Platinum Salts Research Articles

Comparative Assessment of Platinum Salts and Taxane Group Hypersensitivity Reactions, The Role of Skin Tests in Diagnosis?

We aimed to investigate the role of skin tests (ST) in the diagnosis of hypersensitivity reactions (HSRs) with platinum salts (PS) and taxane (TX) groups drugs and their reliability in patient management. Patients' data who developed immediate HSR with PS and TX were recorded and ST was performed. The gradual challenge was applied to all patients with ST negative and grade 1-2 with the suspect drug. In total, the data of 104 patients (74 with PS, 30 with TX) who developed HSR against PS and TX were shared. The gradual challenge was applied to 72 ST negative and grade 1-2 patients (46 PS group, 26 TX group). The gradual challenge was negative in 39 patients in the PS group and 23 patients in the Tx group. The negative predictive value (NPV) for PS was 83% and NPV for TX was 88%. We found significantly higher skin test positivity in patients with PS and TX and grade 3 HSR (p = 0.007, p = 0.001). A significant correlation was found between skin test positivity and early onset of symptoms (p = 0.001 for PS, p = 0.015 for TX). In terms of symptoms witnessed in HSR, we observed the itching, urticaria, hypotension, syncope, and abdominal pain symptoms significantly more in the group with a positive skin test (p < 0.024, p < 0.001, p < 0.001, p < 0.002, and p < 0.025, respectively). We found very high NPV values for PS and TX. We found that the gradual challenge applied to patients with negative skin tests is reliable if Grade 3 HSR is not observed and with this approach, unnecessary desensitization processes and/or drug alterations can be avoided.

Graphene Derivatives As Carbon Support Material in Alkaline Direct Ethanol Fuel Cells

The increasing global demand for energy and the associated rise in CO2 emissions due to the use of fossil fuels require the development and use of renewable energy sources. In this context, fuel cells are identified as one of the key technologies for clean energy production. Nevertheless, there are three critical technical barriers for fuel cells that limit their commercialization: performance (activity), durability (stability) and cost. Alkaline fuel cells, particularly alkaline direct ethanol fuel cells (ADEFCs), have attracted much attention in recent decades because ethanol fuel is easy to handle, store, and transport, has low cost, and is environmentally friendly.ADEFCs are limited by their slow kinetics, especially the electrochemical reaction at the anode. Currently, no catalyst is available that cleaves the carbon-carbon bond of ethanol, resulting in a CO2 efficiency of 100% (C1 pathway). The ethanol oxidation reaction (EOR) in alkaline media is incomplete and predominantly follows the C2 pathway. Ethanol is oxidized by hydroxide ions to acetate as the main oxidation product and 4e- instead of 12e-, CO2 and water are released during the complete oxidation. During EOR, acetate is adsorbed on the catalyst surface as the active species. Nevertheless, various reaction intermediates deactivate the catalyst due to poisoning of the active sites, thus reducing the EOR performance. Palladium is currently the most suitable catalyst to replace platinum in ADEFCs. Palladium precursor salts are also cheaper than platinum salts and Pd/C catalysts show higher EOR activity (ethanol oxidation reaction) than Pt/C under alkaline conditions. This can be attributed to the higher oxophilic properties and the inherent ability of Pd to cleave C-C bonds. This positive effect also results in higher stability and lower susceptibility to poisoning of the active sites of the Pd catalyst during EOR. In addition, many non-precious metal co-catalysts are available for palladium, which further reduce the material cost while improving the catalytic activity, by-product tolerance and stability for alkaline EOR [1,2].The development of new anode catalysts with high activity and stability towards alkaline EOR is essential to improve the performance of direct ethanol fuel cell. Carbon materials, especially N-doped or reduced graphene oxides (rGO), are a promising catalyst support due to their low cost, high electrical conductivity, large surface area, and reasonable stability [3]. The deposition of the metal nanoparticles on the graphene oxide support generates a higher active surface area of the catalysts, which increases the electrocatalytic activity while reducing the cost.In the current studies, palladium-based catalysts are synthesized with different graphene oxide (GO) support materials (N-doped GO and rGO) by the modified instant method. The prepared catalysts were characterized ex-situ by the thin film rotating disk electrode technique using a standard three-electrode setup. To determine the electrochemical active surface area and EOR activity, cyclic voltammetry and EOR measurements were recorded in N2 purged potassium hydroxide and alkaline ethanol solution (1 M), respectively. Chronoamperometry was performed to investigate the stability of the catalysts. The cyclic voltammograms (CV) of the two catalysts compared show minor differences in peak current density, onset potential and by-product tolerance for the alkaline EOR. Further details will be discussed in the poster presentation.The authors acknowledge the financial support by the Austrian Science Fund (FWF): I 3871-N37 and by the Slovenian Research Agency (ARRS) through the Research Funding Programme P1-0175 and Bilateral Research Funding Project N2-0087.[1] B.Cermenek, J.Ranninger, V.Hacker; In Ethanol: Science and Engineering, A.Basile, A.Iulianelli, F.Dalena, N.T.Veziroglu, Eds.; Elsevier Inc.: Amsterdam, 2019, 383-405.[2] B.Cermenek, J.Ranninger, B.Feketeföldi, I.Letofsky-Papst, N.Kienzl, B. Bitschnau, V. Hacker, Nano Research, 2019, 12 (3), 683-693.[3] M. Nosan, M. Löffler, I. Jerman, M. Kolar, I. Katsounaros, and B. Genorio, ACS Appl. Energy Mater. 2021 Figure 1

On the role of N-methylmorpholine-N-oxide (NMMO) in the generation of elemental transition metal precipitates in cellulosic materials

Several literature reports describe the role of aqueous solutions of N-methylmorpholine-N-oxide monohydrate (NMMO) as a suitable medium for the generation of transition metal (nano)particles in or on cellulosic materials and further elaborate its role as a co-reactant of the transition metal salts that are reduced to the elemental metal. However, this would assign NMMO the role of a reductant, which is in contradiction of its obvious oxidative nature. In the present study, the exemplary cases of silver, gold, and platinum salts as the precursors of the respective metal (nano)particles in aqueous NMMO/cellulose mixtures were investigated. Naturally, NMMO did not act as a reducing agent in any case—this role was taken over by the frequently used NMMO stabilizer propyl gallate, or by cellulose itself, into which carbonyl and carboxyl groups were introduced. Also, hypochlorite—produced intermediately from chloride ions and subsequently undergoing disproportionation into chloride and chlorate—or transient N-methylene(morpholinium) ions generated from NMMO, which are in turn oxidized to formyl morpholide, can act as the corresponding reductants while the metal ions are reduced, depending on the reaction conditions. Apart from providing interesting mechanistic insights, the study points to the importance of a precise description of the composition of the chemical systems used, as well as the importance of seemingly inert auxiliaries, which turned out to be essential co-reactants in the metal (nano)particle generation.Graphic abstract

Bypassing the Resistance Mechanisms of the Tumor Ecosystem by Targeting the Endoplasmic Reticulum Stress Pathway Using Ruthenium- and Osmium-Based Organometallic Compounds: An Exciting Long-Term Collaboration with Dr. Michel Pfeffer.

Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960’s. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes. Then, they discovered that these organo-ruthenium/osmium complexes could act independently of DNA damage and bypass the requirement for the tumor suppressor gene TP53 to induce the endoplasmic reticulum (ER) stress pathway, which is an original cell death pathway. They showed that other types of ruthenium complexes—as well complexes with other metals (osmium, iron, platinum)—can induce this pathway as well. They also demonstrated that ruthenium complexes accumulate in the ER after entering the cell using passive and active mechanisms. These particular physico-chemical properties of the organometallic complexes designed by Dr. Pfeffer contribute to their ability to reduce tumor growth and angiogenesis. Taken together, the pioneering work of Dr. Michel Pfeffer over his career provides us with a legacy that we have yet to fully embrace.

A BMDC assay for studying the respiratory sensitisation mechanism: first results with platinum salts.

A BMDC assay for studying the respiratory sensitisation mechanism: first results with platinum salts.

Homologous Recombination Deficiency Alterations in Colorectal Cancer: Clinical, Molecular, and Prognostic Implications.

Tumors with homologous recombination deficiency (HRD) show high sensitivity to platinum salts and poly(ADP-ribose) polymerase-inhibitors in several malignancies. In colorectal cancer (CRC), the role of HRD alterations is mostly unknown. Next-generation sequencing, whole transcriptome sequencing, and whole exome sequencing were conducted using CRC samples submitted to a commercial Clinical Laboratory Improvement Amendments certified laboratory. Tumors with pathogenic and/or presumed pathogenic mutations in 33 genes involved in the homologous recombination pathway were considered HRD, the others were homologous recombination proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI+bevacizumab vs FOLFOX+bevacizumab were analyzed with next-generation sequencing. The analyses were separately conducted in microsatellite stable or proficient mismatch repair (MSS/pMMR) and microsatellite instable-high or deficient mismatch repair (MSI-H/dMMR) groups. All statistical tests were 2-sided. Of 9321 CRC tumors, 1270 (13.6%) and 8051 (86.4%) were HRD and HRP, respectively. HRD tumors were more frequent among MSI-H/dMMR than MSS/pMMR tumors (73.4% vs 9.5%; P < .001; q < 0.001). In MSS/pMMR group, HRD tumors were more frequently tumor mutational burden high (8.1% vs 2.2%; P < .001; q < 0.001) and PD-L1 positive (5.0% vs 2.4%; P < .001; q = 0.001), enriched in all immune cell and fibroblast populations and genomic loss of heterozygosity-high (16.2% vs 9.5%; P = .03). In the TRIBE2 study, patients with MSS/pMMR and HRD tumors (10.7%) showed longer overall survival compared with MSS/pMMR and HRP tumors (40.2 vs 23.8 months; hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.45 to 0.98; P = .04). Consistent results were reported in the multivariable model (HR = 0.67, 95% CI = 0.45 to 1.02; P = .07). No interaction effect was evident between homologous recombination groups and treatment arm. HRD tumors are a distinctive subgroup of MSS/pMMR CRCs with specific molecular and prognostic characteristics. The potential efficacy of agents targeting the homologous recombination system and immune checkpoint inhibitors in this subgroup is worthy of clinical investigation.

Highly Active TiO2 Photocatalysts for Hydrogen Production through a Combination of Commercial TiO2 Material Selection and Platinum Co-Catalyst Deposition Using a Colloidal Approach with Green Reductants

In this contribution, four different commercial TiO2 catalysts (P25, P90, PC105, and PC500) were screened for the photocatalytic production of hydrogen using ethanol as the sacrificial agent. The physico-chemical properties of the TiO2 powders were characterized by using different methods. The photocatalysts mainly vary in the ratio of anatase and rutile phases, and in the surface area. It was found that the photocatalytic activity is governed by the surface area of the photocatalyst. Pure TiO2,PC500 showed the best performance, and in comparison to P25, the activity was more than twenty times higher due to its high surface area of about 270 m2 g−1. For further improvement of the photocatalytic activity, platinum nanoparticles (PtNPs) were immobilized onto TiO2,PC500 using two methods: a colloidal approach and a photodeposition method. For the reduction of the platinum salt precursor in the colloidal approach, different green reducing agents were used in comparison to ascorbic acid. The obtained platinum nanoparticles using natural reductants showed a higher photocatalytic activity due to the formation of smaller nanoparticles, as proven by transmission electron microscopy (TEM). The highest activity was obtained when mangosteen was used as the green reducing agent. Compared to ascorbic acid as a classical reducing agent, the photocatalytic activity of the Pt@TiO2,PC500 prepared with mangosteen was about 2–3 times higher in comparison to other as-prepared photocatalysts. The Pt@TiO2,PC500 catalyst was further studied under different operating conditions, such as catalyst and sacrificial agent concentration.

Highly Active TiO2 Photocatalysts for Hydrogen Production through a Combination of Commercial TiO2 Material Selection and Platinum Co-Catalyst Deposition Using a Colloidal Approach with Green Reductants

In this contribution, four different commercial TiO2 catalysts (P25, P90, PC105, and PC500) were screened for the photocatalytic production of hydrogen using ethanol as the sacrificial agent. The physico-chemical properties of the TiO2 powders were characterized by using different methods. The photocatalysts mainly vary in the ratio of anatase and rutile phases, and in the surface area. It was found that the photocatalytic activity is governed by the surface area of the photocatalyst. Pure TiO2,PC500 showed the best performance, and in comparison to P25, the activity was more than twenty times higher due to its high surface area of about 270 m2 g−1. For further improvement of the photocatalytic activity, platinum nanoparticles (PtNPs) were immobilized onto TiO2,PC500 using two methods: a colloidal approach and a photodeposition method. For the reduction of the platinum salt precursor in the colloidal approach, different green reducing agents were used in comparison to ascorbic acid. The obtained platinum nanoparticles using natural reductants showed a higher photocatalytic activity due to the formation of smaller nanoparticles, as proven by transmission electron microscopy (TEM). The highest activity was obtained when mangosteen was used as the green reducing agent. Compared to ascorbic acid as a classical reducing agent, the photocatalytic activity of the Pt@TiO2,PC500 prepared with mangosteen was about 2–3 times higher in comparison to other as-prepared photocatalysts. The Pt@TiO2,PC500 catalyst was further studied under different operating conditions, such as catalyst and sacrificial agent concentration.

Open questions and controversies in the systemic treatment of breast cancer.

Personalized therapy has revolutionized our approach to breast cancer (BC). Patient selection strategies and new biomarkers are the basis for increasingly complex diagnostic and therapeutic algorithms. In this short review, we discuss recent developments in breast oncology, focusing on controversial topics with relevance for clinical practice. The use of gene expression signatures to guide adjuvant therapy in hormone receptor-positive tumors and personalized strategies for systemic treatment of early stage HER2-positive disease represent significant advances. Additionally, the current role of platinum salts, immune checkpoint inhibitors, and CDK4/6 inhibitors in the (neo)adjuvant treatment remains controversial, with several ongoing randomized clinical trials exploring their use. In the metastatic disease setting, we identify important unmet needs such as the development of predictive biomarkers and the definition of the ideal sequencing algorithm with the incorporation of innovative agents in all subtypes of BC. Advances in understanding the molecular biology and heterogeneity of BC have led to the development of new biomarkers and therapeutic agents that significantly impact current and future clinical practice.

Neuroendocrine Carcinomas of the Digestive Tract: What Is New?

Simple SummaryIn this narrative review, we describe the current data and management of neuroendocrine carcinomas (NEC) of the digestive tract. These tumors are very rare and suffer from a lack of clinical trials which would allow for standardized therapeutic management. To date, most guidelines come from studies in small-cell lung cancer, which is a similar entity in the lung. The incidence of NEC is rising and their prognostic is very low, underlying the urgent need for more trials to help define their best management.Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management.

Wnt/β-Catenin Inhibition Disrupts Carboplatin Resistance in Isogenic Models of Triple-Negative Breast Cancer

Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by limited treatment options and higher relapse rates than hormone-receptor-positive breast cancers. Chemotherapy remains the mainstay treatment for TNBC, and platinum salts have been explored as a therapeutic alternative in neo-adjuvant and metastatic settings. However, primary and acquired resistance to chemotherapy in general and platinum-based regimens specifically strongly hampers TNBC management. In this study, we used carboplatin-resistant in vivo patient-derived xenograft and isogenic TNBC cell-line models and detected enhanced Wnt/β-catenin activity correlating with an induced expression of stem cell markers in both resistant models. In accordance, the activation of canonical Wnt signaling in parental TNBC cell lines increases stem cell markers’ expression, formation of tumorspheres and promotes carboplatin resistance. Finally, we prove that Wnt signaling inhibition resensitizes resistant models to carboplatin both in vitro and in vivo, suggesting the synergistic use of Wnt inhibitors and carboplatin as a therapeutic option in TNBC. Here we provide evidence for a prominent role of Wnt signaling in mediating resistance to carboplatin, and we establish that combinatorial targeting of Wnt signaling overcomes carboplatin resistance enhancing chemotherapeutic drug efficacy.

A wake-up call for cancer DNA damage: the role of Schlafen 11 (SLFN11) across multiple cancers.

DNA-damaging agents exploit increased genomic instability, a hallmark of cancer. Recently, inhibitors targeting the DNA damage response (DDR) pathways, such as PARP inhibitors, have also shown promising therapeutic potential. However, not all tumors respond well to these treatments, suggesting additional determinants of response are required. Schlafen 11 (SLFN11), a putative DNA/RNA helicase that induces irreversible replication block, is emerging as an important regulator of cellular response to DNA damage. Preclinical and emerging clinical trial data suggest that SLFN11 is a predictive biomarker of response to a wide range of therapeutics that cause DNA damage including platinum salts and topoisomerase I/II inhibitors, as well as PARP inhibitors, which has raised exciting possibilities for its clinical application. In this article, we review the function, prevalence, and clinical testing of SLFN11 in tumor biopsy samples and circulating tumor cells. We discuss mounting evidence of SLFN11 as a key predictive biomarker for a wide range of cancer therapeutics and as a prognostic marker across several cancer types. Furthermore, we discuss emerging areas of investigation such as epigenetic reactivation of SLFN11 and its role in activating immune response. We then provide perspectives on open questions and future directions in studying this important biomarker.

The lncRNA 'UCA1' modulates the response to chemotherapy of ovarian cancer through direct binding to miR-27a-5p and control of UBE2N levels.

Ovarian cancer (OC) is the leading cause of death in patients with gynecologic cancers. Due to late diagnosis and resistance to chemotherapy, the 5‐year survival rate in patients with OC is below 40%. We observed that UCA1, a lncRNA previously reported to play an oncogenic role in several malignancies, is overexpressed in the chemoresistant OC cell line OAW42‐R compared to their chemotherapy‐sensitive counterpart OAW42. Additionally, UCA1 overexpression was related to poor prognosis in two independent patient cohorts. Currently, the molecular mechanisms through which UCA1 acts in OC are poorly understood. We demonstrated that downregulation of the short isoform of UCA1 sensitized OC cells to cisplatin and that UCA1 acted as competing endogenous RNA to miR‐27a‐5p. Upon UCA1 downregulation, miR‐27a‐5p downregulated its direct target UBE2N leading to the upregulation of BIM, a proapoptotic protein of the Bcl2 family. The upregulation of BIM is the event responsible for the sensitization of OC cells to cisplatin. In order to model response to therapy in patients with OC, we used several patient‐derived organoid cultures, a model faithfully mimicking patient’s response to therapy. Inhibition of UBE2N sensitized patient‐derived organoids to platinum salts. In conclusion, response to treatment in patients with OC is regulated by the UCA1/miR‐27a‐5p/UBE2N axis, where UBE2N inhibition could potentially represent a novel therapeutic strategy to counter chemoresistance in OC.

Abstract LB113: Regulation of PARP-1 expression in mammary tumor cell lines after treatment with olaparib

Abstract Introduction: Breast cancer is the most common tumor type among women and has a high mortality rate, which is associated with late detection of the disease and treatment failure due to the acquisition of resistance to protocol treatments. It is known that a variety of antitumor drugs are capable of inducing chemoresistance by activating DNA repair pathways. Among these, the PARPs are involved in the recognition and repair of simple-strand breaks. As a consequence, new drugs such as PARP inhibitors (olaparib), are being investigated as potential therapeutic targets in cancer, as an alternative to evade the resistance of tumor cells to chemotherapeutic agents, such as those in the class of platinum salts. In this context, the aim of this study was to evaluate the PARP expression after olaparib tratament with in mammary tumor cell lines. Materials and Methods: Mammary tumor cell lines MDA-MB-468 and CF41 was cultured in DMEM high glucose culture medium, at 37°C in 5% CO2. Cell viability was measured by MTT assay after treatment with different concentrations of carboplatin. Once stablished the concentration of 10µM for carboplatin and 10µM of olaparib, the protein and gene expression of PARP-1 were detected by immunofluorescence and real time PCR, respectively. Results: There was a significantly decrease of cell viability after treatment with different concentrations of carboplatin in 24 hours. Both PARP-1 protein and gene expression significantly decreased after treatment with carboplatin and olaparib. In some cases, the treatment action was potentiated when performed in combination. Conclusion: Our results suggest the efficacy of olaparib in controlling the mechanism of DNA repair activated by PARPs in human and canine breast cancer cells. Citation Format: Marina Gobbe Moschetta-Pinheiro, Jucimara Colombo, Murilo de Souza Tuckumantel, Gabriela Karam Rebolho, Debora Aparecida Zuccari. Regulation of PARP-1 expression in mammary tumor cell lines after treatment with olaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB113.

R-DHA-Oxaliplatin before Autologous Stem Cell Transplantation Prolongs PFS and OS As Compared to R-DHA-Carboplatin and R-DHA-Cisplatin in Patients with Mantle Cell Lymphoma, a Subgroup Analysis of the LyMa Trial

BACKGROUND. The LyMA (ClinicalTrials.gov, NCT00921414) trial is a prospective international randomized phase III trial that investigated Rituximab maintenance (RM) after autologous-stem cell transplantation (ASCT) in young previously untreated mantle cell lymphoma (MCL) patients (Le Gouill et al., in press, 2017). Patients were included at diagnosis (<66y; stage >I) and induction immuno-chemotherapy consisted of 4 courses of R-DHAP-21 (Rituximab, Dexamethasone, High-dose cytarabine, Platinum salt) followed by ASCT consolidation. The conditioning regimen for ASCT was R-BEAM. Patients in response after ASCT were randomized (1:1) between RM or observation. 299 patients (<66y) were included of whom 240 were randomly assigned to RM or observation after ASCT. Median follow-up from randomization after ASCT was 50.2 (46.4-54.2) months. The final analysis demonstrates that RM is superior to observation with respect of EFS, PFS and OS. For induction with R-DHAP, local investigators were free to choose between cisplatin (continuous infusion cisplatin 100 mg/m2 over 24 h on day 1; DHA-Cis), carboplatin (with AUC = 5 mg/ml.min ; target Area Under the concentration vs. time Curve using the Calvert formula ; DHA-Ca) or oxaliplatin (130 mg/m² on day 1 ; DHA-Ox).METHODS. In the present analysis, we investigated the prognostic impact on PFS and OS of the nature of platinum salt used in the R-DHAP regimen. The intention-to-treat (ITT) analysis includes all patients who have received at least one course of R-DHAP (n=298; data missing in one patient) and per protocol analysis (PP) includes all patients who have received the same platinum salt during induction phase (n=227).RESULTS. Cisplatin, Carboplatin and oxaliplatin were used at course 1 in 184, 76 and 38 patients, respectively. Patients' characteristics at diagnosis (including MIPI) and randomization arm (RM or observation) were well balanced between the 3 groups. Twenty-seven (15%) and 38 (21%) out of 184 patients who received cisplatin from course 1 switched to carboplatin and oxaliplatin because of toxicity, respectively. In contrast, only one patient with DHA-Ca switched to DHACis and one patient with R-DHAOx switched to R-DHACa. All cases of renal failure during induction (n=8) occurred in the R-DHACis group. PFS and OS in both ITT and PP were identical in the R-DHACis and R-DHACa groups while there was a trend in favor of R-DHAOx in both PFS (p=0.092 in ITT and 0.0675 in PP) and OS (p= 0.013 in ITT and p= 0.0859 in PP). Because patients' outcome was identical with R-DHACa and R-DHACis, both groups were combined in one group (R-DHACa/DHACis) and then compared to R-DHAOx. In ITT, the 4y PFS and OS in the R-DHAOx vs R-DHACis/Ca were 86.5% (95%CI; 70.5 to 94.1) vs 65% (95%CI; 58.8 to 70.6) and 92% (95%CI; 77.1 to 97.3) vs 75.9% (95%CI; 70.1 to 80.7), respectively. In ITT, patients with R-DHAOx have a better PFS (HR=0.438; 95%CI, 0.204-0.944; p=0.035) and OS (HR=0.373; 95%CI, 0.136-1.023; p=0.0554) as compared to patients with R-DHACa/DHACis . Similar results were reached in the PP analysis: PFS (HR=0.414; 95%CI, 0.191-0.899; p=0.0257) and OS (HR=0.347; 95%CI, 0.126-0.959; p=0.0412). In multivariate analysis (with MIPI), R-DHAOx was independent prognostic marker for PFS and OS.Conclusion. The present analysis shows for the first time that R-DHAOx is a better induction regimen than R-DHACa and R-DHACis in MCL patients and strongly suggests that platinium salt are critical (and not only high dose AraC) in the R-DHAP regimen. Our finding may also have a major impact in other forms of lymphoma where R-DHAP is frequently used as a standard salvage therapy. DisclosuresLe Gouill:Roche: Consultancy, Honoraria, Research Funding; janssen: Consultancy, Honoraria; servier: Consultancy, Honoraria, Research Funding; bayer: Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Research Funding. Thieblemont:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Ribrag:BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Pharmamar: Consultancy; Esai: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel, accommodation, expenses; ArgenX: Research Funding. Jourdan:NOVARTIS: Consultancy, Honoraria. Delarue:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Salles:morphosys: Consultancy, Honoraria; BMS: Consultancy; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Tilly:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria. Lamy:Roche: Consultancy, Honoraria.

Expansion of Dendrimer Template Function for Subnanoparticle Synthesis

Unusual complex formation of PtBr4 in THF was investigated for phenylazomethine dendrimer templates. The characteristics made it possible to reverse-order assemble platinum salts by changing the solvent composition of the dendrimers. This reverse-order assembly method enabled full-range tuning of metal ratios for hybridization, which was inherently difficult for templates with a typical dendritic structure.

Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?

Simple SummaryRAD51 is an essential gene for cell survival. Its function is central to DNA repair and it protects cells from life-threatening damage to the genome. Interestingly, RAD51 is expressed at high levels in a large proportion of cancers, and elevated RAD51 expression is associated with a bad outcome and reduced response to treatment. Hence, reducing RAD51 expression and/or interfering with its function could be of great therapeutic value. We review here the multiple levels of regulation of RAD51 expression and function and explore potential therapeutic leads.The RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a template for repair. RAD51 filaments are detectable by immunofluorescence as distinct foci in the cell nucleus, and their presence is a read out of HR proficiency. RAD51 is an essential gene, protecting cells from genetic instability. Its expression is low and tightly regulated in normal cells and, contrastingly, elevated in a large fraction of cancers, where its level of expression and activity have been linked with sensitivity to genotoxic treatment. In particular, BRCA-deficient tumors show reduced or obliterated RAD51 foci formation and increased sensitivity to platinum salt or PARP inhibitors. However, resistance to treatment sets in rapidly and is frequently based on a complete or partial restoration of RAD51 foci formation. Consequently, RAD51 could be a highly valuable therapeutic target. Here, we review the multiple levels of regulation that impact the transcription of the RAD51 gene, as well as the post-translational modifications that determine its expression level, recruitment on DNA damage sites and the efficient formation of homofilaments. Some of these regulation levels may be targeted and their impact on cancer cell survival discussed.

Synthesis and Spectroscopic Characterization of Platinum Nanoparticles by Plasma Jet Method

In this research, Argon gas was used to generate atmospheric plasma in the manufacture of platinum nanomaterials, to study the resultant plasma spectrum and to calculate the cellular toxicity of those manufactured nanomaterials. This research is keen on the generation of nonthermal atmospheric pressure plasma using aqueous platinum salts (H2PtCl6 6H2O) with different concentrations and exposure of cold plasma with a different time period used to produce platinum nanoparticles, to ensure typical preparation of nanoparticles. Visible UV and X-rays were performed for this purpose, and the diameter of the system probe was (1[Formula: see text]mm) with the Argon gas flow of 2.5[Formula: see text]min/L to prepare the platinum nanoparticles, and spectroscopic study of plasma parameter including, electron temperature, electron density, Debye length and plasma frequency, were computed using spectral analysis techniques. The effect of nanoparticles on natural lymphocytes was studied to calculate cytotoxicity and the greatest proportion was at the concentration of 100% nanoparticle platinum is 37.4%. The study results revealed that cold in the atmosphere is a promising technology when used in the production of nanoparticle materials which can be used for many industrial and medical applications.

Serial measurements of fractional exhaled nitric oxide at home and at work: A useful tool for monitoring workers with platinum salt allergy after exposure reduction.

Serial measurements of fractional exhaled nitric oxide at home and at work: A useful tool for monitoring workers with platinum salt allergy after exposure reduction.

Biosynthesis and characterization of platinum nanoparticles using Iraqi Zahidi dates and evaluation of their biological applications

Platinum nanoparticles (Pt NPs) were synthesized by utilizing the Zahidi dates extract by green synthesis technique. Platinum salts were successfully reduced to their corresponding Pt NPs in the presence of aqueous dates extract which considers a rich source of phytochemicals that led to the reduction of Pt+4 to Pt° atoms by providing electrons for these ions. Many techniques characterized the nanoparticles. TEM analysis showed that the Pt NPs were exhibited in diameters ranging from (30−45) nm. FE-SEM images display nanoparticles in spherical shapes. AFM screening shows that Platinum nanoparticles had small size distribution. XRD diffraction examination showed that the formation of Platinum nanoparticles exhibits a face centred cubic crystalline structure by spectrum comparative to the standard confirmed spectrum of Platinum particles produced in the experiments were in the shape of nanocrystals. The fourier transform infrared spectroscopy spectrum showed various peaks ranging from (400–4000) cm−1 used to identify the functional groups responsible for reducing and capping of Pt NPs. Cancer cells including the ovarian cancer SKO-3 cell line and Oesophageal cancer SK-GT-4 cell line were exposed to a series of prepared Platinum nanoparticle concentrations (0.00125, 0.0025, 0.005, 0.01) M, and the inhibition rate of growth in cells was measured for 72 h. The cytotoxicity screening showed that there was a highly toxic effect on the cancer cells. Gram-negative bacterial strain Pseudomonas aeruginosa and Gram-positive bacterial strain Streptococcus pyogenes were exposed to a series of concentrations from prepared Platinum nanoparticles (0.00125, 0.0025, 0.005, 0.01) M. The results exhibited significant inhibitory activity and the rate of bacterial growth inhibition increased with increasing concentration.