodies.

Neuropathy with anti-myelin-associated glycoprotein (MAG) antibodies commonly demonstrates distal-dominant prolongation of nerve conduction. However, recent electrophysiological studies have shown that distal motor demyelination is not always a distinct feature. We aimed to elucidate whether the longitudinal progression of nerve impairment occurs in a distal-dominant manner. Seven patients with neuropathy with anti-MAG antibodies were enrolled. Sequential nerve conduction studies revealed nerve conduction reduction only at the wrist segment in the median nerve of the patients, but not in the ulnar nerve. Median nerve entrapment at the wrist may play a role in longitudinal disease progression in neuropathy with anti-MAG antibodies.

Progressive supranuclear palsy often develops idiopathic normal pressure hydrocephalus-like magnetic resonance imaging features.

BACKGROUND AND PURPOSE: Idiopathic normal pressure hydrocephalus (iNPH) is a clinical entity without established pathological hallmarks. Previous autopsy studies reported that patients with an antemortem diagnosis of iNPH had a different postmortem diagnosis, commonly progressive supranuclear palsy (PSP). Disproportionately enlarged subarachnoid space hydrocephalus (DESH) has been reported as a characteristic feature of iNPH on magnetic resonance imaging (MRI). In addition, periventricular white matter hyperintensities (PVHs) are noted in most patients with iNPH; these PVHs are supposed to reflect transependymal movement of ventricular cerebrospinal fluid. It is hypothesized that PSP develops more iNPH-like MRI features than other neurodegenerative disorders. METHODS: Thirty-eight patients with a clinical diagnosis of PSP, 42 with Parkinson's disease (PD) without dementia, 30 with PD with dementia (PDD) and 29 with Alzheimer's disease (AD) were enrolled. The DESH score and PVH grade were measured using the conventional MRI sequence and were compared amongst the patient groups. RESULTS: Disproportionately enlarged subarachnoid space hydrocephalus score was significantly higher in patients with PSP than PD without dementia, and there was a trend that the DESH score was higher in patients with PSP than PDD or Alzheimer's disease. PVH grade was significantly larger in patients with PSP than PD without dementia. In the components of the DESH score, callosal angle was significantly smaller in patients with PSP than in PD without dementia or PDD. CONCLUSIONS: This study demonstrated that some PSP patients develop iNPH-like MRI features, suggesting the presence of iNPH-like features in the clinical spectrum of PSP. A clinical phenotype of PSP with hydrocephalus is proposed, which should be further investigated in future studies.

Safety of tapering tacrolimus dose in patients with well-controlled anti-acetylcholine receptor antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS: We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction. RESULTS: Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, P = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, P = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cut-off values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction. CONCLUSION: Tapering of tacrolimus was possible in most patients with well-controlled anti-acetylcholine receptor antibody-positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease.

Retrospective analysis of risk factors for liposomal amphotericin B-associated nephrotoxicity.

In this study, we examined patients who received liposomal amphotericin B (L-AMB) to determine the risk factors associated with nephrotoxicity before and during L-AMB treatment. In this retrospective, single-center, observational cohort study, we examined 37 patients who received L-AMB treatment between April 2018 and December 2019. Nephrotoxicity was observed in 11 (29.7%) patients. We focused on the baseline albumin level and body surface area (BSA) before L-AMB treatment. Univariate analysis showed that the BSA and baseline albumin levels in patients with nephrotoxicity were significantly higher than those in patients without nephrotoxicity. Moreover, univariate analysis showed that albumin supplementation was significantly associated with the frequency of nephrotoxicity during L-AMB treatment. Multiple logistic regression analysis revealed the following independent risk factors for nephrotoxicity before or during L-AMB treatment: baseline albumin level (odds ratio [OR] = 16.000; 95% CI 1.480-172.000; P = 0.022) and albumin supplementation (OR = 40.800; 95% CI 2.210-753.000; P = 0.013). In conclusion, we identified baseline albumin level and albumin supplementation as novel risk factors for L-AMB-induced nephrotoxicity.

Randomized phase III and extension studies: efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer.

BACKGROUND: The efficacy and safety of naldemedine (a peripherally acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase III, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary end point, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary end points, including quality of life (QOL) assessments from these studies. PATIENTS AND METHODS: In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 97) or placebo (n = 96) for 2 weeks, and those who continued on to COMPOSE-5 received naldemedine for 12 weeks (n = 131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ≥1 SBM or CSBM within 24 h postinitial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at weeks 1 and 2. Time to the first SBM or CSBM postinitial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires. RESULTS: Naldemedine improved bowel function for all secondary efficacy assessments versus placebo (all P ≤ 0.0002). The timely onset of naldemedine activity versus placebo was evidenced by median time to the first SBM (4.7 h versus 26.6 h) and CSBM (24.0 h versus 218.5 h) postinitial dose (all P < 0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P = 0.045) and PAC-QOL dissatisfaction domain (P = 0.015). In COMPOSE-5, significant improvements from baseline were observed for overall and individual domain scores of PAC-SYM and PAC-QOL. CONCLUSIONS: Naldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer. TRIAL REGISTRATION ID: www.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).

Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02).

Background: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN. Patients and methods: Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100 mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients. Results: Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63 years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia. Conclusions: The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population. Registered clinical trial number: UMIN000010507.

Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study.

BACKGROUND: Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC). METHODS: Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee. RESULTS: From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. CONCLUSIONS: The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. TRIAL REGISTRATION: ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).

Comparison of neoadjuvant chemotherapy versus upfront surgery with or without chemotherapy for patients with clinical stage III esophageal squamous cell carcinoma.

Neoadjuvant chemotherapy (NAC) and chemoradiotherapy have been shown to extend postoperative survival, and preoperative therapy followed by esophagectomy has become the standard treatment worldwide for patients with esophageal squamous cell carcinoma (ESCC). The Japan Clinical Oncology Group 9907 study showed that NAC significantly extended survival in advanced ESCC, but the survival benefit for patients with clinical stage III disease remains to be elucidated. We compared the survival rates of NAC and upfront surgery in patients with clinical stage III ESCC. Consecutive patients histologically diagnosed as clinical stage III (excluding cT4) ESCC were eligible for this retrospective study. Between September 2002 and April 2007, upfront transthoracic esophagectomy was performed initially and, for patients with positive lymph node (LN) metastasis in a resected specimen, adjuvant chemotherapy using cisplatin and 5-fluororouracil every 3 weeks for two cycles was administered (Upfront surgery group). Since May 2007, a NAC regimen used as adjuvant chemotherapy followed by transthoracic esophagectomy has been administered as the standard treatment in our institution (NAC group). Patient characteristics, clinicopathological factors, treatment outcomes, post-treatment recurrence, and overall survival (OS) were compared between the NAC and upfront surgery groups. Fifty-one and 55 patients were included in the NAC and upfront surgery groups, respectively. The R0 resection rate was significantly lower in the NAC group than in the upfront surgery group (upfront surgery, 98%; NAC, 76%; P = 0.003). In the upfront surgery group, of 49 patients who underwent R0 resection and pathologically positive for LN metastasis, 22 (45%) received adjuvant chemotherapy. In the NAC group, 49 (96%) of 51 patients completed two cycles of NAC. In survival analysis, no significant difference in OS was observed between the NAC and upfront surgery groups (NAC: 5-year OS, 43.8%; upfront surgery: 5-year overall surgery, 57.5%; P = 0.167). Patients who underwent R0 resection showed significantly longer OS than did those who underwent R1, R2, or no resection (P = 0.001). In multivariate analysis using age, perioperative chemotherapy, depth of invasion, LN metastasis, surgical radicality, postoperative pneumonia, and anastomotic leakage as covariates, LN metastasis [cN2: hazard ratio (HR), 1.389; P = 0.309; cN3: HR, 16.019; P = 0.012] and surgical radicality (R1: HR, 3.949; P = 0.009; R2 or no resection: HR, 2.912; P = 0.022) were shown to be significant independent prognostic factors. In clinical stage III ESCC patients, no significant difference in OS was observed between NAC and upfront surgery. Although potential patient selection bias might be a factor in this retrospective analysis, the noncurative resection rate was higher after NAC than after upfront surgery. The survival benefit of more intensive NAC needs to be further evaluated.

Spinal cord ring enhancement in patients with neuromyelitis optica.

OBJECTIVES: Clinical and pathological significance of gadolinium (Gd)-enhancing pattern on magnetic resonance imaging (MRI), including ring enhancement (RE), is well documented in multiple sclerosis but not in neuromyelitis optica (NMO), especially in the spinal cord. The purpose of this study is to examine the prevalence of spinal cord RE in NMO and to determine the association between clinical characteristics and spinal cord RE. MATERIALS AND METHODS: We retrospectively examined Gd-enhanced spinal cord MRI scans, during the acute phase, in patients with anti-aquaporin 4-positive NMO, including NMO spectrum disorder. We then analysed their clinical features and MRI imaging characteristics of spinal cord lesions. RESULTS: Of the 30 patients with NMO, we enrolled 12 patients with 16 Gd-enhanced spinal cord MRI scans in this study. Five scans revealed RE (31.2%). Male ratio, as well as myelin basic protein (MBP) levels, in the cerebrospinal fluid (CSF) of patients with RE was significantly higher than those of patients without RE (P = 0.018, P = 0.026, respectively). CONCLUSIONS: Spinal cord RE is common in patients with NMO. Higher MBP levels in the CSF of patients with RE can be associated with a higher degree of myelin damage.

Topographical representations of taste response characteristics in the rostral nucleus of the solitary tract in the rat.

The rostral nucleus of the solitary tract (rNST) is the first-order taste relay in rats. This study constructed topographical distributions of taste response characteristics (best-stimulus, response magnitude, and taste-tuning) from spike discharges of single neurons in the rNST. The rNST is divided into four subregions along the rostrocaudal (RC) axis, which include r1-r4. We explored single-neuron activity in r1-r3, using multibarreled glass microelectrodes. NaCl (N)-best neurons were localized to the rostral half of r1-r3, while HCl (H)-best and sucrose (S)-best neurons showed a tendency toward more caudal locations. NaCl and HCl (NH)-best neurons were distributed across r2-r3. The mean RC values and Mahalanobis distance indicated a significant difference between the distributions of N-best and NH-best neurons in which N-best neurons were located more rostrally. The region of large responses to NaCl (net response >5 spikes/s) overlapped with the distribution of N-best neurons. The region of large responses to HCl extended widely over r1-r3. The region of large responses to sucrose was in the medial part of r2. The excitatory region (>1 spike/s) for quinine overlapped with that for HCl. Neurons with sharp to moderate tuning were located primarily in r1-r2, while those with broad tuning were located in r2-r3. The robust responses to NaCl in r1-r2 primarily contributed to sharp to moderate taste-tuning. Neurons in r3 tended to have broad tuning, apparently due to small responses to both NaCl and HCl. Therefore, the rNST is spatially organized by neurons with distinct taste response characteristics, suggesting that these neurons serve different functional roles.

Functional properties of putative pyramidal neurons and inhibitory interneurons in the rat gustatory cortex.

In order to address how taste information is modulated by inhibitory neuronal interactions in the rat gustatory cortex, we examined putative pyramidal neurons (PY units) and putative inhibitory interneurons (fast spiking [FS] units) that were distinguished by their spike waveforms and discharge rates. FS units were strikingly different from PY units in that the majority of FS units were N- or NH-best neurons and narrowly tuned to 1 or 2 tastant(s), whereas PY units were broadly tuned to plural tastants. Compared with PY units, FS units were characterized by a shorter response latency and/or a longer response duration. These results suggest that inhibitory modulations in the gustatory cortex are carried out in a taste specific and tonic manner. Sensitivity to tastant concentrations in PY units was similar to that in FS units for NaCl but higher for HCl. FS units may act to enhance concentration sensitivity in PY units by reducing PY units' response activity. High density of FS and PY units was observed in the superficial and middle layers (mainly layers III and IV). Responses in N-best FS units in these layers were significantly larger than those in the deep layers, suggesting the existence of layer-specific inhibitory interactions.

BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer.

BACKGROUND: Activating mutation of KRAS and BRAF are focused on as potential prognostic and predictive biomarkers in patients with colorectal cancer (CRC) treated with anti-EGFR therapies. This study investigated the clinicopathological features and prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC patients. METHOD: Patients with advanced and recurrent CRC treated with systemic chemotherapy (n=229) were analysed for KRAS/BRAF genotypes by cycleave PCR. Prognostic factors associated with survival were identified by univariate and multivariate analyses using the Cox proportional hazards model. RESULTS: KRAS and BRAF mutations were present in 34.5% and 6.5% of patients, respectively. BRAF mutated tumours were more likely to develop on the right of the colon, and to be of the poorly differentiated adenocarcinoma or mucinous carcinoma, and peritoneal metastasis. The median overall survival (OS) for BRAF mutation-positive and KRAS 13 mutation-positive patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for patients with wild-type (wt) KRAS and BRAF (40.6 months) (BRAF; HR=4.25, P<0.001, KRAS13; HR=2.03, P=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor OS (HR=4.23, P=0.019). CONCLUSION: Presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent CRC. The KRAS13 mutation showed a trend towards poor OS in patients with advanced and recurrent CRC.

Limitin: An interferon-like cytokine that preferentially influences B-lymphocyte precursors.

We have identified an interferon-like cytokine, limitin, on the basis of its ability to arrest the growth of or kill lympho-hematopoietic cells. Limitin strongly inhibited B lymphopoiesis in vitro and in vivo but had little influence on either myelopoiesis or erythropoiesis. Because limitin uses the interferon alpha/beta receptors and induces interferon regulatory factor-1, it may represent a previously unknown type I interferon prototype. However, preferential B-lineage growth inhibition and activation of Janus kinase 2 in a myelomonocytic leukemia line have not been described for previously known interferons.

Casimersen for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a genetic disorder affecting 1 in 5,000 males which causes progressive muscle deterioration, loss of mobility and eventual death, with an average lifespan of around 25 years. While no cure currently exists for DMD, a novel treatment known as antisense-mediated exon skipping therapy has shown great promise. Exon skipping therapy induces the skipping of mutated exons, restoring the reading frame in dystrophin transcripts and resulting in a truncated but partially functional protein product. In February 2021, Sarepta Therapeutics received accelerated Food and Drug Administration (FDA) approval for their new antisense oligonucleotide, casimersen (brand name Amondys 45). Casimersen targets exon 45 of the dystrophin gene and is expected to treat ~8% of the DMD patient population. The continued approval of this drug will be dependent on satisfactory clinical results from an ongoing phase III trial. This article summarizes the preclinical and clinical data currently available for casimersen, emphasizing pharmacokinetics and safety.

A Japanese Multicenter Study on PET and Other Biomarkers for Subjects with Potential Preclinical and Prodromal Alzheimer's Disease.

BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the "ATN" (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer's disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aß1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.

The beta subunit of human granulocyte-macrophage colony-stimulating factor receptor forms a homodimer and is activated via association with the alpha subunit.

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) receptor (hGMR) consists of alpha and beta subunits, and the precise stoichiometry of these subunits has remained to be determined. In this work, oligomerization of the beta subunit was studied using a chemical cross-linker. In Ba/F3, a mouse interleukin-3-dependent cell line expressing both subunits of hGMR (Ba/F3-alpha,beta), a protein with a molecular mass corresponding to that of a homodimer of the beta subunit (beta homodimer) was detected only when cells were treated with the cross-linker. Dimerization of the beta subunit was confirmed by coimmunoprecipitation of a tagged beta subunit with the wild type beta subunit COS7 cells. The beta homodimer had already formed in the absence of hGM-CSF, whereas stimulation with the ligand brought both alpha and beta subunits into a complex, the result being tyrosine phosphorylation of the beta homodimer. Tyrosine phosphorylation of the subunit was impaired by deletion of the cytoplasmic domain of the alpha subunit without interfering with the association of both subunits. These results indicate that the beta homodimer, which alone is insufficient for signaling, forms the functional hGMR with the alpha subunit in response to hGM-CSF.

Human recombinant interleukin 4 induces Fc epsilon receptors (CD23) on normal human B lymphocytes.

Human rIL-4 is able to induce the expression of low-affinity receptors for IgE (Fc epsilon RL/CD23) on resting B lymphocytes, as determined by the binding of either the anti Fc epsilon RL/CD23-specific mAb 25 or IgE. Stimulation of B cells with insolubilized anti-IgM antibody increases the number of cells expressing Fc epsilon RL/CD23 upon culturing with IL-4 and enhances the level of Fc epsilon RL/CD23 expression on these cells. Fc epsilon RL/CD23 induction is specific for IL-4 since IL-1 alpha, IL-2, IFN-gamma, B cell-derived B cell growth factor (BCGF), and a low-molecular-weight BCGF were ineffective. IFN-gamma strongly inhibited the induction of Fc epsilon RL/CD23 by IL-4.

Neutropenia as a prognostic factor in advanced gastric cancer patients undergoing second-line chemotherapy with weekly paclitaxel.

BACKGROUND: Neutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several types of cancers, although there are no reports in pretreated patients. METHODS: We retrospectively analyzed 242 patients with advanced gastric cancer (AGC) who received weekly paclitaxel (Taxol) as second-line chemotherapy. Background characteristics and neutropenia as time-varying covariates (TVCs) were analyzed as prognostic factors. RESULTS: Of the 242 patients, mild neutropenia (grades 1-2) occurred in 101 patients (41.7%) and severe neutropenia (grades 3-4) occurred in 63 patients (26.0%). The other 78 patients (32.2%) did not experience neutropenia. According to a multivariate Cox model with neutropenia as a TVC, hazard ratios of death were 0.61 [95% confidence interval (CI) 0.43-0.85; P = 0.004] for patients with mild neutropenia and 0.61 (95% CI 0.41-0.88; P = 0.009) for those with severe neutropenia. Among the patients in landmark analysis (landmark of 2.5 months; median time to treatment failure of paclitaxel), mild and severe neutropenia remained significant prognostic factors. CONCLUSIONS: Our results indicate that neutropenia during chemotherapy is associated with improved survival in patients with AGC who received weekly paclitaxel as second-line chemotherapy. Prospective trials are required to assess whether dosing adjustments based on neutropenia may improve chemotherapy efficacy.

Golodirsen for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a life-shortening X-linked genetic disorder characterized by progressive wasting and weakening of muscles in boys. Loss-of-function mutations in the DMD gene, which codes for dystrophin, lead to this disease. The majority of mutations in this gene result in the exclusion of one or more exons from the transcript, eventually causing the remaining exons not to fit together correctly (i.e., out-of-frame mutations). Antisense oligonucleotides, e.g., phosphorodiamidate morpholino oligomers (PMOs), can induce therapeutic exon skipping during pre-mRNA processing to restore the reading frame of the primary transcript of DMD. As a result, truncated but partially functional dystrophin is produced, potentially slowing down the disease progression. Golodirsen is a provisionally approved PMO-based drug for approx. 8% of all DMD patients amenable to exon 53 skipping. This article summarizes golodirsen's pharmacology, efficacy and safety information. It also discusses some controversies that golodirsen met after the approval.