Reversal Of Resistance Research Articles

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2–5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14− myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

Extreme resistance to the novel siderophore-cephalosporin cefiderocol in an extensively drug-resistant Klebsiella pneumoniae strain causing fatal pneumonia with sepsis: genomic analysis and synergistic combinations for resistance reversal.

Cefiderocol (CFDC) is the first-in-class siderophore-cephalosporin. Klebsiella pneumoniae strain that is extremely resistant to CFDC (MIC: 256 µg/ml) was isolated for the first time in the United Arab Emirates from a patient with pneumonia and sepsis. It belonged to sequence-type 14 (ST14), with a novel core genome ST. Resistance was driven by the co-expression of β-lactamases (blaNDM-1, blaOXA-232 and blaCTX-M-15) and a mutation in catecholate-siderophore receptor, utilized by CFDC to enter the bacterial cell. Synergistic combinations (β-lactamase inhibitors, aztreonam plus CFDC) re-sensitized the bacteria to CFDC. Although CFDC resistance is multifactorial, the combination with β-lactamase inhibitors represents a promising approach in resistance reversal for fighting superbugs.

Characterization of mesosulfuron-methyl + iodosulfuron-methyl and pyroxsulam–resistant annual bluegrass (Poa annua) in an annual cropping system

AbstractHerbicide-resistant annual bluegrass (Poa annua L.) has become a problem in non-arable land areas. In arable fields, P. annua is frequently of lower priority in weed control program due to the variety of control options available and the relatively modest impact on crop yield compared with other species. In Ireland, postemergence herbicides are not primarily intended for P. annua control, but some herbicides, including the acetolactate synthase (ALS) inhibitor mesosulfuron-methyl + iodosulfuron-methyl, exhibit P. annua activity. In this study, a suspected P. annua population (POAAN-R) that survived mesosulfuron-methyl + iodosulfuron-methyl at 0.75 of the field recommended rate was sampled from a wheat (Triticum aestivum L.) field in County Dublin, Ireland. Single-dose testing confirmed that the suspected POAAN-R had evolved resistance to mesosulfuron-methyl + iodosulfuron-methyl and, additionally, to pyroxsulam (not registered in Ireland for P. annua control), but was sensitive to clethodim, glyphosate, pendimethalin, and flufenacet. Dose–response experiments indicated that POAAN-R was more resistant (GR50 resistance index) to both mesosulfuron-methyl + iodosulfuron-methyl (47.8 times) and pyroxsulam (38.0 times) than sensitive POAAN-S, and this was associated with the mutation at Trp-574 in the ALS protein. Malathion (a cytochrome P450 [P450] inhibitor) pretreatment did not reverse POAAN-R resistance to mesosulfuron-methyl + iodosulfuron-methyl or pyroxsulam at the field rate or above. The natural inherent mutation at Ile-1781 in acetyl-CoA carboxylase protein had no effect on both POAAN-R and POAAN-S sensitivity to clethodim. The glyphosate sensitivity of POAAN-R also corresponded with no known mutation in 5-enolpyruvylshikimate-3-phosphate synthase protein. Based on field histories, poor early-season weed control coupled with intensive use of mesosulfuron-methyl + iodosulfuron-methyl (often at reduced rates) has unintentionally selected for ALS inhibitor–resistant POAAN-R. This is the first report to characterize resistance in P. annua to ALS-inhibiting herbicides mesosulfuron-methyl + iodosulfuron-methyl and pyroxsulam in an arable setting. There is an opportunity to effectively control POAAN-R using herbicides, but this needs a wide-ranging and varied approach, coupled with cultural/nonchemical practices.

Umbilical Cord Blood-Derived M1 Macrophage Exosomes Loaded with Cisplatin Target Ovarian Cancer In Vivo and Reverse Cisplatin Resistance.

We investigated the therapeutic efficacy of umbilical cord blood (UCB)-derived M1 macrophage exosomes loaded with cisplatin (CIS) in ovarian cancer and platinum resistance. M1 macrophages were purified by using CD14 magnetic beads and characterized by flow cytometry. Our analyses included morphology, particle size, particle concentration, potential, drug loading capacity, counts of entry into cells, antitumor effect in vivo, and the ability to reverse drug resistance. A2780, SKOV3, and A2780/DDP, SKOV3/DDP ovarian cancer cells (CIS-sensitive and CIS-resistant cell lines, respectively) were treated with CIS or CIS-loaded M1 macrophage exosomes (M1exoCISs). The encapsulation efficiency of CIS loading into M1 macrophage exosomes was approximately 30%. In vitro, M1exoCIS treatment reduced the CIS IC50 values of both A2780, SKOV3, and A2780/DDP, SKOV3/DDP cells. We evaluated the effect of M1exoCIS on tumor growth using a mouse ovarian cancer subcutaneous transplantation tumor model inoculated with A2780/DDP cells. M1exoCIS was observed in the liver, spleen, and tumor sites 24 h posttreatment; the fluorescence intensity of M1exoCIS is higher than that of CIS. After 7 days, M1exoCIS significantly inhibited the growth of subcutaneously transplanted tumors compared with CIS alone and had a longer survival time. Moreover, the toxicity test shows that M1exoCIS has less hepatorenal toxicity than CIS. To investigate the mechanism of M1exoCIS targeting, homing, and reversing drug resistance, we performed RT-PCR, Western blotting, and Proteome Profiler Human Receptor Array analyses. We found that A2780 and A2780/DDP cells expressed the integrin β1/CD29 receptor, while M1 exosomes expressed integrin β1/CD29. In addition, M1exos carries long noncoding RNA H19, implicated in PTEN protein upregulation and miR-130a and Pgp gene downregulation, leading to the reversal of CIS drug resistance. Therefore, UCB-derived M1exoCIS target tumor sites of ovarian cancer in vivo and can be used to increase the CIS sensitivity and cytotoxicity.

Multi-springs model for suction caisson under monotonic lateral loading

Suction caisson has been widely used as the foundation for the offshore wind turbines. The behaviors of suction caisson under lateral loading caused by the combined effects of wind, wave and current, are quite significant for engineering design. In this paper, a novel multi-springs model is proposed to estimate the foundation displacement behavior and soil resistance distribution under lateral loading. In the proposed model, the p-y and t-z springs are divided into multiple groups and their combined effect is considered to reflect the uneven distribution of interface normal stress outside the caisson. In this way, the enhancement and direction reversal of vertical friction resistance can be reflected, which is also validated by the centrifuge tests of suction caisson. Afterwards, the multi-springs model is adopted to study the static performance of suction caisson under monotonic lateral loading. It is found that the soil displacement field is gradually dominated by the caisson rotation, whose rotation centre moves upwards and stabilizes at about 0.7-0.8L. Compared to p-y and Q-z springs, t-z spring plays the key role in resisting the foundation overturning at the slightly rotation angle of caisson.

Enhanced reversal of ABCG2-mediated drug resistance by replacing a phenyl ring in baicalein with a meta-carborane.

Success of chemotherapy is often hampered by multidrug resistance. One mechanism for drug resistance is the elimination of anticancer drugs through drug transporters, such as breast cancer resistance protein (BCRP; also known as ABCG2), and causes a poor 5-year survival rate of human patients. Co-treatment of chemotherapeutics and natural compounds, such as baicalein, is used to prevent chemotherapeutic resistance but is limited by rapid metabolism. Boron-based clusters as meta-carborane are very promising phenyl mimetics to increase target affinity; we therefore investigated the replacement of a phenyl ring in baicalein by a meta-carborane to improve its affinity towards the human ABCG2 efflux transporter. Baicalein strongly inhibited the ABCG2-mediated efflux and caused a fivefold increase in mitoxantrone cytotoxicity. Whereas the baicalein derivative 5,6,7-trimethoxyflavone inhibited ABCG2 efflux activity in a concentration of 5 μm without reversing mitoxantrone resistance, its carborane analogue 5,6,7-trimethoxyborcalein significantly enhanced the inhibitory effects in nanomolar ranges (0.1 μm) and caused a stronger increase in mitoxantrone toxicity reaching similar values as Ko143, a potent ABCG2 inhibitor. Overall, in silico docking and in vitro studies demonstrated that the modification of baicalein with meta-carborane and three methoxy substituents leads to an enhanced reversal of ABCG2-mediated drug resistance. Thus, this seems to be a promising basis for the development of efficient ABCG2 inhibitors.

THU380 A Case Of Alpelisib Induced Diabetic Ketoacidosis (Dka) In A Patient With Type 2 Diabetes Mellitus And Rechallenge With SGLT2 Inhibitor

Abstract Disclosure: V. Sekar: None. S. Shaik: None. Introduction: Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor recently used in treatment of advanced breast cancer. Hyperglycemia is an expected adverse effect with the use of PI3K inhibitors. We report a case of Alpelisib induced worsening hyperglycemia in a patient with type 2 diabetes mellitus who developed DKA while on Empagliflozin and was rechallenged with Dapagliflozin to achieve better glycemic control. Case Description: 60-year-old female with known history of type 2 diabetes mellitus was referred to Endocrinology prior to the start of PI3K inhibitor, Alpelisib for metastatic breast cancer. On initial visit her Hemoglobin A1C was 7.4 % and she was on Empagliflozin 25 mg daily, Sitagliptin 100 mg daily, Metformin XR 500 mg daily and Insulin Glargine 30 units daily. Three weeks after initiation of Alpelisib, patient reported uncontrolled fasting and post-prandial hyperglycemia, therefore her basal insulin was up-titrated and added on prandial insulin. Sitagliptin was discontinued. Two weeks later patient was admitted with Euglycemic diabetic ketoacidosis (DKA) which was treated with IV insulin and IV fluids. Empagliflozin was stopped and discharged on basal bolus regimen. In the next 6 weeks basal bolus regimen was significantly up-titrated and added on correctional insulin along with increasing Metformin XR to 500 mg twice a day due to poor glycemic control. During this time patient was cautiously restarted on Dapagliflozin 5 mg daily after discussing the better outcomes for Alpelisib induced hyperglycemia versus risk of DKA with reuse of SGLT2 inhibitors. Since being on Dapagliflozin her blood sugars were better controlled and the insulin requirements plateaued. Patient was closely monitored, and she didn’t develop further episode of DKA. Discussion: The PI3K pathway controls the effect of insulin intracellularly and its activation promotes tumor development, spread and failure to anticancer treatment. PI3K inhibitor blocks the intracellular action of insulin which causes reversible insulin resistance and hyperglycemia which is the major side effect of this drug. Use of insulin to treat hyperglycemia was shown to partially reactivate the PI3K pathway in tumoral cells, leading to cellular proliferation. Therefore, insulin should be kept as the last line antihyperglycemic agent. Exploratory analysis of SOLAR-1* trial has shown better glycemic control with use of SGLT2 inhibitors in patient with Alpelisib induced hyperglycemia along with improved efficacy of Alpelisib against tumor growth. Both PI3K inhibitor and SGLT2 inhibitor has risk of causing DKA, but close monitoring and patient education helps to reduce the risk. Reference *Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women with Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment Presentation: Thursday, June 15, 2023

Fundamentals for the repurposing of hydralazine as an anti-neoplastic drug

Hydralazine (HDZ) is a drug patented in 1949 that has been used for the treatment of arterial hypertension since 1953. New and better anti-hypertensive drugs have almost moved HDZ into oblivion. Interestingly, anti-cancer effects were found and this drug is seriously being considered for repurposing it for cancer treatment. The main mechanism of action against tumors seems to be its ability to act as a demethylator agent. By demethylating the promoter region of tumor suppressor genes HDZ seems to restore the effects of these genes, which are frequently inhibited in cancer through epigenetic mechanisms. However, HDZ also has some other important involved mechanisms such as anti-angiogenesis, and reversal of resistance to imatinib. Particularly important is its ability to restore the activity of non-mutated p16 in cancer. HDZ ability to inhibit glutamate oxaloacetate transaminase 1 is a recent finding that will probably add further interest to the drug in cancer treatment. This review analyzes the anti-tumoral effects of HDZ.

Synthesis and Evaluation of Some New Pyridines as Possible P-gp Inhibitors with Reduced Calcium Channel Blocking Activity

The 1,4-dihydropyridine derivatives (DHPs) (3a-b and 4a-c) were oxidized with iodine in methanol to produce five new, hitherto unreported pyridine derivatives (5a-b and 6a-c). The “Everted sac method” was used to assess the DHPs and their pyridines for potential p-glycoprotein (P-gp) inhibitory or multidrug resistance reversal action. Domperidone, a P-gp substrate, was examined for intestinal absorption in everted rat jejunal segments in the presence and absence of DHPs (3a-b and 4a-c) and pyridines (5a-b and 6a-c) at doses of 30 μg/mL and 100 μg/mL. The standard was Verapamil, a known P-gp inhibitor (30 μg/mL and 100 μg/mL). The P-gp inhibition of all the tested compounds was higher than Verapamil. The P-gp inhibition of compounds 5b and 6b was the highest. Utilizing isolated rat ileum, the newly synthesized pyridine derivatives calcium channel blocking efficacy was also investigated. The strongest Ca2+ channel-blocking action was seen with compound 5b. It was determined to be equivalent to Nifedipine, the gold standard. Strong P-gp inhibitor compound 6b has little calcium channel-blocking action.

Enhancing ultrafiltration performance for dairy wastewater treatment using a 3D printed turbulence promoter

Dairy factories annually generate an increasing amount of wastewater, which can cause eutrophication due to high concentrations of amino acids and lipids. To address this issue, membrane technology has emerged as a promising solution, but membrane fouling remains a significant challenge, since it can cause decreased flux, decrease membrane rejection performance, and increased energy demand. This study aimed to reduce membrane fouling by integrated a three-dimensional printed (3DP) turbulence promoter into an ultrafiltration dead-end cell and varying stirring speeds. Two mathematical models, Hermia and resistance-in-series, were used to analyze the fouling process. According to both models, the cake layer formation model indicated the most prevalent fouling mechanism. Specific energy demand, permeate flux, membrane rejection, and membrane reversible and irreversible resistances were measured, calculated, and compared. The results suggest that the combination of an integrated 3DP turbulence promoter and high stirring speeds can effectively reduce membrane fouling in a dairy wastewater treatment module.

Cycloartane-type triterpenoids and steroids from Trichilia connaroides and their multidrug resistance reversal activities

Four undescribed cycloartane-type triterpenoids (1−4) and seven undescribed steroids (6−12), along with five known analogues (5 and 13−16), were isolated from the leaves of Trichilia connaroides. Their structures were identified based on the NMR data and HRESIMS, and the absolute configurations were determined through single-crystal X-ray diffraction analysis, Mosher's method, and ECD calculations. The multidrug resistance (MDR) reversal activities of all the isolates were assessed, and compounds 10 and 11 showed significant activities to reverse the MDR of MCF-7/DOX cells with IC50 values of 2.90 and 3.76 μM, respectively. These bioactive compounds may bring fresh insights into the research and development of MDR reversal agents.

Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis.

It is essential to revisit the global biodiversity, search for ethnopharmacologically relevant plants, and unveil their untapped potential to overcome the complications associated while treating infections triggered by multiple antibiotic-resistant Staphylococcus aureus. Catharanthus roseus (L.) G. Don of the Apocynaceae family is a medicinal plant used for remedial purposes against infectious diseases from ancient times. In this study, we intended to evaluate the mechanism by which the ethanolic extract of C. roseus root (EECRR) causes the reversal of ampicillin resistance in S. aureus. To achieve this goal, we have stained EECRR-treated S. aureus with acridine orange, analysed DNA damage by comet assay, and studied the alteration of plasmid band pattern and expression of penicillin-binding protein 2a (PBP2a) protein. Experiments revealed better S. aureus killing efficiency of EECRR at its minimum inhibitory concentration (MIC) doses due to DNA damage and reducing plasmid band intensities along with a decline in the expression of PBP2a in EECRR-treated cells at half-MIC dose. EECRR proved to be an efficient growth inhibitor of S. aureus that reduces the expression of PBP2a. Therefore, EECRR can also render ampicillin-resistant S. aureus susceptible to the antibiotic.

Photopolymerized keratin-PGLa hydrogels for antibiotic resistance reversal and enhancement of infectious wound healing

Infectious wounds have become serious challenges for both treatment and management in clinical practice, so development of new antibiotics has been considered an increasingly difficult task. Here, we report the design and synthesis of keratin 31 (K31)-peptide glycine-leucine-amide (PGLa) photopolymerized hydrogels to rescue the antibiotic activity of antibiotics for infectious wound healing promotion. K31-PGLa displayed an outstanding synergistic effect with commercial antibiotics against drug-resistant bacteria by down-regulating the synthesis genes of efflux pump. Furthermore, the photopolymerized K31-PGLa/PEGDA hydrogels effectively suppressed drug-resistant bacteria growth and enhanced skin wound closure in murine. This study provided a promising alternative strategy for infectious wound treatment.

Drug resistance mechanism and reversal strategy in lung cancer immunotherapy.

Among all malignant tumors, lung cancer has the highest mortality and morbidity rates. The non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the most common histological subtypes. Although there are a number of internationally recognized lung cancer therapy regimens, their therapeutic effects remain inadequate. The outlook for individuals with lung carcinoma has ameliorated partly thanks to the intensive study of the tumor microenvironment and immune checkpoint inhibitors. Numerous cancers have been effectively treated with immunotherapy, which has had positive therapeutic results. Global clinical trials have validated that PD-1/PD-L1 inhibitors are effective and safe for treating lung cancer either independently or in combination, and they are gradually being recommended as systemic treatment medications by numerous guidelines. However, the immunotherapy resistance restricts the immunotherapy efficacy due to the formation of tumor immunosuppressive microenvironment and tumor mutations, and immunotherapy is only effective for a small percentage of lung cancer patients. To summarize, while tumor immunotherapy is benefiting an increasing number of lung cancer patients, most of them still develop natural or acquired resistance during immunotherapy. Consequently, a crucial and urgent topic is understanding and tackling drug resistance triggered by immunotherapy in lung cancer treatment. This review will outline the presently recognized mechanisms of immunotherapy resistance and reversal strategies in lung cancer.

Novel insight into secondary effluent quality improvement and ultrafiltration fouling mitigation by UV/peracetic acid pretreatment

Ultrafiltration (UF) technology is widely used in the treatment for deep purification of municipal secondary effluent, however, the membrane fouling and low removal of N, P, and organic matter during actual operation have been the main bottlenecks limiting its wide-spread application. To address the above problems, this study employed peracetic acid (PAA) and UV/PAA to evaluate the effects of PAA-based pre-oxidation on ultrafiltration membrane fouling and secondary effluent water quality. The results demonstrated that the activated PAA pre-oxidation could prominently enhance the hydrophilicity of effluent organic matter, effectively destroy the high molecular weight organic matter and mineralize the low molecular weight organic matter. PAA and its metabolites, as well as the by-products of EfOM, increased the C/P ratio in water samples from 118 to 563 and the C/N ratio from 0.86 to 8.53. After UV/20 mg/L PAA pretreatment, the reversible and irreversible membrane fouling resistance significantly decreased by 55.97 % and 65.67 %, respectively. Moreover, the extended Derjaguin–Landau–Verwey–Overbeek (XDLVO) theory showed lower adhere potential of the foulants to the membrane surface. In general, UV/PAA as ultrafiltration pretreatment has a huge potential for secondary effluent treatment for membrane fouling mitigation and water quality improvement.

Ultra Rate‐Dependent Pressure Sensitive Adhesives Enabled by Soft Elasticity of Liquid Crystal Elastomers

AbstractThe fabrication of pressure sensitive adhesives (PSAs) using liquid crystal elastomers (LCEs), which are known for their excellent dissipation properties, is explored in this work. The adhesive properties of the PSAs are evaluated using the 180° peeling test at various conditions. The performance of the LCE adhesives is found to show significant rate and temperature dependence. When the adhesion energy is plotted against the rate, LCE shows an anomalously large power law exponent (n ≈ 1.17) compared to existing PSAs (n ≈ 0.1–0.6). The unusual rate sensitivity is hypothesized to originate from the synergy of soft elasticity and non‐linear viscoelasticity. The adhesive properties at various rates and temperatures are correlated to the results from dynamic mechanical analysis. Moreover, the large strain stiffening behavior of LCE under uniaxial tension reveals the distinctive advantages offered by LCE as adhesives. Time‐temperature superposition is used to obtain a master curve of adhesion energy that spans rates beyond typical experimental limits. The extreme rate dependence and the large strain stiffening of LCE yield a new category of adhesives that possess special properties, such as reversible adhesion and impact resistance, unlike traditional adhesives.

Photocatalytic membrane coated with α-Fe2O3/Fe3O4 for enhanced filtration performance and antifouling property in surface water treatment

A photocatalytic membrane coated with α-Fe2O3/Fe3O4 nanoparticles has been developed to address the challenges of membrane fouling and organic removal in the treatment of natural surface water. The photocatalytic and filtration properties of the membranes were investigated through a variety of methods. The successful preparation of iron oxide was confirmed by UV–vis diffuse reflectance spectra and X-ray diffractometry, with α-Fe2O3 identified as the primary photocatalytic agent. A commercial ultrafiltration (UF) membrane was employed as a comparison to evaluate the photocatalytic performance and filtration properties of the modified membrane. Results showed that the photocatalytic membrane achieved better removal rates for UV254 (22.0%) and specific fluorescent organic compounds, such as component 2 (19.38%) and component 3 (16.89%), compared to the control group. Furthermore, both irreversible and reversible fouling resistances of the prepared membranes were significantly lower than that of the control group, with reductions of 39.4% and 50.2%, respectively. The membrane coated with α-Fe2O3/Fe3O4 nanoparticles exhibited moderate removal of protein-like and terrestrially derived humic-like fluorescent organics while controlling membrane fouling. Although the α-Fe2O3/Fe3O4 nanoparticles-coated photocatalytic membrane demonstrated good anti-fouling properties, the removals of organic matters were not as effective as anticipated due to the shorter hydraulic retention time. This study provides valuable insights for enhancing pollutant degradation and anti-fouling properties of membranes through the utilization of solar photocatalytic α-Fe2O3/Fe3O4 surface-modified membranes in the treatment of natural surface water.

Can Nitric Oxide-Based Therapy Be Improved for the Treatment of Cancers? A Perspective.

Since the early observations that nitric oxide (•NO) at high concentrations is cytotoxic to cancer cells and that it may play an important role in the treatment of human cancers, a significant number of compounds (NO-donors) have been prepared to deliver •NO to tumors. •NO also sensitizes various clinically active anticancer drugs and has been shown to induce the reversal of multi-drug resistance in tumor cells expressing ATP-binding cassette-transporter proteins. For the successful treatment of cancers, •NO needs to be delivered precisely to tumors, and its adverse toxicity must be limited. Like other chemotherapeutics, the precise delivery of drugs has been a problem and various attempts have been made, such as the encapsulation of drugs in lipid polymers, to overcome this. This prospective study examines the use of various strategies for delivering •NO (using NO-donors) for the treatment of cancers. Finding and utilizing such a delivery system is an important step in delivering cytotoxic concentrations of •NO to tumors without adverse reactions, leading to a successful clinical outcome for patient management.

Effect of C-reactive protein deficiency on insulin resistance reversal in rats with polycystic ovary syndrome through augmented leptin action

BackgroundC-reactive protein(CRP), is an inflammatory marker that weaken leptin bioavailability and insulin sensitivity to disturb energy and glucose metabolism. Polycystic ovary syndrome (PCOS) exhibit a metabolic component consisting of higher plasma CRP levels, hyperinsulinemic and hyperleptinemia. The ability of leptin to regulation of hepatic glucose production (HGP) in the absence of CRP in PCOS remain unknown.MethodsDehydroepiandrosterone (DHEA) was used to induce PCOS in rats. We assessed the effects of CRP gene knockout in PCOS model rats on body weight, energy expenditure glucose metabolism and insulin sensitivity. We conducted experiments involving the administration of leptin to both the peripheral and central systems in PCOS model rats with CRP knockout, and studied the effects on changes in glucose kinetics during hyperinsulinemic-euglycemic clamps.ResultsIn female PCOS rats, the lack of CRP resulted in decreased leptin resistance and weight gain, increased energy expenditure, and improved insulin sensitivity. Additionally, the deletion of the CRP gene strengthened the HGP-lowering effects of leptin when administered peripherally or centrally. This effect was accompanied by a decrease in the expression of hepatic gluconeogenic enzymes and an increase in hepatic insulin signaling. Finally, inhibition of glucose production was also enhanced for central leptin administration during lipid infusion in PCOS rats.ConclusionsOur findings highlight the therapeutic potential of targeting CRP to restore glucose homeostasis and insulin sensitivity for leptin in PCOS.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer

BackgroundTreatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec),...