Gather wisdom to overcome barriers: Well-designed nano-drug delivery systems for treating gliomas.

Due to the special physiological and pathological characteristics of gliomas, most therapeutic drugs are prevented from entering the brain. To improve the poor prognosis of existing therapies, researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy. Although these strategies can be used clinically to overcome the blood‒brain barrier (BBB), the accurate delivery of drugs to the glioma lesions cannot be ensured. Nano-drug delivery systems (NDDS) have been widely used for precise drug delivery. In recent years, researchers have gathered their wisdom to overcome barriers, so many well-designed NDDS have performed prominently in preclinical studies. These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions, drug release in response to the glioma microenvironment, biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein, and carriers created according to the active ingredients of traditional Chinese medicines. We reviewed these well-designed NDDS in detail. Furthermore, we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy, and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.

The best postoperative adjuvant therapy for patients with early stage cervical adenosquamous carcinoma.

BACKGROUND: Cervical adenosquamous carcinoma (ASC) was previously thought to be a subtype of cervical adenocarcinoma, but recent studies have found that the clinical features of the two diseases are different. Moreover, the pathological characteristics, survival, prognosis, and optimal ASC therapy remain unknown. This study aims to retrospectively analyze the postoperative survival of patients with early-stage ASC and to evaluate their condition after treatment with postoperative concurrent chemoradiotherapy (CCRT) and prophylactic irradiation of the para-aortic lymphatic drainage area. METHODS: This study enrolled 131 patients with pathologically confirmed ASC screened from 3502 patients with confirmed stage I-II cervical cancer diagnosis who had completed surgical treatments in our hospital. Among the 131 enrolled patients, 75 patients received CCRT, 33 patients received chemotherapy (CT), and 23 patients did not receive adjuvant treatment (named surgery alone (S alone). Of the 75 patients CCRT, 43 patients received prophylactic irradiation of the para-aortic lymphatic drainage area. The efficacy of the postoperative treatments of patients among groups (CCRT, CT, and S alone) was compared. RESULTS: The median follow-up time, age, and overall survival (OS) were 76 months, 43 years, and 74 months, respectively. The 3- and 5-year survival rates were 82% and 71.4%, respectively. The median disease-free survival (DFS) was 64 months. Cox regression analysis showed that postoperative adjuvant treatment modalities and positive lymph node metastases were associated with OS and DFS. Patients who received CCRT treatment had higher OS and DFS than those with CT and S alone. Prophylactic irradiation of the para-aortic lymphatic drainage area did not improve the OS and DFS of patients with CCRT treatment. However, further subgroup analysis suggested that it might improve survival rates in patients who had positive pelvic lymph nodes as confirmed by postoperative pathology. CONCLUSION: Postoperative CCRT improved the survival rates in patients with early-stage ASC. The value of prophylactic irradiation of the para-aortic lymphatic drainage area remains debatable, but it may benefit patients with pelvic lymph node involvement.

[Experimental research on characteristics of temperature field distribution of mild moxibustion and sparrow-pecking moxibustion].

OBJECTIVE: To explore the temperature field distribution and variation rules during treatment with mild moxibustion and sparrow-pecking moxibustion of TCM. METHODS: Six healthy subjects were selected. Mild moxibustion and sparrow-pecking moxibustion were exerted at Zusanli (ST 36) respectively, for 25 min. Using infrared thermal imaging instrument, the temperature field distribution was measured during moxibustion at Zusanli (ST 36). The simulated thermometer was adopted to measure the temperature field distribution during moxibustion at the imitated cortex. At 20 min of mild moxibustion and sparrow-pecking moxibustion, the temperature field distribution generated by moxibustion was observed at the imitated cortex and Zusanli (ST 36) separately. The temperature values were collected at the sites 0.7, 2.1 and 3.5 cm far from the center of the moxibustion-exerted places successively, and then the characteristics of temperature field distribution and variation rules were compared between different moxibustion methods at the imitated cortex and Zusanli (ST 36). RESULTS: At 20 min of mild moxibustion and sparrow-pecking moxibustion at Zusanli (ST 36), the temperature field distribution focused on the center of moxibustion-exerted site and the temperature was reduced to all directions and illustrated as a curved surface graph, whereas, the temperature field distribution at the imitated cortex was consistent with that at Zusanli (ST 36). With mild moxibustion, the temperature field was distributed uniformly along the longitudinal temperature gradient; whereas, with sparrow-pecking moxibustion, the longitudinal temperature of the temperature field was greatly different, in which, the maximum temperature and the average temperature were higher than those with mild moxibustion respectively and the first time up to the peak value of sparrow-pecking moxibustion was shorter than that with mild moxibustion. The thermal transfer was presented at the non-moxibustion exerted areas during the moxibustion experiment at Zusanli (ST 36). CONCLUSION: A distance feature is presented in the temperature field measured by simulated thermometer and generated under suspension moxibustion at Zusanli (ST 36). The warm stimulation effect of sparrow-pecking moxibustion is much more obvious at the moxibustion-exerted center as compared with mild moxibustion and the area of warm stimulation generated by sparrow-pecking moxibustion is more concentrated as compared with mild moxibustion. The radiation energy produced by suspension moxibustion is scattered and attenuated in skin tissue, resulting in a certain temperature gradient in the temperature field. The warm stimulation generated at skin surface by moxibustion has a warming-dredging effect.

Effectiveness and Safety of Moxibustion Robots on Primary Dysmenorrhea: A Randomized Controlled Pilot Trial.

OBJECTIVE: To conduct a pilot trial to explore the effectiveness and safety of moxibustion robots in treating primary dysmenorrhea (PD) and evaluate its feasibility in clinic. METHODS: A total of 70 participants with PD were allocated to either moxibustion robot (MR) group (35 cases) or manual moxibustion (MM) group (35 cases) using computer-generated randomization. One acupoint Guanyuan (CV 4) was selected to receive moxa heat stimulation. Two groups of participants were given 3 menstrual cycles of MM and MR treatment respectively (once a day, 5 days a session) and received another 3 menstrual cycles follow-up. The degree of pain was evaluated by short-form McGill pain questionnaire (SF-MPQ) and the symptoms of dysmenorrhea were evaluated by Cox Menstrual Symptom Scale (CMSS). The safety was measured by the occurrence rate of adverse events (AEs), including burns (blisters, red and swollen), itching, bowel changes, menstrual cycle disorder, menorrhagia and fatigue, etc. RESULTS: A total of 62 patients completed the trial, 32 in MR group and 30 in MM group. Compared with baseline, scores of SF-MPQ and CMSS significantly decreased in both groups (P<0.05), and no significant difference was observed between the two groups in the 3rd and 6th menstrual cycles (P>0.05). The total occurrence rate of AEs in MR group was 2.1%, which was significantly lower than MM group (7.2%, P<0.05). CONCLUSIONS: MR has the same effect as MM at SF-MPQ and CMSS in patients with PD. However, MR is safer than MM (Trial registration No. ChiCTR1800018236).

[Development and application of a moxibustion instrument with multi-jointed manipulator].

In view of the limitations of the existing moxibustion instruments, i.e. possible accidental injury when using moxibustion instruments, the negative effects of products from moxibustion instruments on treatment efficacy and health of medical staff and patients, a moxibustion instrument with multi-jointed manipulator is designed. This moxibustion instrument could accurately control the temperature, maintain a safe moxibustion distance, automatically process the burning ashes of moxa and selectively handle moxa smoke. The experimental results shows that this instrument could maintain the constant temperature of target acupoint, reduce the risk of empyrosis, and reasonably deal with the products of moxibustion. The purification rate of moxa smoke is 44.9%, which not only ensures the therapeutic effect of moxa smoke, but also reduces the negative effects of high-concentration moxa smoke on the health of medical staff and patients.

[Design and application of moxibustion mechanical arm].

Traditional moxibustion treatment mainly relies on doctors using specific techniques to stimulate the patient's acupoints with ignited moxa sticks. In view of the poor reproducibility, and different methods of different doctors, difficult to carry out quantitative and qualitative research work in clinical research, a moxibustion mechanical arm was designed. The hardware modules of the mechanical arm are composed of power, micro controller STM32, position servos, moxibustion strip thruster, human-computer interaction panel and sensors; the software parts are composed of main control program and interrupt service program. The use of this moxibustion mechanical arm will enhance the system's multi-task adaptability and could perform a variety of moxibustion methods including circling moxibustion and sparrow-pecking moxibustion. The data collected in real time will be transmitted to PC through bluetooth, displayed on OLED, and the system operation modes could be switched by button. Clinical trials showed that moxibustion mechanical arm had the same treatment effects with traditional moxibustion. Meanwhile, its convenience of ope-ration, repeatability of treatment, doctors and patients's treatment experience are all better than those of traditional moxibustion.

Acquired Fanconi syndrome secondary to light chain deposition disease associated with monoclonal gammopathy of renal significance: A case report.

RATIONALE: Renal Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. It is characterized by the impairment of renal proximal tubular function leading to normoglycemic glycosuria, aminoaciduria, hypophosphatemia, hypouricemia and proximal renal tubular acidosis. Renal impairment in monoclonal gammopathy, without fulfilling the criteria of multiple myeloma, is categorized as monoclonal gammopathy of renal significance (MGRS). PATIENT CONCERNS: A 54-year-old male presented with progressively aggravated bone pain and limitation of activity was admitted to our department. A proximal renal tubular damage was suggested by hypophosphatemia, compensated metabolic acidosis, renal glycosuria, aminoaciduria, and hypouricemia. M-protein of IgA kappa was detected by immunofixation electrophoresis. Mildly increased plasma cells were found in bone marrow cytomorphologic examination. Renal biopsy revealed diffuse linear monoclonal IgA-kappa light chain deposits along tubular basement membranes (TBMs), while lambda was negative. Electron microscopy showed granular electron-dense deposits along the outer aspect of TBMs. DIAGNOSES: The patient was diagnosed as FS induced osteomalacia secondary to monoclonal gammopathy of renal significance (MGRS) (IgA-κ type) and LCDD. INTERVENTIONS: He was treated with bortezomib, supplementation by phosphate, alkali agents, and active vitamin D. He responded well to the treatment symptomatically. OUTCOMES: We reported a rare case of adult acquired FS with hypophosphatemic osteomalacia secondary to LCDD associated with MGRS and the patient was successfully treated with bortezomib. LESSONS: Although few cases of LCDD with isolated symptoms of tubulointerstitial nephropathy, rather than glomerular symptoms have been reported. It still needs to be recognized as a differential diagnosis in monoclonal gammopathy.

Curcumin attenuates cyclosporine A­induced renal fibrosis by inhibiting hypermethylation of the klotho promoter.

Chronic kidney disease is increasingly considered to be a worldwide public health problem and usually leads to renal fibrosis. In the present study, curcumin, a polyphenol pigment extracted from turmeric, was demonstrated to exert protective effects on renal fibrosis via the suppression of transforming growth factor­ß (TGF­ß) downstream signaling, such as plasminogen activator inhibitor­1 (PAI­1), α­smooth muscle actin (α­SMA) and collagen I (Col I) downregulation. The present findings demonstrate that curcumin exerted a protective effect on cyclosporine A­induced renal fibrosis via a klotho (KL)­dependent mechanism, which inhibits the TGF­ß signaling pathway. Further research indicated that curcumin induced KL expression in HK­2 tubular epithelial cells by inhibiting CpG hypermethylation in the KL promoter, which mediates the loss of expression in cells. Methylation­specific polymerase chain reaction (PCR) combined with bisulfite sequencing identified numerous key CpG sites, such as 249, 240 and 236, whose methylation statuses are important for KL expression. A PCR reporter assay was utilized to further confirm these findings. In addition, the effects of curcumin on the regulation of DNA methyltransferase 1 (Dnmt1) expression were evaluated, and the data suggest that curcumin inhibits Dnmt1 expression and restricts CpG hypermethylation. Thus, the current study reveals that curcumin attenuated renal fibrosis by suppressing CpG methylation in the KL promoter, thus inducing KL expression, which inhibited TGF­ß signaling, which may provide a novel therapeutic approach for the treatment of renal fibrosis.