Logic "AND Gate Circuit"-Based Gasdermin Protein Expressing Nanoplatform Induces Tumor-Specific Pyroptosis to Enhance Cancer Immunotherapy.

Pyroptosis mediated by gasdermin protein has shown great potential in cancer immunotherapies. However, the low expression of gasdermin proteins and the systemic toxicity of nonspecific pyroptosis limit its clinical application. Here, we designed a synthetic biology strategy to construct a tumor-specific pyroptosis-inducing nanoplatform M-CNP/Mn@pPHS, in which a pyroptosis-inducing plasmid (pPHS) was loaded onto a manganese (Mn)-doped calcium carbonate nanoparticle and wrapped in a tumor-derived cell membrane. M-CNP/Mn@pPHS showed an efficient tumor targeting ability. After its internalization by tumor cells, the degradation of M-CNP/Mn@pPHS in the acidic endosomal environment allowed the efficient endosomal escape of plasmid pPHS. To trigger tumor-specific pyroptosis, pPHS was designed according to the logic "AND gate circuit" strategy, with Hif-1α and Sox4 as two input signals and gasdermin D induced pyroptosis as output signal. Only in cells with high expression of Hif-1α and Sox4 simultaneously will the output signal gasdermin D be expressed. Since Hif-1α and Sox4 are both specifically expressed in tumor cells, M-CNP/Mn@pPHS induces the tumor-specific expression of gasdermin D and thus pyroptosis, triggering an efficient immune response with little systemic toxicity. The Mn2+ released from the nanoplatform further enhanced the antitumor immune response by stimulating the cGAS-STING pathway. Thus, M-CNP/Mn@pPHS efficiently inhibited tumor growth with 79.8% tumor regression in vivo. We demonstrate that this logic "AND gate circuit"-based gasdermin nanoplatform is a promising strategy for inducing tumor-specific pyroptosis with little systemic toxicity.

Biomimetic-gasdermin-protein-expressing nanoplatform mediates tumor-specific pyroptosis for cancer immunotherapy.

Pyroptosis, mediated by gasdermin proteins, has shown excellent efficacy in facilitating cancer immunotherapy. The strategies commonly used to induce pyroptosis suffer from a lack of tissue specificity, resulting in the nonselective activation of pyroptosis and consequent systemic toxicity. Moreover, pyroptosis activation usually depends on caspase, which can induce inflammation and metabolic disorders. In this study, inspired by the tumor-specific expression of SRY-box transcription factor 4 (Sox4) and matrix metalloproteinase 2 (MMP2), we constructed a doubly regulated plasmid, pGMD, that expresses a biomimetic gasdermin D (GSDMD) protein to induce the caspase-independent pyroptosis of tumor cells. To deliver pGMD to tumor cells, we used a hyaluronic acid (HA)-shelled calcium carbonate nanoplatform, H-CNP@pGMD, which effectively degrades in the acidic endosomal environment, releasing pGMD into the cytoplasm of tumor cells. Upon the initiation of Sox4, biomimetic GSDMD was expressed and cleaved by MMP2 to induce tumor-cell-specific pyroptosis. H-CNP@pGMD effectively inhibited tumor growth and induced strong immune memory effects, preventing tumor recurrence. We demonstrate that H-CNP@pGMD-induced biomimetic GSDMD expression and tumor-specific pyroptosis provide a novel approach to boost cancer immunotherapy.

Porphyromonas gingivalis as a promotor in the development of the alcoholic liver disease via ferroptosis.

Alcoholic liver disease (ALD) is a liver disease caused by heavy drinking. Porphyromonas gingivalis (P.g), a major cause of periodontitis, whose antibodies are elevated in severe ALD patients in the plasma. The purpose of this study is to further study the role and the molecular mechanism of P.g in the progress of ALD. In this study, saliva of patients with ALD was collected. Then, an animal model of ALD with oral P.g administration was established, pathology of liver and spleen, intestinal microorganisms and metabolites were analyzed. The molecular mechanism of P.g on ALD was analyzed in vitro. ALD and intestinal microflora and metabolite changes were observed more serious in the alcohol and P.g groups than the alcohol group. Moreover, ferroptosis was aggravated by P.g in the liver. Meanwhile, P.g promoted ferroptosis accomplication with alcohol in vitro, which can be reversed by ferroptosis inhibitors. In conclusion, P.g aggravates ALD through exacerbation gut microbial metabolic disorder in mice with alcohol, which maybe depend on ferroptosis activation in hepatocytes. The study provides a new strategy for prevention and treatment of ALD by improving the oral micro-environment.

Fish oil-based microemulsion can efficiently deliver oral peptide blocking PD-1/PD-L1 and simultaneously induce ferroptosis for cancer immunotherapy.

Peptide immune checkpoint inhibitors in cancer immunotherapy have attracted great attention recently, but oral delivery of these peptides remains a huge challenge due to the harsh gastrointestinal environment, large molecular size, high hydrophilic, and poor transmembrane permeability. Here, for the first time, a fish oil-based microemulsion was developed for oral delivery of programmed death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blocking model peptide, OPBP-1. The delivery system was characterized, in vitro and in vivo studies were conducted to evaluate its overall implication. As a result, this nutraceutical microemulsion was easily formed without the need of co-surfactants, and it appeared light yellow, transparent, good flowability with a particle size of 152 ± 0.73 nm, with a sustained drug release manner of 56.45 ± 0.36% over 24 h and a great stability within the harsh intestinal environment. It enhanced intestinal drug uptake and transportation over human intestinal epithelial Caco-2 cells, and drastically elevated the oral peptide bioavailability of 4.1-fold higher than that of OPBP-1 solution. Meanwhile, the mechanism of these dietary droplets permeated over the intestinal enterocytic membrane was found via clathrin and caveolae-mediated endocytic pathways. From the in vivo studies, the microemulsion facilitated the infiltration of CD8+ T lymphocytes in tumors, with increased interferon-γ (IFN-γ) secretion. Thus, it manifested a promising immune anti-tumor effect and significantly inhibited the growth of murine colonic carcinoma (CT26). Furthermore, it was found that the fish oil could induce ferroptosis in tumor cells and exhibited synergistic effect with OPBP-1 for cancer immunotherapy. In conclusion, this fish oil-based formulation demonstrated great potential for oral delivery of peptides with its natural property in reactive oxygen species (ROS)-related ferroptosis of tumor cells, which provides a great platform for functional green oral delivery system in cancer immunotherapy.

Discovery of a novel dual-targeting D-peptide to block CD24/Siglec-10 and PD-1/PD-L1 interaction and synergize with radiotherapy for cancer immunotherapy.

BACKGROUND: Aside from immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), intervention of CD47/Sirpα mediated 'don't eat me' signal between macrophage and tumor cell is considered as a promising therapeutic approach for cancer immunotherapy. Compared with CD47, the novel immune checkpoint CD24/Siglec-10 can also deliver 'don't eat me' signal and CD24 shows much lower expression level in normal tissue which might avoid unwanted side effects. METHODS: Cell-based phage display biopanning and D-amino acid modification strategy were used to identify the CD24/Siglec-10 blocking peptide. Cell-based blocking assay and microscale thermophoresis assay were used to validate the blocking and binding activities of the peptide. Phagocytosis and co-culture assays were used to explore the in vitro function of the peptide. Flow cytometry was performed to assess the immune microenvironment after the peptide treatment in vivo. RESULTS: A CD24/Siglec-10 blocking peptide (CSBP) with hydrolysis-resistant property was identified. Surprisingly, we found that CSBP could not only block the interaction of CD24/Siglec-10 but also PD-1/PD-L1. CSBP could induce the phagocytosis of tumor cell by both the macrophages and monocytic myeloid-derived suppressor cells (M-MDSCs), which can further activate CD8+ T cells. Besides, combination of radiotherapy and CSBP synergistically reduced tumor growth and altered the tumor microenvironment in both anti-PD-1-responsive MC38 and anti-PD-1-resistant 4T1 tumor models. CONCLUSIONS: In summary, this is the first CD24/Siglec-10 blocking peptide which blocked PD-1/PD-L1 interaction as well, functioned via enhancing the phagocytosis of tumor cells by macrophages and M-MDSCs, and elevating the activity of CD8+ T cells for cancer immunotherapy.

Enhanced dehydrogenation properties of MgH2by the synergetic effects of transition metal carbides and graphene.

Transition metal carbides show remarkable catalysis for MgH2, and the addition of carbon materials can attach excellent cycling stability. In this paper, Mg-doped with transition metal carbides (TiC) and graphene (G) composite (denoted as Mg-TiC-G) is designed to assess the influence of TiC and graphene on the hydrogen storage performance of MgH2. The as-prepared Mg-TiC-G samples showed favorable dehydrogenation kinetics compared to the pristine Mg system. After adding TiC and graphene, the dehydrogenation activation energy of MgH2decreases from 128.4 to 111.2 kJ mol-1. The peak desorption temperature of MgH2doped with TiC and graphene is 326.5 °C, which is 26.3 °C lower than the pure Mg. The improved dehydrogenation performance of Mg-TiC-G composites is attributed to synergistic effects between catalysis and confinement.

The influence of antibody CD166 on the treatment of tumor and the immunological mechanism in mice bearing oral squamous cell carcinoma.

Background: This study aimed to investigate the influence of antibody CD166 on the inhibition of tumor and further investigate the influence on immune cells of tumor tissues in mice bearing oral squamous cell carcinoma (OSCC). Methods: The xenograft model was established through subcutaneously injection of mouse OSCCs cells. Ten mice were randomly divided into two groups. The treatment group was treated with antibody CD166 and the control group was injected with the same volume normal saline. Hematoxylin and eosin (H&E) was used to confirm the tissue histopathology of xenograft mice model. Flow cytometry was used to detect the proportion of CD3+CD8+ T cells, CD8+PD-1+ cells and CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) cells in the tumor tissues. Results: After treatment with antibody CD166, the tumor volume and weight in xenograft mice model were significantly reduced. The result of flow cytometry showed that antibody CD166 showed no obvious influence on the proportion of CD3+CD8+ and CD8+PD-1+ T lymphocyte cells in the tumor tissues. In the antibody CD166 treatment group, the proportion of CD11b+Gr-1+ MDSCs cells in tumor tissues was 1.930%±0.5317%, which was significantly lower than that of the control group, 4.940%±0.3252% (P=0.0013). Conclusions: Antibody CD166 treatment helped reduce the proportion of CD11b+Gr-1+ MDSCs cells, and produced obvious therapeutic effect on the treatment of mice bearing OSCC.

N6-methyladenosine (m6A) RNA methylation mediated by methyltransferase complex subunit WTAP regulates amelogenesis.

N6-methyladenosine (m6A) RNA methylation, one of the most widespread posttranscriptional modifications in eukaryotes, plays crucial roles in various developmental processes. The m6A modification process is catalyzed by a methyltransferase complex that includes Wilms tumor 1-associated protein (WTAP) as a key component. Whether the development of dental enamel is regulated by m6A RNA methylation in mammals remains unclear. Here, we reveal that WTAP is widely expressed from the early stage of tooth development. Specific inactivation of Wtap in mouse enamel epithelium by the Cre/loxp system leads to serious developmental defects in amelogenesis. In Wtap conditional KO mice, we determined that the differentiation of enamel epithelial cells into mature ameloblasts at the early stages of enamel development is affected. Mechanistically, loss of Wtap inhibits the expression of Sonic hedgehog (SHH), which plays an important role in the generation of ameloblasts from stem cells. Together, our findings provide new insights into the functional role of WTAP-mediated m6A methylation in amelogenesis in mammals.

Intelligent Biomimetic Nanoplatform for Systemic Treatment of Metastatic Triple-Negative Breast Cancer via Enhanced EGFR-Targeted Therapy and Immunotherapy.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, and it is associated with a high recurrence rate, metastatic potential, and poor prognosis. Thus, effective therapeutic strategies for TNBC are urgently required. The epidermal growth factor receptor (EGFR) is considered to be a potential therapeutic target for TNBC. However, there are limitations to the use of targeted therapies, such as afatinib (AFT), particularly drug resistance. Here, we investigated a poly(d,l-lactide-glycolide) (PLGA)-based intelligent bionic nanoplatform, termed AFT/2-BP@PLGA@MD, which combined targeted therapy with immunotherapy. In this platform, PLGA was used to encapsulate 2-bromo-palmitate (2-BP), a palmitoylation inhibitor, to enhance the efficacy of AFT against TNBC cells. PLGA was coated with a cancer cell membrane anchored with a cleavable peptide by matrix metalloproteinase-2 to block programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1). 2-BP significantly enhanced the capacity of AFT to inhibit the proliferation and migration of tumor cells in vitro. Moreover, the tumor cell membrane-coated AFT/2-BP@PLGA@MD nanoparticles exhibited enhanced tumor targeting ability in vivo. The AFT/2-BP@PLGA@MD nanoparticles significantly inhibited the growth and metastasis of 4T1 tumor and prolonged the survival of tumor-bearing mice. The nanoparticles also triggered antitumor immune response. Collectively, we report an effective therapeutic strategy for clinically refractory TNBC.

CD73 in small extracellular vesicles derived from HNSCC defines tumour-associated immunosuppression mediated by macrophages in the microenvironment.

Research on tumour cell-derived small extracellular vesicles (sEVs) that regulate tumour microenvironment (TME) has provided strategies for targeted therapy of head and neck squamous cell carcinoma (HNSCC). Herein, we demonstrated that sEVs derived from HNSCC cancer cells carried CD73 (sEVsCD73 ), which promoted malignant progression and mediated immune evasion. The sEVsCD73 phagocytosed by tumour-associated macrophages (TAMs) in the TME induced immunosuppression. Higher CD73high TAMs infiltration levels in the HNSCC microenvironment were correlated with poorer prognosis, while sEVsCD73 activated the NF-κB pathway in TAMs, thereby inhibiting immune function by increasing cytokines secretion such as IL-6, IL-10, TNF-α, and TGF-ß1. The absence of sEVsCD73 enhanced the sensitivity of anti-PD-1 therapy through reversed immunosuppression. Moreover, circulating sEVsCD73 increased the risk of lymph node metastasis and worse prognosis. Taken together, our study suggests that sEVsCD73 derived from tumour cells contributes to immunosuppression and is a potential predictor of anti-PD-1 responses for immune checkpoint therapy in HNSCC.

A Three-In-One Assembled Nanoparticle Containing Peptide-Radio-Sensitizer Conjugate and TLR7/8 Agonist Can Initiate the Cancer-Immunity Cycle to Trigger Antitumor Immune Response.

Radiotherapy (RT) has been shown to cause immunogenic cell death (ICD) of cancer cells, which promote the release of tumor-associated antigens, and trigger the cancer-immunity cycle (CIC). However, ICD induced by RT usually does not occur in hypoxic tumor cells due to their resistance to radiation. Moreover, RT also induces programmed death ligand 1 (PD-L1) upregulation on tumor cells, which has an inhibitory effect on T lymphocytes. Therefore, therapy based on CIC must selectively target the restricted steps of antitumor immunity. Herein, the authors design a versatile three-in-one assembling nanoparticle that can simultaneously execute these obstacles. The amphiphilic peptide drug conjugate NIA-D1, containing the hydrophobic radio-sensitizer 2-(2-nitroimidazol-1-yl) acetic acid (NIA), a peptide substrate of matrix metalloproteinase-2, and a hydrophilic PD-L1 antagonist D PPA-1, is constructed and co-assembled with hydrophobic Toll-like receptor (TLR) 7/8 agonist R848 to form nanoparticle NIA-D1@R848. The NIA-D1@R848 nanoparticles combined with RT can trigger the apoptosis of tumor cells and initiate the CIC. In the presence of R848, it promotes the maturation of dendritic cells, which together with protein programmed cell death protein 1 (PD-1) and its ligand PD-L1  blockade to relieve T cell suppression, and amplify the antitumor immune cycle. In conclusion, a functionalized three-in-one nanoparticle NIA-D1@R848 is successfully constructed, which can induce strong systemic antitumor immune response.

Erratum: Cancer-associated Fibroblast-derived IL-6 Promotes Head and Neck Cancer Progression via the Osteopontin-NF-kappa B Signaling Pathway: Erratum.

[This corrects the article DOI: 10.7150/thno.22182.].

Deeds and Words: Farmers' Attitude-Paradox in Collective Action for Small-Scale Irrigation.

We explore the mechanisms of the attitude-behavior paradox and how multiple stakeholders strategize to compromise their attitudes and behaviors. Through an instrumental variable probit model, we examine the effect of income heterogeneity and social ties on the farmers' attitude-behavior paradox for collective action. The empirical results demonstrate that weak and strong ties, income heterogeneity, interaction terms, education, community environment, and community rules negatively affect the paradox, whereas water stealing and water use conflicts positively affect it. After dividing the paradox into two forms, we find that weak ties, the interaction terms thereof, negatively affect the paradox for "having negative attitude but do have behavior", while income heterogeneity negatively affects the paradox for "having positive attitude but no behavior". We contribute to the understanding of mechanisms whereby economic incentives and social structures interplay in addressing the above paradox. We conclude by discussing the implications for policies to overcome this social dilemma.

Severe visual loss caused by inhalational methanol poisoning in fireworks production: A report on 3 cases.

BACKGROUND: Workers in fireworks production are mainly at risk for explosion injury. However, there are few reports on the consequences of methanol poisoning in fireworks laborers. CASE PRESENTATION: We report on three patients with visual loss caused by inhalation exposure to high concentrations of methanol, who were engaged in the granulation process of the fireworks manufacturing industry. They presented with severe metabolic acidosis and visual impairments, accompanied by headache, chest tightness, shortness of breath, dizziness, and vomiting. All were diagnosed with acute methanol poisoning. One patient developed bilateral blindness and two patients improved after timely hemodialysis treatment. CONCLUSIONS: These case reports emphasize the risk of methanol poisoning in the fireworks industry or other factories using commercial alcohol with high methanol content. Early hemodialysis intervention and metabolic acidosis correction are crucial for rescuing visual impairment caused by methanol exposure. Awareness and supervision of commercial alcohol use are indispensable for similar industrial processes.

VDAC1 oligomerization may enhance DDP-induced hepatocyte apoptosis by exacerbating oxidative stress and mitochondrial DNA damage.

Cisplatin (DDP)-based chemotherapy is a preferred treatment for a broad spectrum of cancers, but the precise mechanisms of its hepatotoxicity are not yet clear. Recently, the role of voltage-dependent anion channel protein 1 (VDAC1) in mitochondrial activity and cell apoptosis has attracted much attention. Our aim was to investigate the effects of mitochondrial outer membrane protein VDAC1 oligomerization in DDP-induced hepatocyte apoptosis. L-02 hepatocytes were divided into 4 groups: (a) control group, (b) 4,4'diisothiocyanate-2,2'-disulfonic acid (DIDS; 40 µm) group, (c) DDP (5 µm) group, and (d) DDP and DIDS combination group. Cell apoptosis was tested by Annexin V/FITC assay, protein expression of caspase-3, γH2AX and NDUFB6 were observed by western blot assay, reactive oxygen species (ROS), and mitochondrial superoxide anion radical (O2•- ) were detected by DCFH-DA and MitoSOX probe, and DNA damage was assessed by comet assay. Moreover, the activity of mitochondrial respiratory chain complex I was determined by the colorimetry method. Compared with the control group, apoptosis rate and activated cleaved-caspase-3 protein, ROS and O2•- generation, DNA damage marker comet tail length, and γH2AX protein level increased in the DDP treatment group (P < 0.05). Activity of mitochondrial COXI decreased after DDP treatment (P < 0.05). DIDS, as a VDAC1 oligomerization inhibitor, antagonized DDP-induced apoptosis by diminishing oxidative stress and DNA damage and protecting mitochondrial complex protein. These results show that VDAC1 oligomerization may play an important role in DDP-induced hepatocyte apoptosis by increasing ROS and mtDNA leakage from VDAC1 pores, exacerbating oxidative stress and mtDNA damage.

Thymopentin treatment of murine premature ovarian failure via attenuation of immune cell activity and promotion of the BMP4/Smad9 signalling pathway.

Premature ovarian failure (POF) is a typical form of pathological aging with complex pathogenesis and no effective treatment. Meanwhile, recent studies have reported that a high-fat and high-sugar (HFHS) diet adversely affects ovarian function and ovum quality. Here, we investigated the therapeutic effect of thymopentin (TP-5) as a treatment for murine POF derived from HFHS and its target. Pathological examination and hormone assays confirmed that TP-5 significantly improved murine POF symptoms. And, TP-5 could reduce oxidative stress injury and blood lipids in the murine POF derived from HFHS. Flow cytometry and qPCR results suggested that TP-5 attenuated activation of CD3+ T cells and type I macrophages. RNA-Seq results indicated somedifferences in gene transcription between the TP-5 intervention group and the control group. KEGG analysis indicated that the expression of genes involved in the mTOR signaling pathway was the most significantly different between the two groups. Additionally, compared with the control groups, the expression levels of interleukin, NFκB, and TNF families of genes were significantly downregulated in the POF+TP-5 group, whereas expression of the TGFß/Smad9 genes was significantly upregulated. Finally, immunofluorescence staining and qPCR confirmed that TP-5 promoted the polarization of Mø2 cells in the ovary by activating the expression of the BMP4/Smad9 signalling pathway. Thus, our study confirmed that TP-5 has a significant therapeutic effect on POF by upregulating BMP4/Smad9 signalling pathway so as to promote the balance and polarization of immune cell and reducing the release of inflammatory factors and reduce lipid oxidative stress injury.

Identification and Confirmation of the miR-30 Family as a Potential Central Player in Tobacco-Related Head and Neck Squamous Cell Carcinoma.

Constituents of tobacco that can cause DNA adduct formation and oxidative stress are implicated in the development of head and neck squamous cell carcinoma (HNSCC). However, there are few studies on the mechanism(s) that underlie tobacco-associated HNSCC. Here, we used a model in which tumors were induced in rats using 4-nitroquinoline 1-oxide (4NQO), which mimicked tobacco-related HNSCC, and analyzed the expression profiles of microRNAs and mRNAs. Our results indicated that 57 miRNAs and 474 mRNA/EST transcripts exhibited differential expression profiles between tumor and normal tongue tissues. In tumor tissue, the expression levels of rno-miR-30 family members (rno-miR-30a, rno-miR-30a-3p, rno-miR-30b-5p, rno-miR-30c, rno-miR-30d, rno-miR-30e and rno-miR-30e-3p) were only 8% to 37% of those in the control group. The GO terms enrichment analysis of the differentially expressed miRNAs indicated that oxidation reduction was the most enriched process. Low expression of miR-30 family members in human HNSCC cell lines and tissues was validated by qPCR. The results revealed that the expression of miR-30b-5p and miR-30e-5p was significantly decreased in the TCGA HNSCC dataset and validation datasets, and this decrease in expression further distinguishes HNSCC associated with tobacco use from other subtypes of HNSCC. CCK8, colony formation, transwell migration and HNSCC xenograft tumor assays indicated that miR-30b-5p or miR-30e-5p inhibited proliferation, migration and invasion in vitro, and miR-30b-5p suppressed tumor growth in vivo. Moreover, we uncovered that KRAS might be the potential target gene of miR-30e-5p or miR-30b-5p. Thus, our data clearly showed that decreased expression of miR-30e-5p or miR-30b-5p may play a crucial role in cancer development, especially that of tobacco-induced HNSCC, and may be a novel candidate biomarker and target for this HNSCC subtype.

VDAC1 as a target in cisplatin anti-tumor activity through promoting mitochondria fusion.

Cisplatin is one of the most effective anti-cancer drugs, but its efficacy is limited by the development of resistance. Previous studies have shown that mitochondria play critical roles in cisplatin cytotoxicity, however, the exact mechanism of mitochondria involved in cisplatin sensitivity has not been clarified. In this study, cisplatin triggered mitochondrial oxidative stress and the decrease of mitochondria membrane potential in human cervical cancer cells. Then we screened a series of mitochondrial relevant inhibitors, including mitochondrial mPTP inhibitors DIDS and CsA, and mitochondrial respiratory complex inhibitors Rot and TTFA. Among these, only DIDS, as the inhibitor of mitochondrial outer membrane protein VDAC1, showed strong antagonism against cisplatin toxicity. DIDS mitigated cisplatin-induced MFN1-dependent mitochondrial fusion, mitochondrial dysfunction and oxidative damage. These findings demonstrated that VDAC1 may serve as a potential therapeutic target in the increase sensitivity of cisplatin, which provides an attractive pharmacological therapy to improve the effectiveness of chemotherapy.