MicroRNA257 promotes secondary growth in hybrid poplar.

Populus, a significant fast-growing tree species with global afforestation and energy potential, holds considerable economic value. The abundant production of secondary xylem by trees, which serves as a vital resource for industrial purposes and human sustenance, necessitates the orchestration of various regulatory mechanisms, encompassing transcriptional regulators and microRNAs (miRNAs). Nevertheless, the investigation of microRNA-mediated regulation of poplar secondary growth remains limited. In this study, we successfully isolated a novel microRNA (Pag-miR257) from 84 K poplar and subsequently integrated it into the 35 S overexpression vector. The overexpression of Pag-miR257 resulted in notable increases in plant height, stem diameter, and fresh weight. Additionally, the overexpression of Pag-miR257 demonstrated a significant enhancement in net photosynthetic rate. The findings from the examination of cell wall autofluorescence indicated a substantial increase in both xylem area and the number of vessels in poplar plants overexpressing Pag-miR257. Furthermore, the cell wall of the Pag-miR257 overexpressing plants exhibited thickening as observed through transmission electron microscopy. Moreover, the Fourier Transforms Infrared (FTIR) analysis and phloroglucinol-HCl staining revealed an elevation in lignin content in Pag-miR257 overexpressing poplar plants. The findings of this study suggest that microRNA257 may play a role in the control of secondary growth in poplar stems, thereby potentially enhancing the development of wood engineering techniques for improved material and energy production.

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.

BACKGROUND: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

Impact of age group on bloodstream infection risk evaluation in immunosuppressed patients: a retrospective, single-centre, 5-year cohort study.

INTRODUCTION: Elderly patients in immunosuppressive status may have an increased occurrence of illness and risk of poor prognosis. It is a generally overlooked population that we should pay more attention to their risk factors of sickness and mortality. METHODS: Eight hundred and nine patients who were diagnosed with bloodstream infection in immunosuppressive states during accepting treatment in our hospital were selected from 2015 to 2019.The demographic data, underlying diseases, comorbidity, inducement, complications, pathogen sources, etiologies, and the antibiotics therapy were analyzed between ages > 65 years groups and ages < 65 years groups. RESULTS: The clinical characteristics of totally 809 immunosuppressed people diagnosed with bloodstream infection were analyzed, and among those people about 371 were ages > 65 years. By univariate logistic regression analysis and multivariate logistic regression analysis, we found that hypertension (OR: 2.864, 95% CI 2.024-4.051, P < 0.0001), cerebral Infarction (OR: 4.687, 95% CI 2.056-10.686, P < 0.0001), coronary heart disease (OR: 1.942, 95% CI 1.168-3.230, P = 0.011), acute pancreatitis (OR: 3.964, 95% CI 2.059-7.632, P < 0.0001), infective endocarditis (OR: 6.846, 95% CI 1.828-25.644, P = 0.004), aortic dissection (OR: 9.131, 95% CI 3.190-26.085, P < 0.0001), chemotherapy (OR: 3.462, 95% CI 1.815-6.603, P < 0.0001), transplant status (OR: 20.031, 95% CI 4.193-95.697, P < 0.0001), and respiratory tract infection (OR: 2.096, 95% CI 1.269-3.461, P = 0.004) were significantly different between ages > 65 years groups and ages < 65 years groups. CONCLUSION: Hypertension, cerebral Infarction, coronary heart disease, acute pancreatitis, infective endocarditis, aortic dissection, chemotherapy, transplant status, and pathogen source of respiratory tract were the independent risk factors of ages > 65 years in immunosuppressed patients, which would have the benefit to discriminate the prognostic factors in immunosuppressive elderly people with bloodstream infection.

Graphitic carbon nitride-based photocatalysts in the applications of environmental catalysis.

Semiconductor photocatalytic technology has shown great prospects in converting solar energy into chemical energy to mitigate energy crisis and solve environmental pollution problems. The key issue is the development of high-efficiency photocatalysts. Various strategies in the state-of-the-art advancements, such as heterostructure construction, heteroatom doping, metal/single atom loading, and defect engineering, have been presented for the graphitic carbon nitride (g-C3N4)-based nanocomposite catalysts to design their surface chemical environments and internal electronic structures to make them more suitable for different photocatalytic applications. In this review, nanoarchitecture design, synthesis methods, photochemical properties, potential photocatalytic applications, and related reaction mechanisms of the modified high-efficiency carbon nitride-based photocatalysts were briefly summarized. The superior photocatalytic performance was identified to be associated with the enhanced visible-light response, fast photoinduced electron-hole separation, efficient charge migration, and increased unsaturated active sites. Moreover, the further advance of the visible-light harvesting and solar-to-energy conversions are proposed.

Prognostic Risk Factors of Carbapenem-Resistant Gram-Negative Bacteria Bloodstream Infection in Immunosuppressed Patients: A 7-Year Retrospective Cohort Study.

Purpose: Carbapenem-resistant Gram-negative bacteria bloodstream infection (CRGNB-BSI) has gradually become a major threat worldwide due to its treatment difficulty and high mortality. This study aimed to determine the risk factors for CRGNB-BSI in immunosuppressed patients. Patients and Methods: A total of 427 immunosuppressed patients with CRGNB-BSI were retrospectively investigated from 2015 to 2021. Both univariate and multivariate logistic regression analyses were applied to evaluate independent risk factors for CRGNB-BSI. Results: The most common etiology was Klebsiella Pneumoniae (50.59%; 216/427), while the Acinetobacillus baumannii infection was associated with the highest mortality (58.25%) among all etiologies. The 60-day mortality of immunosuppressed patients with CRGNB-BSI was 52.48% (224/427). Procalcitonin (PCT) > 0.5 µg/L (OR = 2.32, 95% CI: 1.28-4.19, P = 0.005) and age > 55 years (OR = 2.06, 95% CI: 1.17-3.64, P = 0.012) were found to be predictors of 60-day mortality of CRGNB-BSI, and tigecycline regimen (OR = 3.20, 95% CI: 1.81-5.67, P < 0.001) was associated with higher mortality. Multivariate analysis also revealed that patients who developed acute kidney injury (AKI) (OR = 2.19, 95% CI: 1.11-4.30, P = 0.023), gastrointestinal bleeding (OR = 3.18, 95% CI: 1.10-9.16, P = 0.032), multiple organ dysfunction syndrome (MODS) (OR = 12.11, 95% CI: 2.61-56.19, P = 0.001), and septic shock (OR = 3.24, 95% CI: 1.77-5.94, P < 0.001) showed worse outcomes. The risk factors were also significantly associated with mortality in the different subgroups. Conclusion: This study demonstrated that PCT > 0.5 µg/L, age > 55 years, and the tigecycline regimen were significantly associated with higher 60-day mortality among immunosuppressed patients with CRGNB- BSI. Patients developing MODS, septic shock, or AKI had worse clinical outcomes. .

The Prognostic Factors of Bloodstream Infection in Immunosuppressed Elderly Patients: A Retrospective, Single-center, Five-year Cohort Study.

Introduction: Elderly patients with immunosuppressive status may have increased risk of mortality. At present, few studies have explored the clinical characteristics of the elderly immunosuppressed population with bloodstream infection. Our objectives were to evaluate the prognostic factors in immunosuppressed elderly patients with bloodstream infection. Methods: Three hundred and seventy-six elderly patients who were diagnosed with bloodstream infection in immunosuppressive status while receiving treatment in our hospital were selected from 2015 to 2019. The demographic data, underlying diseases, comorbidity, inducement, complications, pathogen sources, etiologies and the antibiotic therapy were analyzed between 90-day survival groups and 90-day mortality groups. The prognostic factors of 90-day mortality were evaluated by univariate logistic regression analysis and multivariate logistic regression analysis. Results: The clinical characteristics of 376 immunosuppressed elderly people diagnosed with bloodstream infection were analyzed, and among those people about 111 were 90-day mortality. By univariate logistic regression analysis and multivariate logistic regression analysis, we found ICU admission (OR: 2.052, 95%CI: 1.088-3.871, p=0.026), the decrease in BMI (OR: 0.307, 95%CI: 0.130-0.723, p=0.007), coronary heart disease (OR: 2.028, 95%CI: 1.078-3.816, p=0.028), biliary infection (OR: 4.406, 95%CI: 1.794-10.821, p=0.001) and the use of tigecycline (OR: 2.480, 95%CI: 1.195-5.147, p=0.015) were significantly different between the 90-day survival and 90-day mortality groups. Conclusion: ICU admission, coronary heart disease, biliary infection, and the use of tigecycline were the independent prognostic risk factors of 90-day mortality in immunosuppressed elderly people, and the decrease in BMI was the protective factor, which would have the benefit of discriminating the prognostic factors in immunosuppressed elderly people with bloodstream infection.

BMS-986012, an Anti-Fucosyl-GM1 Monoclonal Antibody as Monotherapy or in Combination With Nivolumab in Relapsed/Refractory SCLC: Results From a First-in-Human Phase 1/2 Study.

Introduction: Fucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1. Methods: CA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival. Results: Patients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 [90%]). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval [CI]) was higher with BMS-986012 plus nivolumab (38% [20.7%-57.7%]) than with monotherapy (4% [0.8%-11.0%]). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4-not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%-20.7%) and 39.3% (21.7%-56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0-7.3) and 18.7 (8.2-37.3) months, respectively. Conclusions: BMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880).

Potential value of tumor stiffness and sE-cadherin in predicting the response to neoadjuvant therapy in HER2-positive breast cancers.

Background: This prospective study compared the diagnostic value of tumor stiffness and serum soluble E-cadherin (sE-cadherin) expression for predicting response to neoadjuvant therapy in HER2-positive breast cancers. Methods: 112 patients with early or locally advanced HER2-positive breast cancer were enrolled. Maximum stiffness (Emax), mean stiffness (Emean) and their relative changes were assessed at t0 and t2. sE-cadherin levels were analyzed using ELISA. Pathological complete response was defined as no invasive disease in the breast and axilla (ypT0/is, ypN0) after surgery. The ability of tumor stiffness, sE-cadherin and the combination of ΔEmean (the relative change in Emean after the second cycle of neoadjuvant therapy) and sE-cadherin in predicting tumor responses was assessed using receiver operating characteristic curves and the Z-test. Results: Tumor stiffness and sE-cadherin decreased during neoadjuvant therapy. ΔEmean and sE-cadherin revealed the best predictive performance, with areas under the curve (AUCs) of 0.843 and 0.857, respectively. No significant differences in AUCs were reported between ΔEmean and sE-cadherin (p = 0.795). The combined use of ΔEmean and sE-cadherin showed the highest sensitivity and specificity (93.22 and 90.57%, respectively), with an AUC of 0.937. Conclusion: The combination of ΔEmean and sE-cadherin may improve the predictive power of each single factor. Although further verification is required, this study may promote noninvasive prediction of neoadjuvant therapy responses and help personalize the treatment regimen.

HER2 positivity in breast cancer is associated with a poor prognosis and shortened overall survival. For patients with HER2-positive early breast cancer, the standard neoadjuvant treatment consists of trastuzumab and pertuzumab plus docetaxel, and produces high response rates. In spite of the success of neoadjuvant therapy, some patients show no response due to drug resistance. An accurate prediction of the response of early HER2-positive breast cancer to neoadjuvant therapy would allow the modification of treatment with a response-guided strategy, thereby improving overall survival. Shear wave elastography and serum soluble E-cadherin may provide useful data on responsiveness to neoadjuvant therapy in breast cancers. This study was conducted to compare the diagnostic value of tumor stiffness and soluble E-cadherin expression for predicting the response to neoadjuvant therapy in HER2-positive breast cancers. Although these results will require further verification with larger studies, this study may promote noninvasive prediction of neoadjuvant therapy responses and help personalize the treatment regimen.

Clinical Characteristics of Bloodstream Infection in Immunosuppressed Patients: A 5-Year Retrospective Cohort Study.

Introduction: Immunosuppressed patients with bloodstream infection are at risk of mortality. Our objective was to assess the independent risk factors of bloodstream infection with mortality in immunosuppressive states. Methods: The medical data of a total of 896 patients who were hospitalized in our hospital were collected from January 2015 to December 2019. Evaluation of the independent risk factors of mortality was done by univariate and multivariate logistic regression analyses. Results: Of the 896 immunosuppressed patients with bloodstream infection, 698 had over 60-day survivals and 198 had 60-day mortality. In our study, PCT (mean ±; standard: 11.40 ±; 31.89 µg/l vs. 62.45 ±; 17.10 µg/l, p = 0.007) and presence of age >60 years (40% vs. 14.19%, p = 0.001) were significantly different between situations with and without 60-day survivals in both univariate and multivariate logistic regression analyses. Age >60 years and PCT could be used as indicators for bloodstream infection with 60-day death in immunosuppressive states; the OR (95% CI) were 1.532 (1.099-2.135) and 2.063 (1.413-3.013), respectively. In different subgroups, PCT and age were also independent risk factors of blood system diseases, Klebsiella pneumoniae infection, diabetes, and ICU-stay subgroups. Conclusions: Age and PCT were independently associated with mortality in immunosuppressive states, which may help to identify the highly risky situation of bloodstream infection in immunosuppressive states.

Diagnostic utility of LDH, CA125 and CYFRA21-1 in tuberculosis pleural effusion.

OBJECTIVE: The aim of this study was to assess the diagnostic value of several markers for tuberculosis pleural effusion (TPE) using the combined analysis of Lactate dehydrogenase (LDH), Carbohydrate antigen 125 (CA125), Cytokeratin-19 fragment (CYFRA21-1). METHODS: From January to December in 2018, a total of 37 patients with pleural effusion (22 cases of transudative pleural effusion, 15 cases of tuberculosis pleural effusion and 22 cases of Transudative pleural effusion who were hospitalized in our hospital were reviewed. Receiver operating characteristic (ROC) curves and logistic regression equations was used to evaluate the diagnostic efficiency of each marker. RESULTS: The levels of LDH and CYFRA21-1 of tuberculosis pleural effusions were obviously higher than those of transudative pleural effusion with statistically significant difference (<0.05). The areas under the ROC curve of LDH, CA125 and CYFRA21-1 were 0.92, 0.344 and 0.656, respectively. The diagnostic sensitivity of LDH, CA125 and CYFRA21-1 were 100%, 13.3%, 73.3%, respectively. The combined detection of LDH, CA125 and CYFRA21-1 were higher than those of any other combinations of the indexes. CONCLUSIONS: The study showed a high diagnostic sensitivity and specificity of combined speculation of LDH, ADA and CYFRA21-1 in Tuberculosis pleural effusion.

A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies.

PURPOSE: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS: Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION: V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.

The Angiotensin-Converting Enzyme Inhibitory State Promotes the Transformation of Non-Small Cell Lung Cancer Blood Supply Pattern Toward Vasculogenic Mimicry Formation.

Tumor microenvironment plays an important role in tumor proliferation, metastasis, and angiogenesis. Local RAS is a key factor to tumor proliferation and metastasis in NSCLC microenvironment, but its role on angiogenesis and VM formation remains unclear. Although overwhelming majority of previous studies suggested that VM is well established in aggressive tumor and facilitates tumor growth and metastasis, we put forward different views from another angle. We proved that status of tumor blood supply patterns, including VM channels and endothelial vessels, can dynamically exchange with each other along with local RAS fluctuations in microenvironment. Quantitatively, ACE2/ACEI promotes VM formation via Nodal/Notch4 activation; while structurally, ACE2/ACEI leads to a strong and solid structure of VM via inhibition of VE-cadherin internalization. These changes induced by ACE2/ACEI relate to relatively low metastasis rate and comforting prognoses of NSCLC patients.

A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors.

Background AT-101 is a BH3 mimetic that inhibits the heterodimerization of Bcl-2, Bcl-xL, Bcl-W, and Mcl-1 with pro-apoptotic proteins, thereby lowering the threshold for apoptosis. This phase I trial investigated the MTD of AT-101 in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods Patients were treated with AT-101 (40 mg) every 12 h on days 1, 2 and 3 of each cycle combined with varying dose levels (DL) of paclitaxel and carboplatin [DL1: paclitaxel (150 mg/m2) and carboplatin (AUC 5) on day 1 of each cycle; DL2: paclitaxel (175 mg/m2) and carboplatin (AUC 6) on day 1 of each cycle]. Secondary objectives included characterizing toxicity, efficacy, pharmacokinetics, and pharmacodynamics of the combination. Results Twenty-four patients were treated across two DLs with a planned expansion cohort. The most common tumor type was prostate (N = 11). Two patients experienced DLTs: grade 3 abdominal pain at DL1 and grade 3 ALT increase at DL2; however, the MTD was not determined. Moderate hematologic toxicity was observed. One CR was seen in a patient with esophageal cancer and 4 patients achieved PRs (1 NSCLC, 3 prostate). PD studies did not yield statistically significant decreases in Bcl-2 and caspase 3 protein levels, or increased apoptotic activity induced by AT-101. Conclusion The combination of AT-101 at 40 mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016.

A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors.

PURPOSE: Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors. METHODS: Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID). RESULTS: Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (N = 18; 51%), fatigue (N = 17; 49%), maculo-papular rash (N = 16; 46%), diarrhea (N = 12; 34%), anorexia (N = 11; 31%), and nausea (N = 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (N = 13) and primarily included fatigue (N = 5; 14%) and maculo-papular rashes (N = 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients. CONCLUSION: The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.

A Novel Antibody-Toxin Conjugate to Treat Mantle Cell Lymphoma.

Matriptase is a transmembrane serine protease, synthesized as an inactive single-chain zymogen on the endoplasmic reticulum and transported to the plasma membrane. Matriptase is activated in different epithelial and some B-cell malignancies and changes its conformation and activity is inhibited mainly by its endogenous inhibitor HAI-1. Activated matriptase plays a key role in tumor initiation as well as tumor progression, including invasiveness, and metastasis. To target the anti-mitotic toxin (monomethyl auristatin-E) to activated matriptase, a novel antibody to activated matriptase was conjugated with this toxin via a valine-citrulline-PABA linker. In a previous study, this antibody-toxin conjugate was found to be effective against triple negative breast cancer cell lines and xenografts, alone, or in combination with cisplatin (1). In this study, we examined the anti-tumor effect of the antibody toxin conjugate (ADC) against activated matriptase positive mantle cell lymphoma cell lines (JeKo-1, Maver, Mino, and Z138). This ADC was cytotoxic to these cell lines with IC50s between 5 and 14 µg/mL. The ADC also showed a dose dependent anti-tumor effect on the JeKo-1 xenograft in mice without toxicity.

Au-Pd/mesoporous Fe2O3: Highly active photocatalysts for the visible-light-driven degradation of acetone.

Three-dimensionally ordered mesoporous Fe2O3 (meso-Fe2O3) and its supported Au, Pd, and Au-Pd alloy (xAuPdy/meso-Fe2O3; x=0.08-0.72wt.%; Pd/Au molar ratio (y)=1.48-1.85) photocatalysts have been prepared via the KIT-6-templating and polyvinyl alcohol-protected reduction routes, respectively. Physical properties of the samples were characterized, and their photocatalytic activities were evaluated for the photocatalytic oxidation of acetone in the presence of a small amount of H2O2 under visible-light illumination. It was found that the meso-Fe2O3 was rhombohedral in crystal structure. The as-obtained samples displayed a high surface area of 111.0-140.8m2/g and a bandgap energy of 1.98-2.12eV. The Au, Pd and/or Au-Pd alloy nanoparticles (NPs) with a size of 3-4nm were uniformly dispersed on the surface of the meso-Fe2O3 support. The 0.72wt.% AuPd1.48/meso-Fe2O3 sample performed the best in the presence of 0.06mol/L H2O2 aqueous solution, showing a 100% acetone conversion within 4hr of visible-light illumination. It was concluded that the good performance of 0.72wt.% AuPd1.48/meso-Fe2O3 for photocatalytic acetone oxidation was associated with its ordered mesoporous structure, high adsorbed oxygen species concentration, plasmonic resonance effect between AuPd1.48 NPs and meso-Fe2O3, and effective separation of the photogenerated charge carriers. In addition, the introduction of H2O2 and the involvement of the photo-Fenton process also played important roles in enhancing the photocatalytic activity of 0.72wt.% AuPd1.48/meso-Fe2O3.

Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics.

Purpose: Zinc metallochaperones (ZMC) are a new class of anticancer drugs that reactivate zinc-deficient mutant p53 by raising and buffering intracellular zinc levels sufficiently to restore zinc binding. In vitro pharmacodynamics of ZMCs indicate that p53-mutant activity is ON by 4-6 hours and is OFF by 24. We sought to understand the mechanism of this regulation and to translate these findings preclinically. We further sought to innovate the formulation of ZMCs to improve efficacy.Experimental Design: We performed in vitro mechanistic studies to determine the role of cellular zinc homeostatic mechanisms in the transient pharmacodynamics of ZMCs. We conducted preclinical pharmacokinetic, pharmacodynamic, and efficacy studies using a genetically engineered murine pancreatic cancer model (KPC) to translate these mechanistic findings and investigate a novel ZMC formulation.Results:In vitro, cellular zinc homeostatic mechanisms that restore zinc to its physiologic levels function as the OFF switch in ZMC pharmacodynamics. In vivo pharmacokinetic studies indicate that ZMCs have a short half-life (< 30 minutes), which is sufficient to significantly improve survival in mice expressing a zinc-deficient allele (p53R172H) while having no effect in mice expressing a non-zinc-deficient allele (p53R270H). We synthesized a novel formulation of the drug in complex with zinc and demonstrate this significantly improves survival over ZMC1.Conclusions: Cellular zinc homeostatic mechanisms function as an OFF switch in ZMC pharmacodynamics, indicating that a brief period of p53-mutant reactivation is sufficient for on-target efficacy. ZMCs synthesized in complex with zinc are an improved formulation. Clin Cancer Res; 24(18); 4505-17. ©2018 AACR.

Activated matriptase as a target to treat breast cancer with a drug conjugate.

The antitumor effects of a novel antibody drug conjugate (ADC) was tested against human solid tumor cell lines and against human triple negative breast cancer (TNBC) xenografts in immunosuppressed mice. The ADC targeting activated matriptase of tumor cells was synthesized by using the potent anti-tubulin toxin, monomethyl auristatin-E linked to the activated matriptase-specific monoclonal antibody (M69) via a lysosomal protease-cleavable dipeptide linker. This ADC was found to be cytotoxic against multiple activated matriptase-positive epithelial carcinoma cell lines in vitro and markedly inhibited growth of triple negative breast cancer xenografts and a primary human TNBC (PDX) in vivo. Overexpression of activated matriptase may be a biomarker for response to this ADC. The ADC had potent anti-tumor activity, while the unconjugated M69 antibody was ineffective in a mouse model study using MDA-MB-231 xenografts in mice. Treatment of a human TNBC (MDA-MB-231) showed potent anti-tumor effects in combination with cisplatin in mice. This ADC alone or in combination with cisplatin has the potential to improve the treatment outcomes of patients with TNBC as well as other tumors overexpressing activated matriptase.

A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma.

Studies demonstrate that GRM, expressed by >60% of human melanomas, may be a therapeutic target. We performed a phase II trial of 100 mg PO bid of riluzole, an inhibitor of GRM1 signaling, in patients with advanced melanoma with the primary endpoint of response rate. Thirteen patients with GRM1-positive tumors were enrolled. No objective responses were observed, and accrual was stopped. Stable disease was noted in six (46%) patients, with one patient on study for 42 weeks. Riluzole was well tolerated, with fatigue (62%) as the most common adverse event. Downregulation of MAPK and PI3K/AKT was noted in 33% of paired tumor biopsies. Hypothesis-generating correlative studies suggested that downregulation of angiogenic markers and increased leukocytes at the active edge of tumor correlate with clinical benefit. Pharmacokinetic analysis showed interpatient variability consistent with prior riluzole studies. Future investigations should interrogate mechanisms of biologic activity and advance the development of agents with improved bioavailability.

Cefoxitin Plasma and Subcutaneous Adipose Tissue Concentration in Patients Undergoing Sleeve Gastrectomy.

PURPOSE: Antibiotic dosing in obese surgical patients has not been adequately evaluated. The objective of this study was to identify whether currently prescribed doses of cefoxitin achieve adequate and sustained plasma and tissue concentrations in obese patients undergoing sleeve gastrectomy. METHODS: A prospective evaluation of plasma and tissue cefoxitin concentrations in patients undergoing sleeve gastrectomy was performed. On the day of the surgical procedure, venous blood samples (5 mL) were collected just before cefoxitin administration and then at 5, 30, 60, 120, and 240 minutes after dose administration. In addition, subcutaneous adipose tissue was collected from the surgical site at the time of surgical incision and at closure. Cefoxitin concentrations in the collected samples were quantified by using an HPLC-ultraviolet method. A standard noncompartmental analysis was performed for each individual cefoxitin plasma concentration-time profile. In addition, the ratio of tissue to plasma concentration was calculated for all patients. FINDINGS: Plasma and tissue pharmacokinetics of cefoxitin were evaluated in 6 patients undergoing sleeve gastrectomy. The mean age and BMI were 48.7 (6.2) years and 42.8 (7.1) kg/m(2), respectively. At the time of surgical closure, subcutaneous adipose tissue concentrations of cefoxitin were subtherapeutic (<8 µg/mL) in all evaluated patients. IMPLICATIONS: Current dosing strategies for cefoxitin in obese surgical patients may be inadequate, and there is an urgent need to define the appropriate dosage.