Adipose Tissue Targeting Ultra-Small Hybrid Nanoparticles for Synergistic Photodynamic Therapy and Browning Induction in Obesity Treatment.

Photodynamic therapy (PDT), as a means of locally and rapidly inducing adipocyte death via light illumination, in combination with adipose browning induction, a more gradual and widespread effect that could transform white adipose tissue into thermogenic adipose tissue, manifests a promising approach to combat obesity. Herein, adipose-targeting ultra-small hybrid nanoparticles (Pep-PPIX-Baic NPs) composed of an adipose-targeting peptide, Fe3+, a photosensitizer (protoporphyrin IX), and a browning agent (baicalin) are introduced. Pep-PPIX-Baic NPs have been designed to simultaneously enhance the photodynamic effect and induce browning. After intravenous injection in obese mice, the hybrid nanoparticles can specifically accumulate in white adipose tissues, especially those rich in blood supply, and drive adipose reduction owing to the synergy of the PDT effect and baicalin browning induction. Overall, Pep-PPIX-Baic NPs exhibited superior anti-obesity potential through PDT synergistic with adipose browning induction. The designed multifunctional adipose-targeting hybrid nanoparticles present a prospective nanoplatform for obesity treatment.

Self-powered freestanding multifunctional microneedle-based extended gate device for personalized health monitoring.

Online monitoring of prognostic biomarkers is critically important when diagnosing disorders and assessing individuals' health, especially for chronic and infectious diseases. Despite this, current diagnosis techniques are time-consuming, labor-intensive, and performed offline. In this context, developing wearable devices for continuous measurements of multiple biomarkers from body fluids has considerable advantages including availability, rapidity, convenience, and minimal invasiveness over the conventional painful and time-consuming tools. However, there is still a significant challenge in powering these devices over an extended period, especially for applications that require continuous and long-term health monitoring. Herein, a new freestanding, wearable, multifunctional microneedle-based extended gate field effect transistor biosensor is fabricated for online detection of multiple biomarkers from the interstitial fluid including sodium, calcium, potassium, and pH along with excellent electrical response, reversibility, and precision. In addition, a hybrid powering system of triboelectric nanogenerator and solar cell was developed for creating a freestanding, closed-loop platform for continuous charging of the device's battery and integrated with an Internet of Things technology to broadcast the measurements online, suggesting a stand-alone, stable multifunctional tool which paves the way for advanced practical personalized health monitoring and diagnosis.

Discovery of dolutegravir-1,2,3-triazole derivatives against prostate cancer via inducing DNA damage.

Prostate cancer (PCa) is the second most frequently diagnosed cancer among men, causing a huge number of deaths each year. Traditional chemotherapy for PCa mostly focused on targeting androgen receptors. However, some of the patients would develop resistance to hormonal therapy. In these cases, it is suggested for these patients to administer treatments in combination with other chemotherapeutics. Current chemotherapeutics for metastatic castration-resistant PCa could hardly reach satisfying effects, therefore it is crucial to explore novel agents with low cytotoxicity. Herein, a common drug against the human immunodeficiency virus (HIV), the dolutegravir (DTG) was modified to become a series of dolutegravir-1,2,3-triazole derivatives. Among these compounds, the 4d and 4q derivatives were verified with high anti-tumor efficiency, suppressing the proliferation of the prostate cancer cells PC3 and DU145. These compounds function by binding to the poly (adenosine diphosphate-ribose) polymerase (PARP), inactivating the PARP and inducing DNA damage in cancer cells. It is noteworthy that the 4d and 4q derivatives showed almost no impact on normal cells and mice. Thereby, the results reveal that these dolutegravir-1,2,3-triazole compounds are potential chemotherapeutics for PCa treatment.

A carrier-free supramolecular nano-twin-drug for overcoming irinotecan-resistance and enhancing efficacy against colorectal cancer.

Irinotecan (Ir) is commonly employed as a first-line chemotherapeutic treatment for colorectal cancer (CRC). However, tremendous impediments remain to be addressed to surmount drug resistance and ameliorate adverse events. Poly-ADP-Ribose Polymerase (PARP) participates in the maintenance of genome stability and the repair of DNA damage, thus playing a critical role in chemotherapy resistance. In this work, we introduce a novel curative strategy that utilizes nanoparticles (NPs) prepared by dynamic supramolecular co-assembly of Ir and a PARP inhibitor (PARPi) niraparib (Nir) through π-π stacking and hydrogen bond interactions. The Ir and Nir self-assembled Nano-Twin-Drug of (Nir-Ir NPs) could enhance the therapeutic effect on CRC by synergistically inhibiting the DNA damage repair pathway and activating the tumor cell apoptosis process without obvious toxicity. In addition, the Nir-Ir NPs could effectively reverse irinotecan-resistance by inhibiting the expression of multiple resistance protein-1 (MRP-1). Overall, our study underscores the distinctive advantages and potential of Nir-Ir NPs as a complementary strategy to chemotherapy by simultaneously overcoming the Ir resistance and improving the anti-tumor efficacy against CRC.

Toxicity Analysis of Mesoporous Polydopamine on Intestinal Tissue and Microflora.

As a promising therapy, photothermal therapy (PTT) converts near-infrared (NIR) light into heat through efficient photothermal agents (PTAs), causing a rapid increase in local temperature. Considering the importance of PTAs in the clinical application of PTT, the safety of PTAs should be carefully evaluated before their widespread use. As a promising PTA, mesoporous polydopamine (MPDA) was studied for its clinical applications for tumor photothermal therapy and drug delivery. Given the important role that intestinal microflora plays in health, the impacts of MPDA on the intestine and on intestinal microflora were systematically evaluated in this study. Through biological and animal experiments, it was found that MPDA exhibited excellent biocompatibility, in vitro and in vivo. Moreover, 16S rRNA analysis demonstrated that there was no obvious difference in the composition and classification of intestinal microflora between different drug delivery groups and the control group. The results provided new evidence that MPDA was safe to use in large doses via different drug delivery means, and this lays the foundation for further clinical applications.

Disease Detection with Molecular Biomarkers: From Chemistry of Body Fluids to Nature-Inspired Chemical Sensors.

This article aims to review nature-inspired chemical sensors for enabling fast, relatively inexpensive, and minimally (or non-) invasive diagnostics and follow-up of the health conditions. It can be achieved via monitoring of biomarkers and volatile biomarkers, that are excreted from one or combination of body fluids (breath, sweat, saliva, urine, seminal fluid, nipple aspirate fluid, tears, stool, blood, interstitial fluid, and cerebrospinal fluid). The first part of the review gives an updated compilation of the biomarkers linked with specific sickness and/or sampling origin. The other part of the review provides a didactic examination of the concepts and approaches related to the emerging chemistries, sensing materials, and transduction techniques used for biomarker-based medical evaluations. The strengths and pitfalls of each approach are discussed and criticized. Future perspective with relation to the information and communication era is presented and discussed.

In vitro effects of lonidamine and 6-aminonicotinamide against Echinococcus granulosussensu stricto and Echinococcus multilocularis.

Echinococcosis is a zoonotic disease caused by cestode species of the genus Echinococcus, which demonstrates considerable medical and veterinary concerns. The development of novel drugs for echinococcosis treatment is urgently needed. In this study, we demonstrated that lonidamine (LND) and 6-aminonicotinamide (6-AN) exhibited considerable in vitro effects against both larval- and adult-stage of E. granulosussensu stricto (s. s.) and E. multilocularis. The combination of LND and 6-AN exhibited a significantly higher activity than the single drug treatment. These results highlight the therapeutic potential of LND, 6-AN and the combination of LND and 6-AN for the treatment of echinococcosis.

Design, synthesis and antitumor activity of icotinib derivatives.

EGFR-TK pathway is of high importance for the treatment of non-small-cell lung cancers (NSCLC), and it will be challenging to develop anti-tumor drugs that could inhibit both EGFR wild-type and mutant tumor cells. Here, a series of icotinib derivatives containing 1,2,3-triazole moiety were designed and synthesized through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. Preliminary CCK-8 assay showed that the prepared icotinib-1,2,3-triazole compounds such as a7 or a12 demonstrated potent in vitro antitumor activity against the NSCLC cells expressing both wild type EGFR and mutational EGFR. Further, the mechanism of action for compounds a7 and a12 induced NSCLC cells death was also detailed, and the results suggested a possible induced NSCLC cells death via inducing mitochondrial apoptosis and arresting cell cycle. Remarkably, the inhibition of EGFR by these icotinib derivatives was also studied. The results showed that compound a12 was a potent inhibitor for EGFR with IC50 value of 1.49 µM. Combining these results, an EGFR inhibitor a12 represents a promising new anti-NSCLC candidate that could induce apoptosis and arrest cell cycle.

In vitro and in vivo effects of 3-bromopyruvate against Echinococcus metacestodes.

While searching for novel anti-echinococcosis drugs, we have been focusing on glycolysis which is relied on by Echinococcus for energy production and intermediates for other metabolic processes. The aim of this study was to investigate the potential therapeutic implication of glycolytic inhibitors on Echinococcus. Our results demonstrate that at an initial concentration of 40 µM, all inhibitors of glycolysis used in the current experiment [3-bromopyruvate (3-BrPA), ornidazole, clorsulon (CLS), sodium oxamate and 2,6-dihydroxynaphthalene (NA-P2)] show considerable in vitro effects against Echinococcus granulosus protoscoleces and Echinococcus multilocularis metacestodes. Among them, 3-BrPA exhibited the highest activity which was similar to that of nitazoxanide (NTZ) and more efficacious than albendazole (ABZ). The activity of 3-BrPA was dose dependent and resulted in severe ultrastructural destructions, as visualized by electron microscopy. An additional in vivo study in mice infected with E. multilocularis metacestodes indicates a reduction in parasite weight after the twice-weekly treatment of 25 mg/kg 3-BrPA for 6 weeks, compared to that of the untreated control. In particular, in contrast to ABZ, the administration of 25 mg/kg 3-BrPA did not cause toxicity to the liver and kidney in mice. Similarly, at the effective dose against Echinococcus larvae, 3-BrPA showed no significant toxicity to human hepatocytes. Taken together, the results suggest that interfering with the glycolysis of the parasite may be a novel chemotherapeutical option and 3-BrPA, which exhibited a remarkable activity against Echinococcus, may be a promising potential drug against cystic echinococcosis (CE) and alveolar echinococcosis (AE).

Effect of anacardic acid against echinococcosis through inhibition of VEGF-induced angiogenesis.

Echinococcosis is a zoonotic infection caused by cestode species of the genus Echinococcus, with limited treatment options. It is urgent to develop new anti-hydatid agent. In this paper, we reported anacardic acid (AA), a natural product isolated from the Brazilian cashew-nut shell liquid, which presented a high activity against metacestodes of Echinococcus multilocularis (E. multilocularis) and Echinococcus granulosus sensu stricto (E. granulosus s.s.) in vitro and in vivo. AA exerted a better efficacy on E. granulosus s.s. protoscoleces and E. multilocularis metacestodes than that of albendazole (ABZ) and dihydroartemisinin (DHA) in vitro, and an inhibition on the growth of Echinococcus metacestode as effective as ABZ in vivo. Moreover, we also found that one of the mechanisms of AA against Echinococcus could be the suppression of angiogenesis on/in the metacestode mass through inhibiting vascular endothelial growth factor (VEGF)-induced signalling pathways. This work finds that AA is a new promising potential candidate drug for echinococcosis treatment.

Therapeutic and immunoregulatory effects of water-soluble alkaloids E2-a from Sophora moorcroftiana seeds as a novel potential agent against echinococcosis in experimentally protoscolex-infected mice.

Novel compounds and more efficient treatment options are urgently needed for the treatment of cystic echinococcosis (CE), which is caused by Echinococcus granulosus. The decoction of Sophora moorcroftiana (Fabaceae) has been used to treat parasitosis for years in traditional Tibetan medicine. The aim of this study was to screen insecticidal water-soluble alkaloids from S. moorcroftiana seeds and evaluate the therapeutic effects against CE and the immune response induced by the alkaloidal fraction. Low polarity compounds (E2-a) were isolated from water-soluble alkaloid (E2) and matrine and sophocarpine were identified as major components. The E2-a fraction was more effective against protoscoleces than other constituents from S. moorcroftiana. After 20 weeks of secondary infection with protoscoleces, mice were orally treated with E2-a (100 mg/kg/day) for 6 weeks to evaluate therapeutic and immunoregulatory activities. Compared with the untreated group, E2-a treatment induced a significant reduction in cyst weight (mean 2.93 g) (p < 0.05) and an impaired ultrastructural modification of the cyst. Interestingly, the application of E2-a resulted in a significant increased frequency of CD3+CD4+ T-cell subsets and decreased frequency of CD3+PD-1+ T-cell subsets, compared with protoscolece-infected mice without treatment. The E2-a fraction of S. moorcroftiana can inhibit the cyst development of CE and boost the specific immune response by reducing the expression of PD-1 and accelerate the cytokine secretion of antigen-specific T-cells. All data suggest the E2-a fraction from S. moorcroftiana seeds may be used as a new potential therapeutic option against E. granulosus infection.

Quercetin Inhibits the Migration and Invasion of HCCLM3 Cells by Suppressing the Expression of p-Akt1, Matrix Metalloproteinase (MMP) MMP-2, and MMP-9.

BACKGROUND Quercetin is a natural bioactive flavonoid that is present in a wide variety of vegetables and fruits and exhibits a promising anti-metastasis property in various human cancer cells. However, the effect of quercetin on human HCCLM3 cells is unclear. MATERIAL AND METHODS In the current study, a wound-healing assay was performed using quercetin-treated HCCLM3 cells to further explore whether quercetin affects the motility of human HCCLM3 cells. Transwell assay was used to explore the potential effect of quercetin in HCCLM3 cells on cell migration and cell invasion. Western blotting analysis was used to explore the expression of p-Akt1, MMP-2, and MMP-9 in quercetin-treated HCCLM3 cells. RESULTS The wound-healing time was delayed in quercetin-treated HCCLM3 cells, and the ability to migrate and invade was inhibited in quercetin-treated human HCCLM3 cells. Moreover, the protein levels of p-Akt1, MMP-2, and MMP-9 were down-regulated in quercetin-treated HCCLM3 cells, as detected by Western blotting. CONCLUSIONS Our data show that quercetin attenuated cell migration and invasion by suppressing the protein levels of p-Akt1, MMP-2, and MMP-9 in HCCLM3 cells.

[Effect of Echinococcus multilocularis Infection on the Activities of Drug-metabolizing Enzymes in Gerbil Liver].

Objective: To study the effect of Echinococcus multilocularis infection on the activities of drug-metabolizing enzymes in gerbil liver. Methods: Ten gerbils （Meriones unguiculatus） were randomly divided into 2 groups, the experimental group in which each animal was intraperitoneally injected with 300 µl E. multilocularis cyst homogenates （containing about 600 protoscoleces）, and the control group in which each animal received 300 µl saline（i.p.）. Five months after infection, the animals were sacrificed by cervical dislocation, and livers were collected. The liver microsomal and cytosolic fractions were obtained by differential centrifugation. Protein concentration was measured by the BCA method. CYP450 and Cyt b5 contents in the microsomal fraction were measured with differential spectroscopy. Activities of 7-ethoxyresorufin（EROD） and 7-methoxyresorufin（MROD） were measured by fluorescence spectrometry. The activities of NADPH-cytochrome C reductase（NCR）, glutathione-S-transferase （GST）, and flavine monooxygenases （FMO） were measured by UV-visible spectrophotometry. Results: The protein content of cytosolic fractions and liver microsomes in experimental group was （11.089±1.277） and （3.212±0.924） mg/ml， those in control group was （12.459±1.625） and （3.894±0.395） mg/ml， respectively. The contents of CYP450 and Cyt b5 in the experimental group [（0.508±0.142）, （0.515±0.077） nmol/mg protein, respectively] were both significantly lower than those in the control [（0.647±0.090）, （0.596±0.051） nmol/mg protein]（P<0.05）. The GST activity decreased significantly in the experimental group ［（1.766±0.339）×103 nmol/（mg·min）］ compared with the control ［（2.001±0.160）×103 nmol/（mg·min）］（P<0.05）. But the FMO and NCR activities increased significantly in the experimental group ［（1.142±0.327） nmol/（mg·min） and （0.602±0.162）×103 nmol/（mg·min）, respectivelyï¼½ compared with the control ［（0.882±0.150） nmol/（mg·min） and （0.442±0.082）×103 nmol/（mg·min）］（P<0.05）. However, there were no significant differences in EROD and MROD activities between the two groups (P>0.05). Conclusion: The activities of FMO and NCR markedly increase, while that of GST significantly decreases in the gerbil liver after E. multilocularis infection.

Flexible fiber nanogenerator with 209 V output voltage directly powers a light-emitting diode.

On the basis of a vertically aligned ultralong Pb(Zr(0.52)Ti(0.48))O(3) (PZT) nanowire array fabricated using electrospinning nanofibers, we developed a new type of integrated nanogenerator (NG) with ultrahigh output voltage of 209 V and current density of 23.5 µA/cm(2), which are 3.6 times and 2.9 times of the previous record values, respectively. The output electricity can be directly used to stimulate the frog's sciatic nerve and to induce a contraction of a frog's gastrocnemius. The NG can instantaneously power a commercial light-emitting diode (LED) without the energy storage process.

Hyaluronic acid dissolving microneedle patch loaded with tranexamic acid for melasma treatment.

Melasma is an acquired hypermelanotic condition characterized by the presence of irregular light-to-dark brown macules that primarily manifest on the sun-exposed areas of the skin, particularly the face. The management of melasma poses significant challenges, as it is often recalcitrant to treatment and tends to recur despite successful treatment. In this study, we explored a safe, easy, and effective melasma treatment strategy. A hyaluronic acid (HA)-based microneedle (MN) patch loaded with tranexamic acid (TXA) was designed to deliver the necessary medication for melasma treatment. The MN patch features uniform needles with adequate mechanical strength and effective penetration and solubility in the skin without cytotoxicity. Remarkably, these MNs substantially reduce the thickness of the epidermis of melasma mice, curtail melanin production, and diminish dopachrome tautomerase (DCT) expression.

Novel Carrier-Free Nanodrug Enhances Photodynamic Effects by Blocking the Autophagy Pathway and Synergistically Triggers Immunogenic Cell Death for the Efficient Treatment of Breast Cancer.

Photosensitizers have been widely used to cause intratumoral generation of reactive oxygen species (ROS) for cancer therapy, but they are easily disturbed by the autophagy pathway, a self-protective mechanism by mitigating oxidative damage. Hereby, we reported a simple and effective strategy to construct a carrier-free nanodrug, Ce6@CQ namely, based on the self-assembly of the photosensitizer chlorin e6 (Ce6) and the autophagy inhibitor chloroquine (CQ). Specifically, Ce6@CQ avoided the unexpected toxicity caused by the regular nanocarrier and also ameliorated its stability in different conditions. Light-activated Ce6 generated cytotoxic ROS and elicited part of the immunogenic cell death (ICD). Moreover, CQ induced autophagy dysfunction, which hindered self-healing in tumor cells and enhanced photodynamic therapy (PDT) to exert a more potent killing effect and more efficient ICD. Also, Ce6@CQ could effectively accumulate in the xenograft breast tumor site in a mouse model through the enhanced permeability and retention (EPR) effect, and the growth of breast tumors was effectively inhibited by Ce6@CQ with light. Such a carrier-free nanodrug provided a new strategy to improve the efficacy of PDT via the suppression of autophagy to digest ROS-induced toxic substances.

Association of iron status with all-cause and cause-specific mortality in individuals with diabetes.

AIMS: Current evidence regarding iron status and mortality risk among patients with diabetes is limited. This study aimed to evaluate association of iron indices with all-cause and cause-specific mortality risk among patients with diabetes. METHODS: The current study included 2080 (with ferritin data), 1974 (with transferrin saturation (Tsat) data), and 1106 (with soluble transferrin receptor (sTfR) data) adults with diabetes from NHANES 1999-2018. Death outcomes were obtained from National Death Index through December 31, 2019. Cox proportional hazards models were employed to calculate hazard ratios and 95% confidence intervals for mortality. RESULTS: Association with all-cause mortality was demonstrated to be J-shaped for serum ferritin (Pnonlinearity < 0.01), U-shaped for Tsat (Pnonlinearity < 0.01) and linear for sTfR (Plinearity < 0.01). Ferritin 300-500 ng/mL possessed lower all-cause mortality risk than ferritin ≤ 100 ng/mL, 100-300 ng/mL, and > 500 ng/mL. Tsat 25-32 % showed a protective effect on all-cause mortality risk compared with Tsat ≤ 20 %, 20-25 %, and > 32 %. Individuals with sTfR < 4 mg/L were associated with a lower risk of all-cause mortality than those with higher sTfR. CONCLUSIONS: Moderate levels of serum ferritin (300-500 ng/mL), Tsat (25 %-32 %) and a lower concentration of sTfR (< 4 mg/L) identified adults with diabetes with lower all-cause mortality risk, adding novel modifiers to diabetes management.

Genetic Basis and Expression Pattern Indicate the Biocontrol Potential and Soil Adaption of Lysobacter capsici CK09.

Lysobacter species have attracted increasing attention in recent years due to their capacities to produce diverse secondary metabolites against phytopathogens. In this research, we analyzed the genomic and transcriptomic patterns of Lysobacter capsici CK09. Our data showed that L. capsici CK09 harbored various contact-independent biocontrol traits, such as fungal cell wall lytic enzymes and HSAF/WAP-8294A2 biosynthesis, as well as several contact-dependent machineries, including type 2/4/6 secretion systems. Additionally, a variety of hydrolytic enzymes, particularly extracellular enzymes, were found in the L. capsici CK09 genome and predicted to improve its adaption in soil. Furthermore, several systems, including type 4 pili, type 3 secretion system and polysaccharide biosynthesis, can provide a selective advantage to L. capsici CK09, enabling the species to live on the surface in soil. The expression of these genes was then confirmed via transcriptomic analysis, indicating the activities of these genes. Collectively, our research provides a comprehensive understanding of the biocontrol potential and soil adaption of L. capsici CK09 and implies the potential of this strain for application in the future.

An ultrasmall PVP-Fe-Cu-Ni-S nano-agent for synergistic cancer therapy through triggering ferroptosis and autophagy.

Photothermal therapy (PTT) is an emerging field where photothermal agents could convert visible or near-infrared (NIR) radiation into heat to kill tumor cells. However, the low photothermal conversion efficiency of photothermal agents and their limited antitumor activities hinder the development of these agents into monotherapies for cancer. Herein, we have fabricated an ultrasmall polyvinylpyrrolidone (PVP)-Fe-Cu-Ni-S (PVP-NP) nano-agent via a simple hot injection method with excellent photothermal conversion efficiency (∼96%). Photothermal therapy with this nano-agent effectively inhibits tumor growth without apparent toxic side-effects. Mechanistically, our results demonstrated that, after NIR irradiation, PVP-NPs can induce ROS/singlet oxygen generation, decrease the mitochondrial membrane potential, release extracellular Fe2+, and consume glutathione, triggering autophagy and ferroptosis of cancer cells. Moreover, PVP-NPs exhibit excellent contrast enhancement according to magnetic resonance imaging (MRI) analysis. In summary, PVP-NPs have a high photothermal conversion efficiency and can be applied for MRI-guided synergistic photothermal/photodynamic/chemodynamic cancer therapy, resolving the bottleneck of existing phototherapeutic agents.

Gut microbiota regulates postprandial GLP-1 response via ileal bile acid-TGR5 signaling.

The gut microbiota interacts with intestinal epithelial cells through microbial metabolites to regulate the release of gut hormones. We investigated whether the gut microbiota affects the postprandial glucagon-like peptide-1 (GLP-1) response using antibiotic-treated mice and germ-free mice. Gut microbiome depletion completely abolished postprandial GLP-1 response in the circulation and ileum in a lipid tolerance test. Microbiome depletion did not influence the GLP-1 secretory function of primary ileal cells in response to stimulators in vitro, but dramatically changed the postprandial dynamics of endogenous bile acids, particularly ω-muricholic acid (ωMCA) and hyocholic acid (HCA). The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) but not farnesoid X receptor (FXR), participated in the regulation of postprandial GLP-1 response in the circulation and ileum, and ωMCA or HCA stimulated GLP-1 secretion via TGR5. Finally, fecal microbiota transplantation or ωMCA and HCA supplementation restored postprandial GLP-1 response. In conclusion, gut microbiota is indispensable for maintaining the postprandial GLP-1 response specifically in the ileum, and bile acid (ωMCA and HCA)-TGR5 signaling is involved in this process. This study helps to understand the essential interplay between the gut microbiota and host in regulating postprandial GLP-1 response and opens the foundation for new therapeutic targets.