Biomimetic biomineralization nanoplatform-mediated differentiation therapy and phototherapy for cancer stem cell inhibition and antitumor immunity activation

Growing evidence suggests that the presence of cancer stem cells(CSCs)is a major challenge in current tumor treatments,especially the transition from non-CSCs to differentiation of CSCs for evading conventional therapies and driving metastasis.Here we propose a therapeutic strategy of synergistic differentiation therapy and phototherapy to induce differentiation of CSCs into mature tumor cells by differentiation inducers and synergistic elimination of them and normal cancer cells through phototherapy.In this work,we synthesized a biomimetic nanoplatform loaded with IR-780 and all-trans retinoic acid(ATRA)via biomineralization.This method can integrate aluminum ions into small-sized protein carriers to form nanoclusters,which undergo responsive degradation under acidic conditions and facilitate deep tumor penetration.With the help of CSC differentiation induced by ATRA,IR-780 inhibited the self-renewal of CSCs and cancer progression by generating hyperthermia and reactive oxygen species in a synergistic manner.Furthermore,ATRA can boost immunogenic cell death induced by phototherapy,thereby strongly causing a systemic anti-tumor immune response and efficiently eliminating CSCs and tumor cells.Taken together,this dual strategy represents a new paradigm of targeted eradication of CSCs and tumors by inducing CSC differentiation,improving photothermal therapy/photodynamic therapy and enhancing antitumor immunity.

Phase Ⅲ Clinical Trials of the Cell Differentiation Agent-2 （CDA-2）： Therapeutic Efficacy on Breast Cancer, Non-Small Cell Lung Cancer and Primary Hepatoma

OBJECTIVE The objective of this study was to explore the effect of CDA-2, a selective inhibitor of abnormal methylation enzymes in cancer cells, on the therapeutic efficacy of cytotoxic chemotherapy. METHODS Advanced cancer patients, all of whom had previously undergone chemotherapy, were randomly divided into 2 groups, one receiving chemotherapy only as the control group, and the other receiving CDA-2 in addition to chemotherapy as the combination group. The therapeutic efficacies and the toxic maniestations of the 2 groups were compared based on the WHO criteria. RESULTS Of 454 cancer patients enrolled in phase Ⅲ clinical trials of CDA-2, 80, 188, and 186 were breast cancer, NSCLC, and primary hepatoma patients, respectively. Among them 378 patients completed treatments according to the protocols. The results showed that the overall effective rate of the combination group was 2.6 fold that of the control group, 4.8 fold in the case of breast cancer, 2.3 fold in the case of primary hepatoma, and 2.2 fold in the case of NSCLC. Surprisingly, the combination therapy appeared to work better for stage Ⅳ than stage Ⅲ patients. CDA-2 did not contribute additional toxicity. On the contrary, it reduced toxic manifestations of chemotherapy, particularly regarding white blood cells, nausea and vomiting. CONCLUSION Modulation of abnormal methylation enzymes by CDA-2 is definitely helpful to supplement chemotherapy. It significantly increased the therapeutic efficacy and reduced the toxic manifestation of cytotoxic chemotherapy on breast cancer and NSCLC.

Molecular pathogenesis and therapeutic strategies of human osteosarcoma

Osteosarcoma（OS）is a devastating illness with rapid rates of dissemination and a poor overall prognosis,despite aggressive standard-of-care surgical techniques and combination chemotherapy regimens.Identifying the molecular mechanisms involved in disease pathogenesis and progression may offer insight into new therapeutic targets.Defects in mesenchymal stem cell differentiation,abnormal expression of oncogenes and tumor suppressors,and dysregulation within various important signaling pathways have all been implicated in development of various disease phenotypes.As such,a variety of basic science and translational studies have shown promise in identifying novel markers and modulators of these disease-specific aberrancies.Born out of these and similar investigations,a variety of emerging therapies are now undergoing various phases of OS clinical testing.They broadly include angiogenesis inhibitors,drugs that act on the bone microenvironment,receptor tyrosine kinase inhibitors,immune system modulators,and other radio-or chemo-sensitizing agents.As new forms of drug delivery are being developed simultaneously,the possibility of targeting tumors locally while minimizing systemic toxicityis is seemingly more achievable now than ever.In this review,we not only summarize our current understanding of OS disease processes,but also shed light on the multitude of potential therapeutic strategies the scientific community can use to make long-term improvements in patient prognosis.

Effect of soothing liver therapy on oocyte quality and growth differentiation factor-9 in patients undergoing in vitro fertilization and embryo transfer

OBJECTIVE:To investigate the effect of Soothing liver therapy on infertile women undergoing in vitro fertilization and embryo transfer(IVF-ET)and to explore its mechanism.METHODS:Fifty-eight women with tubal infertility were randomized into two groups:30 in an experimental group treated with Xiaoyao powder(Shugan)plus gonadotropin-releasing hormone analog(GnRHa)/follicle-stimulating hormone(FSH)/human chorionic gonadotropin(hCG)and 28 in the control group who were treated with GnRHa/FSH/hCG only.The total gonadotropin(Gn)doses required,endometrial thickness,oocyte numbers,high quality embryo production rate and pregnancy rate of the two groups were compared.The concentration of growth differentiation factor-9(GDF-9)in follicular fluid was detected by western blotting and the expression of GDF-9 mRNA in granulosa cells was measured using reverse tran-scription-polymerase chain reaction amplification.RESULTS:In the experimental group,the Gn dose was significantly lower than that in the control group;the endometrial thickness,high quality embryo production and pregnancy rates were significantly higher and the expression of GDF-9 mRNA was also significantly higher than in the control group(all P<0.05).CONCLUSION:Shugan treatment can improve the pregnancy rate of women with tubal infertility;its mechanism is possibly related to the increased expression of GDF-9 in granulosa cells.

Clinical Observation on Syndrome Differentiation Staging Therapy of Central Serous Chorioretinopathy

Objective: To observe the effect of traditional Chinese medicine in Syndrome Differentiation Staging therapy （SDST） in treating central serous chorioretinopathy （CSC）. Methods: One hundred patients of CSC were divided into two groups, the TCM group and the control group, and were treated with SDST and western medicine respectively. Results: The total effective rate of the two groups was 98 % and 82 % respectively and their mean cure time 35 ± 7.0 days and 39 ± 8.8 days respectively. Comparison between the two groups showed significant difference （P＜0.05）, effect in the TCM group was superior to that in the control group.Conclusion: SDST treatment was helpful in curing CSC. Its basic action is to relieve Qi stagnation and blood stasis, which were taken as the basic physiopathologic change of CSC. And the staging therapy could enhance the therapeutic effect in different stages of the disease.

Low-dose and high-dose ^(131)I therapy for low and intermediate risk differentiated thyroid cancer: a randomized controlled clinical study

Objective To compare the ablation efficacy and therapy response with low-dose（1.1 GBq）and high-dose（3.7 GBq） 131I in postoperative patients with low and in-termediate risk DTC.Methods A total of 140 patients（37 males,103 females,age range:18-75 years）were enrolled from October 2014 to June 2015,and

Clinical study on depression differentiated as yang deficiency treated with the combined therapy of ginger-isolated moxibustion and western medicine

Objective To compare the differences in the clinical efficacy on depression differentiated as yang deficiency between the combined therapy of ginger isolated moxibustion and escitalopram and the simple application escitalopram.Methods Eighty patients of depression differentiated as yang deficiency were randomized into an observa-

Postoperative Stimulated Thyroglobulin Level and Recurrence Risk Stratification in Differentiated Thyroid Cancer

Background： Postoperative preablative stimulated thyroglobulin （ps-Tg） has been evaluated in predicting prognosis and success of ablation regarding differentiated thyroid cancer （DTC）; however, its relationship with recurrence risk and radioiodine decision-making remains uncertain, especially in Chinese DTC patients. We aimed to evaluate the association between ps-Tg and recurrence risk stratification in DTC, to provide incremental values for ps-Tg in postoperative assessment and radioiodine management. Methods： Seven hundred and seven patients with DTC were included; low-risk （L; n = 90）, intermediate-risk （I; n = 283）, and high-risk （H; n = 334, 117 with distant metastasis [M 1 ]） patients were divided according to recurrence risk stratification. The M 1 group was further analyzed regarding evidence of metastasis. Cut-off values of ps-Tg were obtained using receiver operating characteristic analysis. Results： Patients with more advanced disease at initial risk stratification were more likely to have higher ps-Tg levels （I vs. L： P 〈 0.05; H vs. 1： P 〈 0.001; H vs. L： P 〈 0.001）. The corresponding cut-off value of ps-Tg for distinguishing sensitivity and specificity in each of the two groups was 2.95 ng/ml （1 vs. L： 61.5%, 63.3%）, 29.5 ng/ml （H vs, I： 41.9%, 92.6%）, 47.1 ng/ml （M1 vs. M0 in the H group： 79.5%, 88.9%） and 47.1 ng/ml （MI vs. M0 in all patients： 79.5%, 93.7%）. With the cut-offvalue at 47.1 ng/ml, ps-Tg was the only factor that could be used to identify distant metastases, and consequently if measured before radioiodine therapy would prevent 10.26% of patients with M1 from undertreatment, Conclusions： Ps-Tg, as an ongoing reassessment marker, favors differential recurrence risk grading and provides incremental values for radioiodine treatment decision-making.

AKT inhibitor Hu7691 induces differentiation of neuroblastoma cells

While neuroblastoma accounts for 15%of childhood tumor-related deaths,treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs.Currently,maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical,especially high-risk patients.However,differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy,unclear mechanism,and few drug options.Through compound library screening,we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691.The protein kinase B(AKT)pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation,yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear.Here,we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines.Further evidence including neurites outgrowth,cell cycle arrest,and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691.Meanwhile,with the introduction of other AKT inhibitors,it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation.Furthermore,silencing AKT was found to have the effect of inducing neuroblastoma differentiation.Finally,confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo,suggesting that Hu7691 is a potential molecule against neuroblastoma.Through this study,we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.

Lipid-polymer hybrid nanoparticle with cell-distinct drug release for treatment of stemness-derived resistant tumor

Drug resistance presents one of the major causes for the failure of cancer chemotherapy.Cancer stem-like cells(CSCs),a population of self-renewal cells with high tumorigenicity and innate chemoresistance,can survive conventional chemotherapy and generate increased resistance.Here,we develop a lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent,all-trans retinoic acid and the chemotherapeutic drug,doxorubicin to overcome the CSC-associated chemoresistance.The hybrid nanoparticles achieve differential release of the combined drugs in the CSCs and bulk tumor cells by responding to their specific intracellular signal variation.In the hypoxic CSCs,ATRA is released to induce differentiation of the CSCs,and in the differentiating CSCs with decreased chemoresistance,DOX is released upon elevation of reactive oxygen species to cause subsequent cell death.In the bulk tumor cells,the drugs are released synchronously upon the hypoxic and oxidative conditions to exert potent anticancer effect.This cell-distinct drug release enhances the synergistic therapeutic efficacy of ATRA and DOX with different anticancer mechanism.We show that treatment with the hybrid nanoparticle efficiently inhibit the tumor growth and metastasis of the CSC-enriched triple negative breast cancer in the mouse models.