Outcome of allogeneic hematopoietic stem cell transplantation for mycosis fungoides and Sézary syndrome

Although allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to provide prolonged remission of relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS), its role has not been fully evaluated. Here, the outcomes of allogeneic HSCT for patients with MF/SS were retrospectively evaluated by using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-eight patients were evaluable and enrolled in the analysis. Median age was 45.5 years. Eighteen patients (38%) received myeloablative conditioning, and 33 (69%) received HSCT from an alternative donor. Disease status was complete or partial response in 25% of the patients and relapsed or refractory in the others. At the time of analysis, 18 patients were alive, with a median follow-up of 31.0 months (range, 3.8-31.1). Three-year overall survival (OS) and progression-free survival (PFS) were 30% (95%CI, 16-45%) and 19% (95%CI, 9-31%), respectively. Disease progression was not observed later than 17 months after transplantation. Both disease status and performance status at transplant significantly affected OS and PFS. Although our findings suggest that allogeneic HSCT provides long-term PFS in patients with MF/SS, the timing of transplantation should be decided carefully based on the disease status and the patient's condition in order to improve the outcome.     

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor,in patients with advanced solid tumors

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first‐in‐human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1‐3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1‐180 mg) was carried out to assess dose‐limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25‐(OH)₂‐vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140‐mg dose; one patient in the 180‐mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose‐dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose‐dependent increases were observed in all pharmacodynamic markers and plateaued at 100‐140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow‐up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.     

结直肠腺瘤危险因素

目的 研究结直肠腺瘤发生相关的危险因素,为结直肠早癌病变的筛查及诊疗提供预警信息。方法 选取2014年1月至2020年6月于河北医科大学第二医院行结肠镜检查经病理诊断为结直肠腺瘤的患者1 126例作为病例组,以同期行结肠镜检查结果阴性的患者1 800例作为对照组。收集患者性别、年龄、吸烟史、饮酒史、排便习惯(正常、腹泻、便秘、腹泻与便秘交替)、总胆固醇及甘油三酯水平等资料。进行多因素Logistic回归分析,探究上述因素对结直肠腺瘤发生的影响。为了进一步排除混杂因素的干扰,组间1∶1匹配,进行多因素条件Logistic回归分析,探究结直肠腺瘤发生的独立危险因素。结果 多因素Logistic回归分析显示,性别、年龄、饮酒史、吸烟史、排便习惯、总胆固醇和甘油三酯水平为结直肠腺瘤发生的独立危险因素(P<0.05)。多因素条件Logistic回归分析显示,排便习惯及甘油三酯水平是结直肠腺癌发生的独立危险因素,慢性腹泻、慢性便秘患者发生结直肠腺瘤的风险高于排便习惯正常者(P<0.05),甘油三酯水平较高患者发生结直肠腺瘤的风险高于甘油三酯水平正常者(P<0.05)。结论 排便习惯及甘油三酯水平是结直肠腺瘤发生的独立危险因素,慢性腹泻、慢性便秘、甘油三酯升高者发生结直肠腺瘤风险更高。     

Dopamine modulates the optomotor response to unreliable visual stimuli in Drosophila melanogaster

State‐dependent modulation of sensory systems has been studied in many organisms and is possibly mediated through neuromodulators such as monoamine neurotransmitters. Among these, dopamine is involved in many aspects of animal behaviour, including movement control, attention, motivation and cognition. However, the precise neural mechanism underlying dopaminergic modulation of behaviour induced by sensory stimuli remains poorly understood. Here, we used Drosophila melanogaster to show that dopamine can modulate the optomotor response to moving visual stimuli including noise. The optomotor response is the head‐turning response to moving objects, which is observed in most sight‐reliant animals including mammals and insects. First, the effects of the dopamine system on the optomotor response were investigated in mutant flies deficient in dopamine receptors D1R1 or D1R2, which are involved in the modulation of sleep‐arousal in flies. We examined the optomotor response in D1R1 knockout (D1R1 KO) and D1R2 knockout (D1R2 KO) flies and found that it was not affected in D1R1 KO flies; however, it was significantly reduced in D1R2 KO flies compared with the wild type. Using cell‐type‐specific expression of an RNA interference construct of D1R2, we identified the fan‐shaped body, a part of the central complex, responsible for dopamine‐mediated modulation of the optomotor response. In particular, pontine cells in the fan‐shaped body seemed important in the modulation of the optomotor response, and their neural activity was required for the optomotor response. These results suggest a novel role of the central complex in the modulation of a behaviour based on the processing of sensory stimulations.     

Effects of Medications and Subthalamic Nucleus-Deep Brain Stimulation on the Cutaneous Silent Period in Patients With Parkinson's Disease

ObjectivesWe sought to evaluate whether the cutaneous silent period (CSP) could be an electrophysiological indicator reflective of the effects of therapy for Parkinson's disease (PD), including anti-PD medications or deep brain stimulation (DBS).Material and MethodsWe recorded the CSP in 43 patients with PD prior to and following the administration of medication during a pre-DBS evaluation (30 cases) and the “on” and “off” states of subthalamic nucleus DBS (13 cases). The CSP was elicited from the abductor pollicis brevis muscle by an electrical stimulation of the index finger that was 2, 4, and 15 times stronger than the sensory threshold (ST). We measured changes in latencies, including the onset, duration, and end of CSP, and waveform scores from 0 to 3. The correlation between the CSP score and unified PD rating score part III (UPDRS-III) also was assessed.ResultsThe onset latency and duration of CSP were significantly different between high- (15ST) and low-strength stimulations (2ST and 4ST). However, there were no significant latency changes (onset, duration, end of CSP) before and after receiving medication, or during the on and off state of the DBS. Anti-PD medications substantially increased the CSP waveform score only in the 4ST state. However, the waveform score significantly increased in all stimuli states during the DBS-on state. Both medication and the DBS-on state decreased the UPDRS-III. Nevertheless, there was no statistically significant correlation between the UPDRS-III and CSP waveform scores.ConclusionDifferent onset latencies and the duration of CSP between low- and high-strength stimuli support the hypotheses proposing two different reflex pathways. Despite being independent from the UPDRS-III, the CSP may be an electrophysiological indicator reflective of the changes in inhibitory activity to the spinal α-motoneuron in response to anti-PD medications and DBS.     

Improving the Acid and Base Resistance of Polyurethane Using Carbon Nanotubes

This paper demonstrates that carbon nanotubes (CNTs) can be used as an effective filler for inhibiting the hydrolysis of polyurethane (PU) under acidic and basic conditions. Although it has been reported that CNTs can quench the radicals on its surface, for the first time, it is confirmed that CNTs undergo reactions that have an inhibiting effect on ion‐mediated hydrolysis. Attenuated total reflectance–infrared spectroscopy measurements on PU and PU–CNT samples reveal that CNTs inhibit the hydrolysis of PU in both acid and alkaline environments. Via quantum chemical calculations, it is shown that CNTs can trap H⁺ ions and OH^? ions on their surface. It is also shown that CNTs can trap multiple ions, even though electrical repulsion is to be expected. The results reveal that CNTs can also function as a hydrolysis inhibitor in addition to their known functions as an antioxidant.