Retrospective Assessment Of Treatment With T-Dm1 After Pertuzumab In Her2-Positive Metastatic Breast Cancer

T-DM1/ ado-trastuzumab emtansine, the most recent addition to the HER2-targeted therapies approved to treat HER2-positive metastatic breast cancer (MBC), is an antibody-drug conjugate with a favorable side effect profile. T-DM1 is currently approved for patients with HER2-positive MBC who previously received trastuzumab and a taxane. Since the trial resulting in T-DM1 approval was conducted, the standard first-line therapy for metastatic HER2-positive breast cancer has changed from trastuzumab and a taxane to a three-drug combination of trastuzumab and a taxane plus pertuzumab. Due to the timing of these approvals, there is no clinical trial or observational data on the activity of T-DM1 in patients who have received prior therapy that included pertuzumab. The goal of this study was to assess the efficacy of T-DM1 in routine clinical practice in a contemporary patient population that received both prior trastuzumab and pertuzumab. To address this goal, a retrospective chart review was performed for all patients with HER2-positive MBC who received T-DM1 after pertuzumab between March 1, 2013 and July 15, 2015 at three institutions (Smilow Cancer Hospital at Yale-New Haven, MD Anderson Cancer Center, and The James Cancer Hospital at the Ohio State University). We manually reviewed the medical records of each case to confirm treatment sequencing and outcome. Eighty-two patients were identified who had received single agent T-DM1 and had received pertuzumab at any time previously. Demographic characteristics and prior therapy were reported for these patients. Seventy-eight patients were available for analysis of response. The rate of prolonged duration on therapy (PDT), defined as duration on therapy \u3e 6 months, was 30.8% (95% CI, 20.6-41.1%) and the tumor response rate was 17.9% (95% CI, 9.4-26.4%). The rate of any benefit (AB), defined as PDT and/or TR, was 37.2% (95% CI, 26.5-47.9%). The median duration on therapy was 4.0 months (95% CI, 2.7-5.1, range 0-22.5). The reason for discontinuation of T-DM1 was progression of disease in 84% of patients. Only 7 patients (10%) discontinued T-DM1 due to toxicity or poor tolerance. Overall, this retrospective analysis provides the first data demonstrating the efficacy of T-DM1 in patients who have received pertuzumab previously. Response rates were lower than prior reports in trastuzumab-resistant HER2-positive MBC, but one third of patients received therapy with T-DM1 for at least 6 months, which suggests tumor control and clinically relevant benefit to T-DM1 in patients who received prior trastuzumab and pertuzumab

Preparation and characterization of gold nanoparticles prepared with aqueous extracts of Lamiaceae plants and the effect of follow-up treatment with atmospheric pressure glow microdischarge

AbstractThe unique properties of gold nanoparticles (AuNPs) make them attractive for use in a number of fields, ranging from cosmetology to medicine. If AuNPs are to be widely used in industrial and medical applications, it is necessary to develop environmentally friendly methods for their synthesis. This can be accomplished by replacing the traditional chemical compounds for the reduction of the Au(III) ions to Au0 during AuNPs synthesis with natural plant extracts or with atmospheric pressure plasmas. Here, the properties of three aqueous plant extracts (Mentha piperita, Melissa officinalis, and Salvia officinalis) in the synthesis of AuNPs were compared and optimized under standardized conditions. The effects of the type of plant extract, the reaction temperature, and the precursor concentration on the production and size of the obtained AuNPs were examined using UV–Vis absorption spectrophotometry, dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). It was observed that the size of the produced AuNPs was dependent on the aqueous plant extract used, and that under the optimized conditions, the aqueous leaf extract of M. piperita resulted in the production of AuNPs with the smallest volume-weighted diameter. Additionally, the bioactive compounds present in each extract were studied. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) indicated that different chemical groups could be involved in the AuNPs synthesis, while a Folin–Ciocalteu (FC) assay revealed a clear role of phenolic compounds. Finally, it was shown that the treatment of the synthesized AuNPs, which were obtained after bioreduction using the plant extracts, with atmospheric pressure glow microdischarge (μAPGD) resulted in their agglomeration and enlargement

Fermented juices as reducing and capping agents for the biosynthesis of size-defined spherical gold nanoparticles

Gold nanoparticles (AuNPs) are of scientific and industrial significance; however, the traditional synthesis methods employ toxic compounds. Hence, non-toxic and environmentally friendly AuNPs synthesis methods are of special interest. Here, AuNPs were produced using four solutions of fermented grape juices. UV/Vis absorption spectrophotometry and transmission electron microscopy indicated that AuNPs synthesized with a solution based on semi-sweet red grapes were mostly spherical with narrow size distribution (average diameter of 82.1 ± 36.2 nm). AuNPs of similar spherical morphology but smaller size were obtained using a solution based on semi-dry red grapes (57.1 ± 16.4 nm). A large variety of AuNPs shapes and broader size distribution were produced when solutions based on semi-sweet or dry white grapes were applied. In this case, the average sizes of the AuNPs were 271.6 ± 130.2 nm and 76.0 ± 47.2 nm, respectively. Using energy dispersive X-ray spectroscopy, Au, C, and O were detected, confirming formation of biogenic AuNPs in all cases. Mie theory calculations for AuNPs synthesized with the aid of solutions based on red grapes suggest that their optical properties are different and best suited for distinct downstream applications. Attenuated total reflectance Fourier transform infrared spectroscopy, the Folin-Ciocalteu assay, and the Bertrand's method were used to examine bioactive compounds present in the solutions applied for synthesis. Phenolics, and to a lesser extent reducing sugars, were identified as likely playing a significant role in reduction and stabilization of the AuNPs. These results display the great potential of these solutions for green synthesis of size defined AuNPs, and illustrate that different grape varieties may be used to obtain AuNPs with unique properties. Keywords: Nanostructures, Bioreduction process, Phenolics, Reducing sugars, Mie scatterin

A prognostic model of all-cause mortality at 30 days in patients with cancer and COVID-19

Background: Patients with cancer are at higher risk of dying of COVID-19. Known risk factors for 30-day all-cause mortality (ACM-30) in patients with cancer are older age, sex, smoking status, performance status, obesity, and co-morbidities. We hypothesized that common clinical and laboratory parameters would be predictive of a higher risk of 30-day ACM, and that a machine learning approach (random forest) could produce high accuracy. Methods: In this multi-institutional COVID-19 and Cancer Consortium (CCC19) registry study, 12,661 patients enrolled between March 17, 2020 and December 31, 2021 were utilized to develop and validate a model of ACM-30. ACM-30 was defined as death from any cause within 30 days of COVID-19 diagnosis. Pre-specified variables were: age, sex, race, smoking status, ECOG performance status (PS), timing of cancer treatment relative to COVID19 diagnosis, severity of COVID19, type of cancer, and other laboratory measurements. Missing variables were imputed using random forest proximity. Random forest was utilized to model ACM-30. The area under the curve (AUC) was computed as a measure of predictive accuracy with out-of-bag prediction. One hundred bootstrapped samples were used to obtain the standard error of the AUC. Results: The median age at COVID-19 diagnosis was 65 years, 53% were female, 18% were Hispanic, and 16.7% were Black. Over half were never smokers and the median body mass index was 28.2. Random forest with under sampling selected 20 factors prognostic of ACM-30. The AUC was 88.9 (95% CI 88.5-89.2). Highly informative parameters included: COVID-19 severity at presentation, cancer status, age, troponin level, ECOG PS and body mass index. Conclusions: This prognostic model based on readily available clinical and laboratory values can be used to estimate individual survival probability within 30-days for COVID-19. In addition, this model can be used to select or classify patients with cancer and COVID-19 into risk groups based on validated cut points, for treatment selection, prophylaxis prioritization, and/or enrollment in clinical trials. Future work includes external validation using other large datasets of patients with COVID-19 and cancer

A C-terminal amphipathic helix is necessary for the in vivo tubule-shaping function of a plant reticulon

​Reticulons (RTNs) are a class of endoplasmic reticulum (ER) membrane proteins that are capable of maintaining high membrane curvature, thus helping shape the ER membrane into tubules. The mechanism of action of RTNs is hypothesized to be a combination of wedging, resulting from the transmembrane topology of their conserved reticulon homology domain, and scaffolding, arising from the ability of RTNs to form low-mobility homo-oligomers within the membrane. We studied the plant RTN isoform RTN13, which has previously been shown to locate to ER tubules and the edges of ER cisternae and to induce constrictions in ER tubules when overexpressed, and identified a region in the C terminus containing a putative amphipathic helix (APH). Here we show that deletion of this region or disruption of the hydrophobic face of the predicted helix abolishes the ability of RTN13 to induce constrictions of ER tubules in vivo. These mutants, however, still retain their ability to interact and form low-mobility oligomers in the ER membrane. Hence, our evidence indicates that the conserved APH is a key structural feature for RTN13 function in vivo, and we propose that RTN, like other membrane morphogens, rely on APHs for their function

End-of-Life Care for Patients with Metastatic Renal Cell Carcinoma in the Era of Oral Anticancer Therapy

PURPOSE:New therapies including oral anticancer agents (OAAs) have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). However, little is known about the quality of end-of-life (EOL) care and systemic therapy use at EOL in patients receiving OAAs or with mRCC.METHODS:We retrospectively analyzed EOL care for decedents with mRCC in two parallel cohorts: (1) patients (RCC diagnosed 2004-2015) from the University of North Carolina's Cancer Information and Population Health Resource (CIPHR) and (2) patients (diagnosed 2007-2015) from SEER-Medicare. We assessed hospice use in the last 30 days of life and existing measures of poor-quality EOL care: systemic therapy, hospital admission, intensive care unit admission, and > 1 ED visit in the last 30 days of life; hospice initiation in the last 3 days of life; and in-hospital death. Associations between OAA use, patient and provider characteristics, and EOL care were examined using multivariable logistic regression.RESULTS:We identified 410 decedents in the CIPHR cohort (53.4% received OAA) and 1,508 in SEER-Medicare (43.5% received OAA). Prior OAA use was associated with increased systemic therapy in the last 30 days of life in both cohorts (CIPHR: 26.5% v 11.0%; P <.001; SEER-Medicare: 23.4% v 11.7%; P <.001), increased in-hospital death in CIPHR, and increased hospice in the last 30 days in SEER-Medicare. Older patients were less likely to receive systemic therapy or be admitted in the last 30 days or die in hospital.CONCLUSION:Patients with mRCC who received OAAs and younger patients experienced more aggressive EOL care, suggesting opportunities to optimize high-quality EOL care in these groups

Application of Silver Nanostructures Synthesized by Cold Atmospheric Pressure Plasma for Inactivation of Bacterial Phytopathogens from the Genera Dickeya and Pectobacterium

Pectinolytic bacteria are responsible for significant economic losses by causing diseases on numerous plants. New methods are required to control and limit their spread. One possibility is the application of silver nanoparticles (AgNPs) that exhibit well-established antibacterial properties. Here, we synthesized AgNPs, stabilized by pectins (PEC) or sodium dodecyl sulphate (SDS), using a direct current atmospheric pressure glow discharge (dc-APGD) generated in an open-to-air and continuous-flow reaction-discharge system. Characterization of the PEC-AgNPs and SDS-AgNPs with UV/Vis absorption spectroscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, and selected area electron diffraction revealed the production of spherical, well dispersed, and face cubic centered crystalline AgNPs, with average sizes of 9.33 ± 3.37 nm and 28.3 ± 11.7 nm, respectively. Attenuated total reflection-Fourier transformation infrared spectroscopy supported the functionalization of the nanostructures by PEC and SDS. Antibacterial activity of the AgNPs was tested against Dickeya spp. and Pectobacterium spp. strains. Both PEC-AgNPs and SDS-AgNPs displayed bactericidal activity against all of the tested isolates, with minimum inhibitory concentrations of 5.5 mg∙L−1 and 0.75–3 mg∙L−1, respectively. The collected results suggest that the dc-APGD reaction-discharge system can be applied for the production of defined AgNPs with strong antibacterial properties, which may be further applied in plant disease management

Plant Extracts Activated by Cold Atmospheric Pressure Plasmas as Suitable Tools for Synthesis of Gold Nanostructures with Catalytic Uses

Because cold atmospheric pressure plasma (CAPP)-based technologies are very useful tools in nanomaterials synthesis, in this work we have connected two unique in their classes approaches&mdash;a CAPP-based protocol and a green synthesis method in order to obtain stable-in-time gold nanoparticles (AuNPs). To do so, we have used an aqueous Gingko biloba leave extract and an aqueous Panax ginseng root extract (untreated or treated by CAPP) to produce AuNPs, suitable for catalytical uses. Firstly, we have adjusted the optical properties of resulted AuNPs, applying UV/Vis absorption spectrophotometry (UV/Vis). To reveal the morphology of Au nanostructures, transmission electron microscopy (TEM) in addition to energy dispersive X-ray scattering (EDX) and selected area X-ray diffraction (SAED) was utilized. Moreover, optical emission spectrometry (OES) in addition to a colorimetric method was used to identify and determine the concentration of selected RONS occurring at the liquid-CAPP interface. Additionally, attenuated total reflectance Fourier transform-infrared spectroscopy (ATR FT-IR) was applied to reveal the active compounds, which might be responsible for the AuNPs surface functionalization and stabilization. Within the performed research it was found that the smallest in size AuNPs were synthesized using the aqueous P. ginseng root extract, which was activated by direct current atmospheric pressure glow discharge (dc-APGD), generated in contact with a flowing liquid cathode (FLC). On the contrary, taking into account the aqueous G. biloba leave extract, the smallest in size AuNPs were synthesized when the untreated by CAPP aqueous G. biloba leave extract was involved in the Au nanostructures synthesis. For catalytical studies we have chosen AuNPs produced using the aqueous P. ginseng root extract activated by FLC-dc-APGD as well as AuNPs synthesized using the aqueous G. biloba leave extract also activated by FLC-dc-APGD. Those NPs were successfully used as homogenous catalysts for the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP)