In vitro and in vivo study of GSK2830371 and RG7388 combination in liver adenocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct and accounts for the second highest incidence of primary liver cancers after hepatocellular carcinoma. The lack of effective treatment leads to a poor prognosis for advanced iCCA, so new targeted therapy is needed. The impairment of wild-type (WT) p53 tumor suppressor function by its negative regulators frequently occurs in iCCA. Therefore, restoration of WT p53 function by inhibiting its negative regulators is a therapeutic strategy being explored for cancer treatment. Combining an MDM2 inhibitor (MDM2i, RG7388) to stabilize p53 and a WIP1 inhibitor (WIP1i, GSK2830371) to increase p53 phosphorylation enhances p53 function. The combination of MDM2 and WIP1 inhibitors has been reported in several cancer types but in vivo studies are lacking. In the current study, liver adenocarcinoma cell lines, RBE and SK-Hep-1, were treated with RG7388 alone and in combination with GSK2830371. Cell proliferation, clonogenicity, protein and mRNA expressions, and cell cycle distribution were performed to investigate the effect and mechanism of growth suppression. To evaluate the antitumor efficacy of RG7388 and GSK2830371 in vivo, SK-Hep-1 xenografts in NOD-SCID mice were treated with combination therapy for two weeks. The combination of MDM2i and WIP1i significantly increased the growth inhibition, cytotoxicty, p53 protein expression, and phosphorylation (Ser15), leading to transactivation of downstream targets (p21^WAF1 and MDM2). The in vivo results demonstrated that the combination treatment can significantly inhibit tumor growth. In this study, the liver adenocarcinoma cell lines responded to combination treatment via reactivation of p53 function evidenced by increased p53 expression, phosphorylation and expression of its downstream targets. This efficacy was also demonstrated in vivo. The current research provides a novel strategy for targeting the p53 pathway in liver adenocarcinoma that warrants further investigation.     

Ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma: CARTITUDE‐1 (phase 2) Japanese cohort

Chimeric antigen receptor (CAR) T cells targeting B‐cell maturation antigen have shown positive responses in patients with multiple myeloma (MM). The phase 2 portion of the CARTITUDE‐1 study of ciltacabtagene autoleucel (cilta‐cel) included a cohort of Japanese patients with relapsed/refractory MM. Following a conditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), patients received a single cilta‐cel infusion at a target dose of 0.75 × 10⁶ (range, 0.5–1.0 × 10⁶CAR‐positive viable T cells/kg). The primary endpoint was overall response rate (ORR; defined as partial response or better) by International Myeloma Working Group criteria. A key secondary endpoint was the rate of very good partial response (VGPR) or better (defined as VGPR, complete response, stringent complete response). This first analysis was performed at 6 months after the last patient received cilta‐cel. Thirteen patients underwent apheresis, nine of whom received cilta‐cel infusion. Eight patients who received cilta‐cel at the target dose responded, yielding an ORR of 100%. Seven of eight (87.5%) patients achieved a VGPR or better. One additional patient who received a below‐target dose of cilta‐cel also achieved a best response of VGPR. MRD negativity (10⁻⁵ threshold) was achieved in all six evaluable patients. Eight of nine (88.9%) patients who received cilta‐cel infusion experienced a grade 3 or 4 adverse event, and eight (88.9%) patients experienced cytokine release syndrome (all grade 1 or 2). No CAR‐T cell neurotoxicity was reported. A positive benefit/risk profile for cilta‐cel was established for heavily pretreated Japanese patients with relapsed or refractory MM.     

The effect of antihistaminic drugs on pentazocine antinociception in the rat

The antinociception produced by pentazocine, diphenhydramine, promethazine, chlorpheniramine, cyclizine and chlorcyclizine in the rat has been measured with a low-temperature (51.5 degrees C) hot-plate from 15 to 75 min following drug administration. The mean reaction times measured at 15 min and the area under the antinociception curves following administration of pentazocine (5 to 30 mg/kg) were linear. Diphenhydramine, chlorpheniramine, promethazine, cyclizine, and chlorcyclizine showed mild antinociceptive potency. The antinociception produced by SC pentazocine (5 and 10 mg/kg) was potentiated, rather than in a simple additive manner, by simultaneous IP administration of 20 mg/kg of diphenhydramine, promethazine, cyclizine, or chlorpheniramine, but not by chlorcyclizine. After concurrent administration of pentazocine and diphenhydramine, diphenhydramine did not alter pentazocine concentrations in the brain and plasma 15 to 75 min following drug administration, nor did pentazocine change diphenhydramine concentrations. Results of this study demonstrate that pentazocine antinociception can be potentiated by several antihistamines and that the potentiation was not due to a mutual effect on metabolism but rather through an as yet undefined mechanism.     

Spinal sagittal malalignment following surgery for primary intramedullary tumours in children.

BACKGROUND/OBJECTIVE: As prior studies analysed predictive factors for various post-laminectomy spinal deformities in mixed spinal regions, age groups or pathologies, their validity and conclusions were unclear. The objective of this study was to determine predictive factors for worsened cervical or thoracic spinal sagittal alignment following laminectomy or laminotomy for primary intramedullary spinal cord tumours in children. METHODS: In this retrospective study, patients treated between 1980 and 1998 were reviewed. Changes in spinal alignment at the last follow-up compared to the pre-operative state were studied. Factors analysed were age, pre-operative spinal alignment, procedure types (laminectomy or laminoplasty), number of laminae operated, surgery of C2 or T1 laminae, histological grade, presence of post-operative neurological deficit and post-operative radiotherapy. RESULTS: There were 27 patients. The mean age was 5.6 years (range 1.3-14.0 years), and the mean duration of follow-up was 3.7 years (range 0.075-9.9 years). In the cervical-cervicothoracic surgical group (n = 12), alignment worsened post-operatively in 3 patients. The number of laminae operated upon had a statistically significant impact on the development of post-operative kyphosis (p = 0.07). In the thoracic-thoracolumbar surgical group (n = 15), alignment worsened in 9 patients. Procedure types were statistically significantly different, with laminectomy associated with an increased risk of post-operative kyphosis (p = 0.01). All 5 patients who had spinal fusion for worsened post-operative alignment were in the thoracic-thoracolumbar group; no patients in the cervical-cervicothoracic group required spinal fusion (p = 0.047). Other predictive factors did not reach statistical significance (p > 0.05). CONCLUSIONS: Worsened spinal sagittal alignment following laminectomy or laminoplasty and the need for spinal fusion is more common in the thoracic-thoracolumbar region than in the cervical-cervicothoracic region. In the cervical-cervicothoracic region, operation on a greater number of laminae tends to increase the risk of worsened alignment. In the thoracic-thoracolumbar region, laminectomy is associated with worsened alignment, while laminoplasty reduces this risk; also, pre-operative kyphotic deformity tends to increase the risk of worsened alignment post-operatively.     

爆裂性骨折所致眼球内陷的CT研究

目的:研究眼眶爆裂性骨折后,眼球内陷与眼眶容积扩大的关系并对眼球内陷进行早期预报。方法:28例单侧眼眶爆裂性骨折后1～350 d患者,分别测量双侧眼球位置和骨性眼眶容积值,计算患侧眼球内陷值(E)和骨性眼眶容积扩大值(V),应用pearson积矩法研究E、V相关性并建立直线回归方程。结果:28例患侧E、V呈正相关(r=0.88,P<0.001);15例≤24 d的患者直线回归方程为E=0.85 V-1.74(r=0.86,P<0.001),13例>24 d的患者直线回归方程为E=0.86 V-0.60(r=0.9,P<0.001)。结论:眼球内陷值与眼眶容积扩大值高度相关;1 mL眼眶容积的扩大,可引起大约0.9mm(0.85～0.86 mm)的眼球内陷。与伤后>24 d的相比,≤24 d的眼球有明显的抗拒内陷的趋势,>24 d之后,这种趋势逐渐消失,随之发生眼球内陷。     

Soybean oil emulsion administration during parenteral nutrition in the preterm infant: effect on essential fatty acid, lipid, and glucose metabolism

To examine the effect of a soybean oil emulsion on essential fatty acid, lipid, and glucose metabolism, preterm infants were randomized to receive 0.5 g/kg/d lipid for 5 days (n = 10, group 1) or 0.5 increased to 2.0 g/kg/d over 5 days (n = 11, group 2). Triene/tetraene ratios did not change in group 1, but decreased in group 2. In both groups, plasma phospholipid linoleate (percent and micrograms per milliliter) increased, the increase being greater in group 2. In both groups, percent content of arachidonate and 5,8,11-eicosatrienoate decreased, and that of oleate remained unchanged. In contrast, absolute content of arachidonate and oleate tended to increase, and that of 5,8,11-eicosatrienoate remained unchanged. At a lipid intake of 0.5 g/kg/d, no infants had hyperlipemia. When lipid intake exceeded 1.0 g/kg/d, the frequency of hypertriglyceridemia (triglycerides greater than 200 mg/dL) and free fatty acidemia, with the free fatty acid/molar albumin ratio exceeding 6:1, increased. Plasma glycerol increased slightly, but was substantially less than the rise in enzymatically determined triglycerides. Hyperglycemia was self-limiting and did not require alteration in dextrose intake. Thus, (1) infusion of a soybean oil emulsion at 0.5 to 2.0 g/kg/d maintains essential fatty acid status and phospholipid arachidonate concentrations; (2) significant hyperlipemia occurs when lipid intake exceeds 1.0 g/kg/d; (3) hyperglycemia associated with lipid infusion tends to be self-limiting and may not require alteration in lipid or dextrose intake; and (4) enzymatically determined triglycerides may be used to monitor lipid tolerance, provided that allowance is made for a small but systematic overestimation resulting from the rise in plasma glycerol.     

Comparative Studies of the Dielectric Properties of Polyester Imide Composite Membranes Containing Hydrophilic and Hydrophobic Mesoporous Silica Particles

In this paper, comparative studies of hydrophilic and hydrophobic mesoporous silica particles (MSPs) on the dielectric properties of their derivative polyester imide (PEI) composite membranes were investigated. A series of hydrophilic and hydrophobic MSPs were synthesized with the base-catalyzed sol-gel process of TEOS, MTMS, and APTES at a distinctive feeding ratio with a non-surfactant template of D-(-)-Fructose as the pore-forming agent. Subsequently, the MSPs were blended with the diamine of APAB, followed by introducing the dianhydride of TAHQ with mechanical stirring for 24 h. The obtained viscous solution was subsequently coated onto a copper foil, 36 μm in thickness, followed by performing thermal imidization at specifically programmed heating. The dielectric constant of the prepared membranes was found to show an obvious trend: PEI containing hydrophilic MSPs > PEI > PEI containing hydrophobic MSPs. Moreover, the higher the loading of hydrophilic MSPs, the higher the value of the dielectric constant and loss tangent. On the contrary, the higher the loading of hydrophobic MSPs, the lower the value of the dielectric constant with an almost unchanged loss tangent.     

Healthy Taiwanese Eating Approach (TEA) toward Total Wellbeing and Healthy Longevity

A healthy dietary pattern review for Asian countries is scarce, which is crucial for guiding healthy eating. We reviewed Taiwanese dietary pattern discovery studies. Included were 19 studies, the majority of which employed dimension reduction methods to find dietary patterns associated with various health conditions. To show what is a high or low intake of foods in Taiwan, we also report the average dietary content and the 25th and 75th percentile values of the adult population for six food groups gathered by the Nutrition and Health Survey in Taiwan, 2017–2020. The healthy Taiwanese dietary approach is cohesive across multiple health outcomes occurring at different ages. It is featured with higher intakes of plant-based foods, aquatic foods, and some beneficial ethnic foods (soy products), drinks (tea), and cooking methods (boiling and steaming); lower intakes of fast foods, fatty and processed meats, sugar, salt rich foods/drinks, and fried foods; but with mixed findings for dairy and egg. Yet, the average Taiwanese person consumed many refined staple foods and livestock, but not sufficient vegetables, fruits, whole grains and roots, beans, and nuts. Dairy consumption remains low. In conclusion, Taiwanese discovery studies point to a mortality-lowering total wellbeing dietary pattern consistent with the current knowledge, which discloses potential benefits of soy product, tea, and boiling and steaming.     

肺癌CT伪彩成像肿瘤红色色彩程度与Ki-67蛋白表达关系初步研究

[摘要] 目的 探讨肺癌16层螺旋CT伪彩成像肿瘤红色色彩程度与其Ki-67蛋白表达的关系。方法 25例肺癌行16层螺旋CT增强扫描及肿瘤病灶VR伪彩成像,对每个肿瘤病灶进行免疫组化Ki-67蛋白表达检测。用肿瘤VR伪彩成像红色色彩程度代表肿瘤强化状况,分析肺癌病灶VR伪彩成像红色色彩程度与肿瘤Ki-67蛋白表达关系。结果 VR伪彩成像重度红色色彩肺癌5例,中度红色色彩肺癌8例,轻度红色色彩肺癌9例,无红色色彩肺癌3例。13例重、中度红色色彩肺癌强化增加CT值为26.32±9.17Hu,肿瘤Ki-67蛋白表达阳性率为69.23%。12例轻及无红色色彩肺癌强化增加CT值为10.87±4.257Hu,肿瘤Ki-67蛋白表达阳性率为33.33%。重、中度色彩组与轻或无色彩组肺癌Ki-67蛋白表达比较差异有显著性。结论 肺癌CT伪彩成像红色色彩程度与肿瘤Ki-67蛋白表达有一定相关性,可初步反映其Ki－67表达状况。