Role of ofatumumab in treatment of chronic lymphocytic leukemia

The management of chronic lymphocytic leukemia (CLL) has dramatically improved in the past decade with the addition of anti-CD20 monoclonal antibodies to the treatment armamentarium. Ofatumumab is a novel anti-CD20 monoclonal antibody recently approved in the US and Europe for the treatment of CLL refractory to alemtuzumab and fludarabine. Preclinical data showed improved complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity compared with rituximab. Clinical studies have shown single-agent activity for ofatumumab in CLL and in other low-grade non-Hodgkin’s lymphomas. Combination studies are being conducted to enhance the therapeutic efficacy of ofatumumab. This paper reviews some of the key clinical studies that led to approval of ofatumumab, and future directions

Caffeinating the biofuels market:Effect of the processing conditions during the production of biofuels and high-value chemicals by hydrothermal treatment of residual coffee pulp

5 figures, 4 tables, supplementary information.-- © 2021. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/The manufacturing of coffee, one of the most popular beverages globally, renders enormous amounts of by-products and wastes, which may trigger severe environmental issues if not treated appropriately. The coffee pulp, resulting from the wet processing of coffee, is the predominant by-product, with around 10 Mt annually produced worldwide. For the first time, this work addresses the hydrothermal treatment of coffee pulp to produce biofuels and platform molecules, scrutinising the influence of the processing conditions (temperature, pressure, reaction time and solid/water ratio) on the process. This strategy allowed the transformation of coffee pulp into bio-crude and hydrochar in different yields (10–26% and 10–42%, respectively), depending on the conditions. The bio-crude included a pool of alkanes, carboxylic acids, ketones, phenols and nitrogen species, with varying quantities of C (54–71 wt%), H (6–7 wt%), O (18–34 wt%) and N (3–5 wt%) and a calorific value shifting from 23 to 32 MJ/kg. The hydrochar contained different proportions of C (57–72 wt%), H (4–6 wt%), O (20–35 wt%) and N (2–3 wt%) and had a calorific value between 22 and 29 MJ/kg. Process optimisation showed that up to 45% of the coffee pulp could be simultaneously converted into energy-rich (29 MJ/kg), merchantable liquid (20% bio-crude) and solid (24% hydrochar) biofuels during the treatment of a 15 wt% coffee pulp suspension at 320 °C and 162 bar for 1 h. At the same time, a bio-crude with a high proportion of profitable phenolic derivatives (42%) can be attained in high yield (25%) when a 5 wt% suspension is treated at 280 °C and 120 bar for 2 h. These promising results, along with the bespoke nature of this hydrothermal treatment, are a landmark achievement for the economy and sustainability of coffee producer countries, thus representing a pioneering step change towards the sustainable management of early-stage coffee leftovers.The authors wish to express their gratefulness to FEDER, the Spanish Ministry of Science, Innovation and Universities (Grant Number ENE2017-83854-R) and the Spanish National Research Council (CSIC) (Grant Number COOPA20367) for providing financial support. Besides, Javier Remón is very grateful to the Spanish Ministry of Science, Innovation and Universities for the Juan de la Cierva (JdC) fellowships (Grant Numbers FJCI-2016-30847 and IJC2018-037110-I) awarded. Lorena Pedraza-Segura and Pedro Arcelus-Arrillaga would like to acknowledge the financial support of INIAT and DINV at Universidad Iberoamericana for their research.Peer reviewe

Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients With CML-CP: The ENRICH Study

AbstractBackgroundMany patients with chronic myeloid leukemia in chronic phase experience chronic treatment-related adverse events (AEs) during imatinib therapy. These AEs can impair quality of life and lead to reduced treatment adherence, which is associated with poor clinical outcomes.Patients and MethodsIn the phase II ENRICH (Exploring Nilotinib to Reduce Imatinib Related Chronic Adverse Events) study (N = 52), the effect of switching patients with imatinib-related chronic low-grade nonhematologic AEs from imatinib to nilotinib was evaluated.ResultsThree months after switching to nilotinib, 84.6% of the patients had overall improvement in imatinib-related AEs (primary endpoint). Of 210 imatinib-related AEs identified at baseline, 62.9% had resolved within 3 months of switching to nilotinib. Of evaluable patients, most had improvements in overall quality of life after switching to nilotinib. At screening, 65.4% of evaluable patients had a major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale). After switching to nilotinib, the rate of the major molecular response was 76.1% at 3 months and 87.8% at 12 months. Treatment-emergent AEs reported with nilotinib were typically grade 1 or 2; however, some patients developed more serious AEs, and 8 patients discontinued nilotinib because of new or worsening AEs.ConclusionOverall, results from the ENRICH study demonstrated that switching to nilotinib can mitigate imatinib-related chronic low-grade nonhematologic AEs in patients with chronic myeloid leukemia in chronic phase, in conjunction with acceptable safety and achievement of molecular responses. This trial was registered at www.clinicaltrials.gov as NCT00980018

Emerging Role of BCR Signaling Inhibitors in Immunomodulation of Chronic Lymphocytic Leukemia

Approved therapies that target the B-cell receptor (BCR) signaling pathway, such as ibrutinib and idelalisib, are known to show activity in chronic lymphocytic leukemia (CLL) via their direct effects on crucial survival pathways in malignant B cells. However, these therapies also have effects on T cells in CLL by mediating toxicity and possibly controlling disease. By focusing on the effects of BCR signaling inhibitors on the T-cell compartment, we may gain new insights into the comprehensive biological outcomes of systemic treatment to further understand mechanisms of drug efficacy, predict the toxicity or adverse events, and identify novel combinatorial therapies. Here, we review T-cell abnormalities in preclinical models and patient samples, finding that CLL T cells orchestrate immune dysfunction and immune-related complications. We then continue to address the effects of clinically available small molecule BCR signaling inhibitors on the immune cells, especially T cells, in the context of concomitant immune-mediated adverse events and implications for future treatment strategies. Our review suggests potentially novel mechanisms of action related to BCR inhibitors, providing a rationale to extend their use to other cancers and autoimmune disorders

Emerging Role of BCR Signaling Inhibitors in Immunomodulation of Chronic Lymphocytic Leukemia

Approved therapies that target the B-cell receptor (BCR) signaling pathway, such as ibrutinib and idelalisib, are known to show activity in chronic lymphocytic leukemia (CLL) via their direct effects on crucial survival pathways in malignant B cells. However, these therapies also have effects on T cells in CLL by mediating toxicity and possibly controlling disease. By focusing on the effects of BCR signaling inhibitors on the T-cell compartment, we may gain new insights into the comprehensive biological outcomes of systemic treatment to further understand mechanisms of drug efficacy, predict the toxicity or adverse events, and identify novel combinatorial therapies. Here, we review T-cell abnormalities in preclinical models and patient samples, finding that CLL T cells orchestrate immune dysfunction and immune-related complications. We then continue to address the effects of clinically available small molecule BCR signaling inhibitors on the immune cells, especially T cells, in the context of concomitant immune-mediated adverse events and implications for future treatment strategies. Our review suggests potentially novel mechanisms of action related to BCR inhibitors, providing a rationale to extend their use to other cancers and autoimmune disorders

Producción de bio-combustibles y productos de valor añadido mediante licuefacción hidrotermal de pericarpios de almendra

1 Tabla.-- Presentado en las XXXVI Jornadas Nacionales de Ingeniería Química, JNIQ 2019, Zaragoza, 4-6 Sep. 2019.Entre los diferentes residuos biomásicos disponibles en España, los pericarpios de almendra obtenidos como subproducto en la industria almendrera son una materia prima de partida muy interesante y completamente inexplorada para la producción sostenible de energía y productos químicos de valor añadido. El pericarpio de la almendra, o recubrimiento externo de la cascara, representa más de la mitad de la masa de este fruto. Se trata de un material lignocelulósico con un alto grado de humedad y que una vez seco está formado principalmente por celulosa, hemicelulosa, lignina y proteínas, en proporciones diferentes dependiendo de la especie. Es importante destacar que la producción mundial de almendras ha aumentado considerablemente en los últimos años (en 2017 se produjeron 1,3 millones de toneladas almendras en todo el mundo), siendo España el segundo país productor a nivel mundial con una producción total de más de 250.000 toneladas anuales. Por lo tanto, la alta disponibilidad de pericarpios de almendra, además de su origen renovable, convierten a este residuo en una materia prima altamente prometedora para la producción sostenible de energía, productos químicos de valor añadido y moléculas plataforma de origen renovable. Una alternativa emergente y muy interesante para la valorización de biomasa es la licuefacción hidrotermal. Este proceso consiste en tratar la biomasa con agua, uno de los disolventes más respetuosos con el medio ambiente, en condiciones hidrotermales: bajas temperaturas (150-350 °C) y presiones moderadas (50-200 bar) 1-4. Esta tecnología tiene una serie de ventajas sobre los métodos convencionales para la valorización de biomasa, tales como pirolisis o gasificación. En concreto, la licuefacción hidrotermal utiliza temperaturas moderadas, permite obtener productos de mayor calidad y no requiere una etapa de secado previa al utilizar agua como medio de reacción, lo que la hace adecuada para el procesamiento de residuos de biomasa húmeda, tales como los pericarpios de almendra. El proceso de licuefacción hidrotermal permite transformar la biomasa lignocelulosica en tres fracciones principales: gas, líquido (bio-oil) y sólido (bio-char) 1-4. Estas fracciones no sólo tienen mayor densidad energética y propiedades mejoradas que la biomasa de partida, facilitando su transporte y almacenamiento, si no que pueden utilizarse como precursores para la obtención de diferentes biocombustibles y compuestos de valor añadido. Concretamente, el gas consiste en una mezcla de H2, CO, CO2 y CH4, cuya composición depende de las condiciones de operación utilizada y la biomasa de partida, y puede utilizarse como un biocombustible gaseoso (hidrógeno o bio-gas) o como precursor de biocombustibles líquidos. El bio-oil contiene los productos de descomposición de la celulosa, hemicelulosa y lignina y tiene excelentes propiedades físico-químicas para utilizarse como precursor de bio-combustibles líquidos y gaseosos, así como para la síntesis de productos químicos valiosos y moléculas plataforma de origen renovable 5-7. El sólido obtenido es un excelente precursor de biocombustibles sólidos y/o adsorbentes renovables. En este contexto, en el presente trabajo se estudia la producción de energía y productos químicos de valor añadido a partir de pericarpios de almendra, un recurso renovable, abundante en España y que nunca ha sido utilizado para tal fin. En concreto, este trabajo aborda el estudio detallado del efecto de temperatura (200-300ºC), presión (100-180 bar), tiempo (20-180 min) y concentración de sólido (5-25 %m/m) en el proceso.Peer reviewe