Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2

Renal cell carcinoma (RCC) is one of the most common malignant tumors affecting the urogenital system, accounting for 90% of renal malignancies. Traditional chemotherapy options are often the front-line choice of regimen in the treatment of patients with RCC, but responses may be modest or limited due to resistance of the tumor to anticarcinogen. Downregulated expression of organic cation transporter OCT2 is a possible mechanism underlying oxaliplatin resistance in RCC treatment. In this study, we observed that miR-489-3p and miR-630 suppress OCT2 expression by directly binding to the OCT2 3′-UTR. Meanwhile, via 786-O-OCT2-miRNAs stable expression cell models, we found that miRNAs could repress the classic substrate 1-methyl-4-phenylpyridinium (MPP⁺), fluorogenic substrate N,N-dimethyl-4-(2-pyridin-4-ylethenyl) aniline (ASP⁺), and oxaliplatin uptake by OCT2 both in vitro and in xenografts. In 33 clinical samples, miR-489-3p and miR-630 were significantly upregulated in RCC, negatively correlating with the OCT2 expression level compared to that in adjacent normal tissues, using tissue microarray analysis and qPCR validation. The increased binding of c-Myc to the promoter of pri-miR-630, responsible for the upregulation of miR-630 in RCC, was further evidenced by chromatin immunoprecipitation and dual-luciferase reporter assay. Overall, this study indicated that miR-489-3p and miR-630 function as oncotherapy-obstructing microRNAs by directly targeting OCT2 in RCC.     

腹腔热灌注联合多西他赛、奥沙利铂静脉化疗治疗晚期卵巢癌疗效观察

目的:探讨肿瘤细胞减灭术(CRS)后腹腔热灌注联合多西他赛、奥沙利铂静脉化疗治疗晚期卵巢癌的临床疗效。方法:取2011年1月至2014年12月在河北医科大学第二医院就诊的晚期卵巢癌患者42例,其中观察组21例(CRS后+腹腔热灌注+多西他赛、奥沙利铂静脉化疗)、紫杉醇+卡铂组21例(CRS后+紫杉醇、卡铂静脉化疗)。比较两组的疗效、肿瘤控制、腹水控制、生活质量、治疗过程中的不良反应及并发症、无进展生存期(PFS)等。结果:观察组与对照组肿瘤控制差异无统计学意义(P0.05);腹水控制、生活质量、PFS均优于对照组,差异有统计学意义(P0.05)。不良反应及并发症无明显差异(P0.05)。结论:在临床上对于晚期卵巢癌患者采取CRS术后腹腔热灌注联合多西他赛、奥沙利铂静脉化疗,对于患者的疗效、肿瘤控制、腹水控制、生活质量、PFS有提高,且不明显增加不良反应及并发症。     

Outpatient-basis chemotherapy of oxaliplatin, 5-fluorouracil, and leucovorin as first-line treatment for patients with metastatic or recurrent colorectal cancer

The objectives of the present study were to evaluate the efficacy and safety of an outpatient-basis chemotherapy of oxaliplatin, 5-fluorouracil, and leucovorin as the first-line treatment for patients with advanced colorectal cancer. Forty-three histologically confirmed patients with metastatic or recurrent colorectal cancer were enrolled. The chemotherapy consisted of oxaliplatin 85 mg/m(2) as a 2-hr infusion on day 1, plus leucovorin 30 mg/m(2) over 10 min, followed by bolus 5-fluorouracil 400 mg/m(2) and an 8-hr infusion of 5-fluorouracil 600 mg/m(2) on days 1 and 2 (modified FOLFOX4), all of which were administered on an outpatient basis every 2 weeks. The median age was 58 yr (range 33-72 yr), and 25 (58.1%) patients had metastatic diseases. Eventually, 39 patients were assessable for efficacy and all assessable for toxicity. Four (9.3%) complete responses and 11 (25.6%) partial responses were confirmed, giving an overall response rate of 34.9% (95% CI; 20.0-49.7%). The median time to progression and median overall survival for all patients was 6.1 months and 17.4 months, respectively. Grade 3/4 neutropenia occurred in 2 patients (4.7%) and febrile neutropenia was observed in 1 patient (2.3%). Modified FOLFOX4, an outpatient-basis regimen, was found to be well-tolerated and effective as the first-line chemotherapy in patients with advanced colorectal cancer.     

伊立替康或多西他赛联合奥沙利铂治疗晚期非小细胞肺癌的临床观察

目的：观察伊立替康或多西他赛联合奥沙利铂治疗晚期非小细胞肺癌（NSCLC）的近期疗效及毒副作用。方法1晚期非小细胞肺癌68例中,伊立替康联合奥沙利铂组（A组）36例,采用伊立替康100mg／m2,第1、8天;奥沙利铂130mg／m2,第2天,静脉滴注。多西他赛联合奥沙利铂组（B组）32例,采用多西他赛75mg／m2,第1天;奥沙利铂130mg／m2,第2天,静脉滴注。21天为1周期,连用2周期后评定疗效。结果：A组和B组有效率分别为41．67％和31．25％,两组差异无统计学意义（P〉0．05）。A组迟发性腹泻和胆碱性综合征发生率明显高于B组（P〈0．01）,但A组粒细胞减少发生率明显低于B组（P〈0．05）。结论：伊立替康或多西他赛联合奥沙利铂治疗晚期非小细胞肺癌有较好的疗效,不良反应可以耐受,安全性好,可以考虑作为晚期非小细胞肺癌治疗方案之一。     

The mechanism of the actions of oxaliplatin on ion currents and action potentials in differentiated NG108-15 neuronal cells

Oxaliplatin (OXAL) is a platinum-based chemotherapeutic agent which is effective against advanced or metastatic gastrointestinal cancer. However, the mechanisms responsible for the development of the neuropathy induced by this agent remain unclear. In this study, we attempted to evaluate the possible effects of OXAL on ion currents and action potentials (APs) in NG108-15 cells differentiated with dibutyryl cyclic-AMP. Application of OXAL decreased the peak amplitude of voltage-gated Na⁺ current (I_Na) with no change in the overall current–voltage relations of the currents. This agent also produced a concentration-dependent slowing of I_Na inactivation. A further application of ranolazine reversed OXAL-induced slowing of I_Na inactivation. Unlike ranolazine or riluzole, OXAL had no effect on persistent I_Na elicited by long ramp pulses. OXAL (100 μM) also had little or no effect on the peak amplitude of L-type Ca²⁺ currents in NG108-15 cells, while it suppressed delayed-rectifier K⁺ current. In current-clamp recordings, OXAL alone reduced the amplitude of APs; however, it did not alter the duration of APs. However, after application of tefluthrin, OXAL did increase the duration of APs. Moreover, OXAL decreased the peak amplitude of I_Na with a concomitant reduction of current inactivation in HEK293T cells expressing SCN5A. The effects of OXAL on ion currents presented here may contribute to its neurotoxic actions in vivo.     

Protection against oxaliplatin-induced mechanical hyperalgesia and intraepidermal nerve fiber loss by minocycline

Treatment with the chemotherapeutic agent oxaliplatin produces a robust painful neuropathy similar to various other neuropathic conditions which result in loss of nerve fibers innervating the skin. This loss of intraepidermal nerve fibers (IENFs) appears to play an important role in neuropathy, but has yet to be investigated in oxaliplatin-induced neuropathic pain. For this study, mechanical hyperalgesia and IENF density were measured in rats receiving oxaliplatin, given at a dosage of 2 mg/kg every other day for four injections. The immunomodulatory agent minocycline (25 mg/kg) was also administered and was given 24 h prior to the first dose of oxaliplatin and continued throughout oxaliplatin treatment. Immunohistochemistry using the pan-neuronal marker PGP9.5 was used to investigate IENF densities in hind paw skin on Day 15 and Day 30. The results show that a robust mechanical sensitivity developed in oxaliplatin treated animals, as did a pronounced decrease in epidermal nerve fibers, and these outcomes were effectively prevented by minocycline treatment. This is the first study to show changes in IENF density in oxaliplatin treated animals, and confirm not only a relationship between IENF loss and hypersensitivity but also prevention of both with minocycline treatment.     

Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-α/NF-κB Signaling in Rats

Antineoplastic drugs such as oxaliplatin (OXA) often induce memory and emotional deficits. At present, the mechanisms underlying these side-effects are not fully understood, and no effective treatment is available. Here, we show that the short-term memory deficits and anxiety-like and depression-like behaviors induced by intraperitoneal injections of OXA (4 mg/kg per day for 5 consecutive days) were accompanied by synaptic dysfunction and downregulation of the NR2B subunit of N-methyl-D-aspartate receptors in the hippocampus, which is critically involved in memory and emotion. The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate (L-TAMS, 604 mg/kg per day, from 2 days before until the end of experiments). We found that OXA injections significantly reduced the free Mg²⁺ in serum and cerebrospinal fluid (from ~ 0.8 mmol/L to ~ 0.6 mmol/L). The Mg²⁺ deficiency (0.6 mmol/L) upregulated tumor necrosis factor (TNF-α) and phospho-p65 (p-p65), an active form of nuclear factor-kappaB (NF-κB), and downregulated the NR2B subunit in cultured hippocampal slices. Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65, as well as microglial activation in the hippocampus and the medial prefrontal cortex. Finally, similar to oral L-TAMS, intracerebroventricular injection of PDTC, an NF-κB inhibitor, also prevented the OXA-induced memory/emotional deficits and the changes in TNF-α, p-p65, and microglia. Taken together, the activation of TNF–α/NF–κB signaling resulting from reduced brain Mg²⁺ is responsible for the memory/emotional deficits induced by OXA. Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.Electronic supplementary materialThe online version of this article (10.1007/s12264-020-00563-x) contains supplementary material, which is available to authorized users.     

紫杉醇或健择联合奥沙利铂治疗非小细胞肺癌的临床对照研究

目的比较健择联合奥沙利铂方案与紫杉醇联合奥沙利铂方案治疗非小细胞肺癌（NSCLC）的疗效及毒副反应。方法选择2003年1月～2009年11月于我院呼吸内科进行化疗的160例Ⅲ～Ⅳ期NSCLC患者,分为健择组及紫杉醇组,两组各80例。紫杉醇组用紫杉醇联合奥沙利铂化疗,健择组用健择醇联合奥沙利铂化疗。结果健择组与紫杉醇组的短期疗效分别为61.3%和45.0%,差异有显著性（P〈0.05）,同时健择组毒副反应发生率较紫杉醇组低。结论健择联合奥沙利铂治疗NSCLC有效率较紫杉醇联合奥沙利铂有效率高,二者之间有显著性差异,且健择联合奥沙利铂方案的毒副作用较少,而且较轻微,故健择联合奥沙利铂方案是治疗NSCLC的较好选择。     

经动脉灌注化学治疗中晚期胃癌的临床效果

目的探讨经动脉灌注化学治疗(简称化疗)中晚期胃癌的临床效果。方法将80例中晚期胃癌患者随机分为观察组和对照组,每组40例。观察组给予DSA引导下经动脉灌注化疗,对照组采用常规SOX方案化疗,比较2组化疗3、6个周期后的疗效,并统计不良反应。绘制2组患者随访24个月时无进展生存时间曲线,比较无进展生存时间。结果3个周期化疗结束时,观察组治疗有效率69.44%(25/36),高于对照组的38.46%(15/39)(P=0.028);6个周期结束时,观察组治疗有效率58.82%(20/34),对照组为41.67%(15/36),组间差异无统计学意义(P=0.511)。6个周期化疗期间2组患者不良反应差异无统计学意义(P均>0.05)。随访24个月时,观察组、对照组中位无进展生存期分别为6.5、6.0个月,组间比较差异有统计学意义(P=0.041)。结论动脉置管持续灌注化疗对中晚期胃癌的短期疗效优于常规SOX化疗方案,并可延长患者无进展生存期,且较安全。     

局部进展期胃癌术后进行奥沙利铂联合替吉奥辅助化疗的安全性和有效性

目的:探究奥沙利铂联合替吉奥（SOX）方案作为局部进展期胃癌D 2根治术后辅助化疗方案的安全性和有效性。 方法:采用描述性病例系列研究方法。病例纳入标准：（1）经胃镜活检或手术标本病理证实为胃腺癌;（2）接受D 2根治手术,且术后接受SOX方案辅助化疗。排除标准：（1）术后病理分期为T...