TAS-102 has a tumoricidal activity in multiple myeloma

TAS-102/Lonsurf is a new oral anti-tumor drug consisting of trifluridine and tipiracil in a 1:0.5 molar ratio. Lonsurf has been approved globally, including US, Europe Union, and China, to treat patients with advanced colorectal cancer. Ongoing clinical trials are currently conducted for the treatment of other solid cancers. However, the therapeutic potential of TAS-102 in hematological malignancies has not been explored. In this study, we investigate the therapeutic efficacy of TAS-102 in multiple myeloma both in vitro and in vivo. We demonstrate that TAS-102 treatment inhibits tumor cell proliferation in six human myeloma cell lines with IC₅₀ values in a range from 0.64 to 9.10 μM. Dot blotting and immunofluorescent staining show that trifluridine is predominately incorporated into genomic DNAs of myeloma cells. TAS-102 treatment induces myeloma cell apoptosis through cell cycle arrest in G1 phase and activation of cGAS-STING signaling in myeloma cells. In the human myeloma xenograft models, TAS-102 treatment reduces tumor progression and prolongs mouse survival. TAS-102 has shown its efficacies in the drug-resistant myeloma cells, and the combination of TAS-102 and bortezomib has a synergistic anti-myeloma activity. Our preclinical studies indicate that TAS-102 is a potential novel agent for myeloma therapy.     

MiR-146a Deletion Protects From Bone Loss in OVX Mice by Suppressing RANKL/OPG and M-CSF in Bone Microenvironment

MicroRNAs play important roles in osteoporosis and show great potential for diagnosis and therapy of osteoporosis. Previous studies have demonstrated that miR-146a affects osteoblast (OB) and osteoclast (OC) formation. However, these findings have yet to be identified in vivo, and it is unclear whether miR-146a is related to postmenopausal osteoporosis. Here, we demonstrated that miR-146a knockout protects bone loss in mouse model of estrogen-deficient osteoporosis, and miR-146a inhibits OB and OC activities in vitro and in vivo. MiR-146a^−/− mice displayed the same bone mass as the wild type (WT) but exhibited a stronger bone turnover than the WT did under normal conditions. Nevertheless, miR-146a^−/− mice showed an increase in bone mass after undergoing ovariectomy (OVX) compared with those subjected to sham operation. OC activities were impaired in the miR-146a^−/− mice exposed to estrogen deficiency, which was diametrically opposite to the enhanced bone resorption ability of WT. Macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) from a bone microenvironment affect this extraordinary phenomenon. Therefore, our results implicate that miR-146a plays a key role in estrogen deficiency–induced osteoporosis, and the inhibition of this molecule provides skeleton protection. © 2019 American Society for Bone and Mineral Research.     

The removal torque of titanium implant inserted in rabbit femur coated with biomimetic deposited Ca-P coating

A number of experimental data on biomimetic deposition CaP (BDCaP) coating implants have reported promising outcomes by histological evaluation. But little is investigated on the role of the BDCaP coating and osseointegration mechanism by interface shear strength. To make a direct biomechanical comparison between the BDCaP coating implants and the uncoated rough titanium implants (control), a well-established animal model for implants removal torque testing was employed in rabbits, using a self-matching experimental design. All implants had an identical cylindrical screw shape without any macroscopic retentive structure. After 2, 4, 6, 8 and 12 weeks of bone healing, removal torque testing was performed to evaluate the interfacial shear strength of each implant type. The torqued implants were sputter-coated with gold for morphology observation and observed with a field-emission electron microscopy. Results showed that the interfacial shear strength of the BDCaP coating implants was similar to that of the uncoated rough implants at 2 and 4 weeks of healing. The mean removal torque values of the BDCaP coating implants were lower than those of control implants (P < 0.05) after 6 weeks of healing. The removal torque values for both types of implants revealed similar mean values after 8 and 12 weeks of healing; there were no significant difference between the two types of implants (P > 0.05). It can be concluded that the BDCaP coating implants had no beneficial effect on the interfacial shear strength at early bone healing stage.     

外斜线取骨自体骨移植及其他牙槽嵴骨增量法的研究进展

针对严重骨缺损且有种植修复意向的牙列缺损位点，自体骨移植是实现种植体三维方向充足骨量的“经典方案”，常用的口内供骨区有颏部和外斜线区域。相比颏部取骨，下颌骨外斜线取骨移植后神经并发症少，但跟其他牙槽嵴骨增量方式相比，术后骨吸收率大。本文重点讲述下颌骨外斜线块状取骨及其局限性，并阐述了其他临床应用广泛的牙槽骨增量方法，对比移植骨术后牙槽嵴宽度及高度变化、术后骨吸收率，为临床提供减小外斜线块状取骨局限性的其他骨增量方法。     

壮骨止痛胶囊调控自噬相关蛋白对去卵巢大鼠骨髓间充质干细胞增殖与骨向分化的影响

目的观察壮骨止痛胶囊调控自噬相关蛋白Beclin1、p62、LC3对去卵巢雌性大鼠骨向分化的影响。方法去除大鼠双侧卵巢进行造模,造模成功后分为模型组、壮骨止痛胶囊组、雷帕霉素(RAPA)组和3-甲基腺嘌呤(3-MA)组,另设空白组、假手术组(仅去除卵巢周围相应体积脂肪),每组7只。通过骨髓间充质干细胞(BMMSCs)原代培养测定生长曲线并检测其碱性磷酸酶(ALP)活力,通过免疫组织化学染色法分析股骨Beclin1、LC3及p62蛋白的表达,酶联免疫分析法检测血清PPAR-γ的表达。结果①与空白组比较,假手术组各项指标表达差异无统计学意义(P>0.05);②与假手术组相比,模型组各项指标均有显著差异(P<0.01);③与模型组相比,壮骨止痛胶囊组、RAPA组和3-MA组三组BMMSCs的增长及ALP活力均显著升高(P<0.01),壮骨止痛胶囊组和3-MA组Beclin1和LC3蛋白平均灰度值表达显著降低(P<0.01),RAPA组表达显著升高(P<0.01);p62蛋白平均灰度值表达显著升高(P<0.01),RAPA组表达显著降低(P<0.01),三组血清PPAR-γ值表达显著降低(P<0.01);④与RAPA组相比,壮骨止痛胶囊组和3-MA组PPAR-γ值、BMMSCs增长及ALP活力表达有差异(P<0.05),Beclin1和LC3蛋白平均灰度值表达显著降低(P<0.01),p62蛋白平均灰度值表达显著升高(P<0.01),且壮骨止痛胶囊组和3-MA组各项指标表达差异无统计学意义(P>0.05)。结论壮骨止痛胶囊通过脂向分化的自噬抑制作用促进成骨。     

不同测量方法和判断标准对血压值的影响研究

[目的]探讨用汞柱式血压计进行不同的血压测量方法、判断标准时血压值的变化。[方法]选择内科病人126例,采用汞柱式血压计通过不同的血压测量和判断方法进行自身对照,比较左右上肢、听诊器胸件置于不同状态时,首次看到水银柱波动值与听到第一声搏动音、变音值与声音消失值血压变化。[结果]左上肢和右上肢的收缩压和舒张压差别有统计学意义;听诊器胸件置于不同状态的收缩压和舒张压也有差异;首次看到水银柱波动和听到第一声搏动音的读数也存在差异;舒张压以第1次变音和声音消失的判断结果也存在差异。[结论]血压测量部位一般选择右上肢,舒张压一般应以消失音(Korotkoff第5期)为准,袖带位置不准确使测得的血压偏低,水银波动值与主动脉压和收缩压的关系有待进一步研究。     

新生儿苯丙酮尿症两种实验室筛查方法的质量评价

目的比较筛查新生儿苯丙酮尿症(PKU)的2种检测苯丙氨酸(Phe)的方法——细菌抑制法(B IA)和荧光法。方法参加美国疾病控制中心(CDC)质量评价,分析B IA和荧光法的批内、批间误差及相对偏差,比较2种方法的结果。结果用CDC质控品测得BIA批内变异系数(CV)为14.29%,荧光法为5.85%;用不同浓度质控品测得B IA批间CV分别为25.34%、20.86%、34.78%和25.72%,荧光法为16.46%、13.22%、19.53%和15.41%;B IA的PKU阳性检出率为5.04/10万,荧光法为7.79/10万。结论荧光法较B IA具有更灵敏、准确、可定量、费时少的优点,国内今后应顺应其发展趋势,普及推广运用荧光法筛查新生儿PKU。     

Immunologic Response After Laparoscopic Colon Cancer Operation Within an Enhanced Recovery Program

Objective

It has been demonstrated that colon operation combined with fast-track (FT) surgery and laparoscopic technique can shorten the length of hospital stay, accelerate recovery of intestinal function, and reduce the occurrence of post-operative complications. However, there are no reports regarding the combined effects of FT colon operation and laparoscopic technique on humoral inflammatory cellular immunity.

Methods

This was a prospective, controlled study. One hundred sixty-three colon cancer patients underwent the traditional protocol and open operation (traditional open group, n?=?42), the traditional protocol and laparoscopic operation (traditional laparoscopic group, n?=?40), the FT protocol and open operation (FT open group, n?=?41), or the FT protocol and laparoscopic operation (FT laparoscopic group, n?=?40). Blood samples were taken prior to operation as well as on days 1, 3, and 5 after operation. The number of lymphocyte subpopulations was determined by flow cytometry, and serum interleukin-6 and C-reactive protein levels were measured. Post-operative hospital stay, post-operative morbidity, readmission rate, and in-hospital mortality were recorded.

Results

Compared with open operation, laparoscopic colon operation effectively inhibited the release of post-operative inflammatory factors and yielded good protection via post-operative cell immunity. FT surgery had a better protective role with respect to the post-operative immune system compared with traditional peri-operative care. Inflammatory reactions, based on interleukin-6 and C-reactive protein levels, were less intense following FT laparoscopic operation compared to FT open operation; however, there were no differences in specific immunity (CD3+ and CD4+ counts, and the CD4+/CD8+ ratio) during these two types of surgical procedures. Post-operative hospital stay in patients randomized to the FT laparoscopic group was significantly shorter than in the other three treatment groups (P?P?Conclusions The laparoscopic technique and FT surgery rehabilitation program effectively inhibited release of post-operative inflammatory factors with a reduction in peri-operative trauma and stress, which together played a protective role on the post-operative immune system. Combining two treatment measures during colon operation produced better protective effects via the immune system. The beneficial clinical effects support that the better-preserved post-operative immune system may also contribute to the improvement of post-operative results in FT laparoscopic patients.     

Berberine Blocks the Relapse of Clostridium difficile Infection in C57BL/6 Mice after Standard Vancomycin Treatment

Vancomycin is a preferred antibiotic for treating Clostridium difficile infection (CDI) and has been associated with a rate of recurrence of CDI of as high as 20% in treated patients. Recent studies have suggested that berberine, an alternative medical therapy for gastroenteritis and diarrhea, exhibits several beneficial effects, including induction of anti-inflammatory responses and restoration of the intestinal barrier function. This study investigated the therapeutic effects of berberine on preventing CDI relapse and restoring the gut microbiota in a mouse model. Berberine was administered through gavage to C57BL/6 mice with established CDI-induced intestinal injury and colitis. The disease activity index (DAI), mean relative weight, histopathology scores, and levels of toxins A and B in fecal samples were measured. An Illumina sequencing-based analysis of 16S rRNA genes was used to determine the overall structural change in the microbiota in the mouse ileocecum. Berberine administration significantly promoted the restoration of the intestinal microbiota by inhibiting the expansion of members of the family Enterobacteriaceae and counteracting the side effects of vancomycin treatment. Therapy consisting of vancomycin and berberine combined prevented weight loss, improved the DAI and the histopathology scores, and effectively decreased the mortality rate. Berberine prevented CDIs from relapsing and significantly improved survival in the mouse model of CDI. Our data indicate that a combination of berberine and vancomycin is more effective than vancomycin alone for treating CDI. One of the possible mechanisms by which berberine prevents a CDI relapse is through modulation of the gut microbiota. Although this conclusion was generated in the case of the mouse model, use of the combination of vancomycin and berberine and represent a novel therapeutic approach targeting CDI.     

Diagnostic Value of GeneChip for Detection of Resistant Mycobacterium tuberculosis in Patients with Differing Treatment Histories

The increasing burden of drug-resistant tuberculosis (TB) poses an escalating threat to national TB control programs. To assist appropriate treatment for TB patients, accurate and rapid detection of drug resistance is critical. The GeneChip test is a novel molecular tool for the diagnosis of TB drug resistance. Performance-related data on GeneChip are limited, and evaluation in new and previously treated TB cases has never been performed. We evaluated the diagnostic performance of GeneChip in detecting resistance to rifampin (RMP) and isoniazid (INH) and in detecting multidrug-resistant tuberculosis (MDR-TB) in comparison with standard drug susceptibility testing (DST) and compared the results in a group of previously treated and newly detected TB patients in an urban area in southeastern China. One thousand one hundred seventy-three (83.8%) new cases and 227 (16.2%) previously treated cases were collected between January 2011 and September 2013. The GeneChip showed a specificity of 97.8% and a sensitivity of 94.8% for detection of RMP resistance and 97.3% and 70.9%, respectively, for INH resistance in new cases. For previously treated cases, the overall sensitivity, specificity, and agreement rate are 94.6%, 91.3%, and 92.1%, respectively, for detection of RMP resistance and 69.7%, 95.4%, and 86.8%, respectively, for INH resistance. The sensitivity and specificity of MDR-TB were 81.8% and 99.0% in new cases and 77.8% and 93.4% in previously treated cases, respectively. The GeneChip system provides a simple, rapid, reliable, and accurate clinical assay for the detection of TB drug resistance, and it is a potentially important diagnostic tool in a high-prevalence area.