RNA chemical modifications are a new but rapidly developing field. They can directly affect RNA splicing, transport, stability, and translation. Consequently, they are involved in the occurrence and development of diseases that have been studied extensively in recent years. However, few studies have focused on the correlation between chemical modifications and drug effects. Here, we provide a landscape of six RNA modifications in pharmacogene RNA (pharmacoepitranscriptomics) to fully clarify the correlation between chemical modifications and drugs. We performed systematic and comprehensive analyses on pharmacoepitranscriptomics, including basic characteristics of RNA modification and modification-associated mutations and drugs affected by them. Our results show that chemical modifications are common in pharmacogenes, especially N6-methyladenosine (m6A) modification. In addition, we found a very close relationship between chemical modifications and anti-tumor drugs. More interestingly, the results demonstrate the importance of m6A modification for anti-tumor drugs, especially for drugs in triple-negative breast cancer (TNBC), ovarian cancer, and acute myelocytic leukemia (AML). These results indicate that pharmacoepitranscriptomics could be a new source of drug-effect biomarkers, especially for m6A and anti-tumor drugs.

Metformin is a widely accepted first-line hypoglycemic agent in current clinical practice, and it has been applied to the clinic for more than 60 years. Recently, researchers have identified that metformin not only has an efficient capacity to lower glucose but also exerts anti-aging effects by regulating intracellular signaling molecules. With the accelerating aging process and mankind\'s desire for a long and healthy life, studies on aging have witnessed an unprecedented boom. Osteoporosis, sarcopenia, degenerative osteoarthropathy, and frailty are age-related diseases of the musculoskeletal system. The decline in motor function is a problem that many elderly people have to face, and in serious cases, they may even fail to self-care, and their quality of life will be seriously reduced. Therefore, exploring potential treatments to effectively prevent or delay the progression of aging-related diseases is essential to promote healthy aging. In this review, we first briefly describe the origin of metformin and the aging of the movement system, and next review the evidence associated with its ability to extend lifespan. Furthermore, we discuss the mechanisms related to the modulation of aging in the musculoskeletal system by metformin, mainly its contribution to bone homeostasis, muscle aging, and joint degeneration. Finally, we analyze the protective benefits of metformin in aging-related diseases of the musculoskeletal system.

Objective: To investigate the efficacy and drug related adverse reactions of sorafenib and sunitinib as first-line tyrosine-kinase inhibitors (TKIs) for patients with metastatic renal cell carcinoma (mRCC) and analyze the clinical prognostic factor for survival. Methods: The data of 271 patients with metastatic renal cell carcinoma who had complete clinicopathological data were retrospectively analyzed, including 174 cases in sorafenib group and 97 cases in sunitinib group, to access patients\' overall survival (OS) and progression-free survival (PFS). Prognostic values of all characteristics were determined by using univariate and multivariate Cox regression models. Results: The objective response rates (ORR) of the sorafenib and sunitinib groups were 14.9% and 19.6%, respectively, and the disease control rates (DCR) were 85.1% and 88.6%, respectively. No significant difference was found between the sorafenib and sunitinib group in ORR (P=0.325) or DCR (P=0.408). The most common grade 3 to 4 adverse events in the sorafenib group were hand-foot syndrome (6.7%), diarrhea (2.3%), and rash (2.3%). The most common grade 3 to 4 adverse events in the sunitinib group were neutropenia (6.2%), hand-foot syndrome (6.2%), and thrombocytopenia (4.6%). During the follow-up, 97 cases death occurred and 81 cases disease progression occurred in sorafenib group. The median PFS was 12 months (95% CI: 9-15 months), and the median OS was 25 months (95% CI: 21-29 months) in sorafenib group. While 74 cases death occurred and 40 cases disease progression occurred in sunitinib group, the median PFS was 12 months (95% CI: 10-12 months) and the median OS was 23 months (95% CI: 20-32 months) in sunitinib group. No significant difference was found between the sorafenib and the sunitinib group in PFS (P=0.771) or OS (P=0.548). Multivariate analysis showed Fuhrman grades (HR=1.358, 95%CI: 1.004-1.835), number of metastatic sites (HR=1.550, 95%CI: 1.143-2.101) and MSKCC risk grade (Intermediate risk group: HR=1.621, 95%CI: 1.117-2.232; Poor risk group: HR=2.890, 95%CI: 1.942-4.298) were independent prognostic factors for PFS. Fuhrman grades (HR=2.135, 95%CI: 1.533-2.974), number of metastatic sites (HR=1.774, 95%CI: 1.279-2.461) and MSKCC risk grade (Intermediate risk group: HR=1.415, 95%CI: 1.002-1.998; Poor risk group: HR=3.161, 95%CI: 2.065-4.838) were independent prognostic factors for OS. Conclusions: The results of this study indicate that sorafenib and sunitinib are both effective as the first-line TKIs for mRCC patients and sorafenib has comparable efficacy to sunitinib. But they have differences in the incidence of adverse effects. Fuhrman grades, number of metastatic sites and MSKCC risk grade are independent prognostic factors for mRCC patients.
目的：评价索拉非尼和舒尼替尼作为一线酪氨酸激酶抑制剂(TKI)治疗转移性肾癌的疗效和安全性，并探讨患者预后的影响因素。 方法：回顾性分析271例临床病理资料完整的转移性肾癌患者的资料，其中索拉非尼组174例，舒尼替尼组97例，评价索拉非尼组和舒尼替尼组的疗效和不良反应。采单因素和多因素Cox比例风险模型分析预后影响因素。 结果：索拉非尼组和舒尼替尼组的客观反应率分别为14.9%和19.6 %，疾病控制率分别为85.1%和88.6%，两组差异均无统计学意义(P值分别为0.325和0.408)。索拉非尼组最常见的3～4级不良反应为手足综合征(6.7%)、腹泻(2.3%)和皮疹(2.3%)。舒尼替尼组最常见的3～4级不良反应为中性粒细胞下降(6.2%)、手足综合征(6.2%)和血小板下降(4.6%)。随访期间，索拉非尼组死亡97例，疾病进展81例。中位无进展生存时间(PFS)为12个月(95%CI：9～15个月)，中位总生存时间(OS)为25个月(95%CI：21～29个月)。舒尼替尼组死亡74例，疾病进展40例。中位PFS为12个月(95%CI：10～12个月)，中位OS为23个月(95%CI：20～32个月)。两组PFS和OS差异均无统计学意义(P值分别为0.771和0.548)。多因素分析显示，Fuhrman分级(HR＝1.358，95%CI：1.004～1.835)、转移器官数(HR＝1.550，95%CI：1.143～2.101)及(纪念斯隆－凯特林癌症中心MSKCC)危险分级(中危组：HR ＝1.621，95%CI：1.117～2.232；高危组：HR＝2.890，95%CI：1.942～4.298)是转移性肾癌患者PFS的独立影响因素。Fuhrman分级(HR＝2.135，95%CI：1.533～2.974)、转移器官数(HR＝1.774，95%CI：1.279～2.461)及MSKCC危险分级(中危组：HR＝1.415，95%CI：1.002～1.998；高危组：HR＝3.161，95%CI：2.065～4.838)是转移性肾癌患者OS的独立影响因素。 结论：索拉非尼与舒尼替尼作为一线TKI药物治疗转移性肾癌疗效显著，两者疗效无明显差异，药物相关不反应分布有所不同。Fuhrman分级、转移器官数和MSKCC评分是转移性肾癌患者预后的独立影响因素。.

Functional magnetic resonance imaging (fMRI) is employed in many behavior analysis studies, with blood oxygen level dependent- (BOLD-) contrast imaging being the main method used to generate images. The use of BOLD-contrast imaging in fMRI has been refined over the years, for example, the inclusion of a spin echo pulse and increased magnetic strength were shown to produce better recorded images. Taking careful precautions to control variables during measurement, comparisons between different specimen groups can be illustrated by fMRI imaging using both quantitative and qualitative methods. Differences have been observed in comparisons of active and resting, developing and aging, and defective and damaged brains in various studies. However, cognitive studies using fMRI still face a number of challenges in interpretation that can only be overcome by imaging large numbers of samples. Furthermore, fMRI studies of brain cancer, lesions and other brain pathologies of both humans and animals are still to be explored.

OBJECTIVE: To study the anti-fibrotic mechanism of amygdalin, a component of Semen Persicae, on fat-storing cells (FSC).
METHODS: Livers of normal adult rats were perfused with Pronas E and collagenase in situ. FSC were isolated by centrifugation with 11% Metrizamide. The subcultured FSC were incubated with 10(-4)-10(-8) mol/L amygdalin for 72 h, and then FSC proliferation and collagen production were assayed, respectively.
RESULTS: Low doses of amygdalin reduced incorporation of L-[(3)H]-thymidine into FSC and L-[5-(3)H]-proline into secreted collagenase-sensitive proteins and cell layer-associated collagenase-sensitive proteins. the strongest effects were seen for the 10(-8) mol/L dose of amygdalin, which inhibited the proliferation of FSC by 25.0%, and decreased collagen production in medium and cell layer by 24.2% and 26.8%, respectively.
CONCLUSIONS: An anti-fibrotic mechanism of amygdalin is to inhibit the proliferation and collagen production of active FSC.

There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.

Hypericin (Hy) has shown great promise as a necrosis-avid agent in cancer imaging and therapy. Given the highly hydrophobic and π-conjugated planarity characteristics, Hy tends to form aggregates. To investigate the effect of aggregation on targeting biodistribution, nonaggregated formulation (Non-Ag), aggregated formulation with overconcentrated Hy in dimethyl sulfoxide (Ag-DMSO) solution, and aggregated formulation in water solution (Ag-water) were selected by fluorescence measurement. They were labeled with ¹³¹I and evaluated for the necrosis affinity in rat model of reperfused hepatic infarction by gamma counting and autoradiography. The radioactivity ratio of necrotic liver/normal liver was 17.1, 7.9, and 6.4 for Non-Ag, Ag-DMSO, and Ag-water, respectively. The accumulation of two aggregated formulations (Ag-DMSO and Ag-water) in organs of mononuclear phagocyte system (MPS) was 2.62 ± 0.22 and 3.96 ± 0.30 %ID/g in the lung, and 1.44 ± 0.29 and 1.51 ± 0.23 %ID/g in the spleen, respectively. The biodistribution detected by autoradiography showed the same trend as by gamma counting. In conclusion, the Non-Ag showed better targeting biodistribution and less accumulation in MPS organs than aggregated formulations of Hy. The two aggregated formulations showed significantly lower and higher accumulation in targeting organ and MPS organs, respectively.

The main treatment of leukemia is traditional radiochemotherapy, which is associated with serious side effects. In the past twenty years, differentiation was found as an important effective measure to treat leukemia with fewer side effects. Gossypol, a natural compound which has been used as an effective contraceptive drug, has been proposed to be a potent drug to treat leukemia, but the differentiation effect has not been studied. In the present study, we investigated the pro-differentiated effects, in vitro, of gossypol on the classic human myeloid leukemia HL-60 cell line. The effects of gossypol were investigated by using morphological changes, nitroblue tetrazolium (NBT) reduction, surface markers, cell-cycle analysis and Western blot analysis, etc. When HL-60 cells were incubated with low concentrations of gossypol (2-5μM) for 48hr, a prominent G0/G1 arrest was observed. At 96 hr of treatment, 90% of HL-60 cells differentiated, as evidenced by morphological changes, NBT reduction, and increase in cell surface expression of some molecules were detected. This study is the first to identify gossypol\'s pro-differentiated effects on the leukemia cell line, and it induced differentiation through the PBK (PDZ-binding kinase)/TOPK (T-LAKcell-originated protein kinase) (PBK/TOPK) pathway. It is concluded that gossypol could induce differentiation in the leukemia HL-60 cells, and it may be a potential therapeutic agent, chemoprevention or chemotherapeutic adjuvant especially in combination drug therapy for leukemia.