Smoking Alters Inflammation and Skeletal Stem and Progenitor Cell Activity During Fracture Healing in Different Murine Strains

Smokers are at a higher risk of delayed union or nonunion after fracture repair. Few specific interventions are available for prevention because the molecular mechanisms that result in these negative sequelae are poorly understood. Murine models that mimic fracture healing in smokers are crucial in further understanding the local cellular and molecular alterations during fracture healing caused by smoking. We exposed three murine strains, C57BL/6J, 129X1/SvJ, and BALB/cJ, to cigarette smoke for 3 months before the induction of a midshaft transverse femoral osteotomy. We evaluated fracture healing 4 weeks after the osteotomy using radiography, micro-computed tomography (μCT), and biomechanical testing. Radiographic analysis demonstrated a significant decrease in the fracture healing capacity of smoking 129X1/SvJ mice. μCT results showed delayed remodeling of fracture calluses in all three strains after cigarette smoke exposure. Biomechanical testing indicated the most significant impairment in the functional properties of 129X1/SvJ in comparison with C57BL/6J and BALB/cJ mice after cigarette smoke exposure. Thus, the 129X1/SvJ strain is most suitable in simulating smoking-induced impaired fracture healing. Furthermore, in smoking 129X1/SvJ murine models, we investigated the molecular and cellular alterations in fracture healing caused by cigarette smoking using histology, flow cytometry, and multiplex cytokine/chemokine analysis. Histological analysis showed impaired chondrogenesis in cigarette smoking. In addition, the important reparative cell populations, including skeletal stem cells and their downstream progenitors, demonstrated decreased expansion after injury as a result of cigarette smoking. Moreover, significantly increased pro-inflammatory mediators and the recruitment of immune cells in fracture hematomas were demonstrated in smoking mice. Collectively, our findings demonstrate the significant cellular and molecular alterations during fracture healing impaired by smoking, including disrupted chondrogenesis, aberrant skeletal stem and progenitor cell activity, and a pronounced initial inflammatory response. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Risk-based,response-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: A China Lymphoma Collaborative Group study

We aimed to determine the survival benefits of chemotherapy (CT) added to radiotherapy (RT) in different risk groups of patients with early-stage extranodal nasal-type NK/T-cell lymphoma (ENKTCL), and to investigate the risk of postponing RT based on induction CT responses. A total of 1360 patients who received RT with or without new-regimen CT from 20 institutions were retrospectively reviewed. The patients had received RT alone, RT followed by CT (RT + CT), or CT followed by RT (CT + RT). The patients were stratified into different risk groups using the nomogram-revised risk index (NRI). A comparative study was performed using propensity score-matched (PSM) analysis. Adding new-regimen CT to RT (vs RT alone) significantly improved overall survival (OS, 73.2% vs 60.9%, P < .001) and progression-free survival (PFS, 63.5% vs 54.2%, P < .001) for intermediate-risk/high-risk patients, but not for low-risk patients. For intermediate-risk/high-risk patients, RT + CT and CT + RT resulted in non-significantly different OS (77.7% vs 72.4%; P = .290) and PFS (67.1% vs 63.1%; P = .592). For patients with complete response (CR) after induction CT, initiation of RT within or beyond three cycles of CT resulted in similar OS (78.2% vs 81.7%, P = .915) and PFS (68.2% vs 69.9%, P = .519). For patients without CR, early RT resulted in better PFS (63.4% vs 47.6%, P = .019) than late RT. Risk-based, response-adapted therapy involving early RT combined with CT is a viable, effective strategy for intermediate-risk/high-risk early-stage patients with ENKTCL in the modern treatment era.     

外伤性迟发性颅内血肿常规CT研究

目的探讨常规CT如何尽早而准确地测出外伤性迟发性颅内血肿。方法搜集常规CT复查证实的外伤性迟发性颅内血肿39例,对其首次常规CT检查及复查的CT图像特点进行分析。结果 39例迟发性颅内血肿首次常规CT检查主要异常表现包括：①局限性蛛网膜下腔出血30例。②局限性脑密度减低,灰白质分界不清15例。③局部轻度占位效应18例。④颅骨骨折5例。结论外伤性迟发性颅内血肿的发生率与伤后首次常规CT检查表现密切相关,应在24 h以内复查,以6～12 h最佳。     

心率变异性联合NT-proBNP对心力衰竭病人再入院率的预测价值

目的探讨心率变异性（HRV）联合血浆N-末端B型利钠肽原（NT-proBNP）水平对慢性心力衰竭（CHF）病人再入院率的预测价值。方法选取179例CHF病人为研究对象,根据心功能分级分组,入院均检测NT-proBNP水平,住院期间均行24 h动态心电图监测,出院后1、3、6个月随访并收集再入院率,分析各组HRV各指标联合NT-proBNP水平对再入院率的预测价值。结果不同级别心功能病人NT-proBNP、SDNN、RMSSD、PNN50和HRV三角指数差异均有统计学意义（P < 0.01）。心功能Ⅲ级与Ⅳ级CHF病人的NT-proBNP及HRV指标均显著高于心功能Ⅱ级（P < 0.01）,心功能Ⅳ级显著高于心功能Ⅲ级者（P < 0.01）。心功能Ⅱ、Ⅲ和Ⅳ级CHF病人出院后1、3、6个月再入院率随着时间增加明显升高（P < 0.01）,出院后同一时间再入院率随着心功能级别上升而显著增加（P < 0.01）。结论HRV各项时域指标联合NT-proBNP水平均对CHF患者再入院率有一定的预测价值。     

乳腺原发性浆细胞瘤2例临床病理分析

目的: 探讨乳腺原发性浆细胞瘤的临床病理特点以及诊断和鉴别诊断。方法: 对2例乳腺原发性浆细胞瘤进行临床病理学分析及免疫组织化学观察,并复习相关文献。结果: 1例为乳腺双侧同时原发性浆细胞瘤,另1例为乳腺单侧孤立性原发性浆母细胞瘤。临床表现肿块无明显症状,镜下浆细胞瘤多数与正常浆细胞相似,散在多见异常和不典型瘤细胞,核分裂象可见;浆母细胞瘤有弥漫大片分布的大圆或卵圆形细胞增生,细胞核居中有明显核仁,核分裂象多见。2例均表达CD138、CD38、多发性骨髓瘤致癌蛋白;重链IgM均阳性,例1表达轻链κ,例2表达轻链λ。浆细胞瘤Ki-67 20%阳性,浆母细胞瘤70%阳性。结论: 乳腺原发性浆细胞瘤病理诊断的主要依据是组织形态和免疫表型。须与浆细胞乳腺炎及浸润性小叶癌相鉴别,治疗以手术切除结合放射治疗效果较好。     

Melatonin promotes the development of immature oocytes from the COH cycle into healthy offspring by protecting mitochondrial function

Melatonin (MT) regulates reproductive performance as a potent antioxidant; however, its beneficial effects on oocyte development remain largely unknown, especially in human oocytes. The collected 193 immature oocytes from the controlled ovarian hyperstimulation (COH) cycle underwent in vitro maturation (IVM) in IVM medium contained 10 μmol/L MT (n = 105, M group) and no MT (n = 88, NM group), followed by insemination and embryo culture. The results showed that the high-quality blastocyst formation rate in the M group (28.4%) was significantly higher than that in the NM group (2.0%) (P = .0001), and the aneuploidy rate was low (15.8%). In the subsequent clinical trials, three healthy infants were delivered. Next, single-cell RNA-seq data revealed 1026 differentially expressed genes (DEGs) between the two groups, KEGG enrichment analysis revealed that the majority of DEGs involved in oxidative phosphorylation pathway, which associated with ATP generation, was upregulated in the M group. Finally, confocal fluorescence staining results revealed that the mitochondrial membrane potential in the oocytes significantly increased and intracellular ROS and Ca²⁺ levels greatly decreased in the M group. Melatonin can promote the development of immature human oocytes retrieved from the COH cycle into healthy offspring by protecting mitochondrial function.     

Anlotinib Monotherapy for Refractory Metastatic Colorectal Cancer: A Double-Blinded,Placebo-Controlled,Randomized Phase III Trial (ALTER0703)

Background

Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC.

Materials and Methods

This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1–14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety.

Results

A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4–4.5) over placebo group (1.5 months; 95% CI, 1.4–1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27–0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8–9.7 vs. 7.2 months; 95% CI, 6.2–8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%).

Conclusion

Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients.

Implications for Practice

In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.