Temsirolimus in the treatment of relapsed and/or refractory mantle cell lymphoma

Patients with mantle cell lymphoma (MCL) have a poor prognosis; consequently, new therapeutic approaches, such as rapamycin and its derivates, mammalian target of rapamycin (mTOR) inhibitors, are warranted. Temsirolimus (also known as CCI-779), a dihydroester of rapamycin, in MCL cell lines inhibited mTOR, downregulated p21 and v-Raf, and induced autophagy. The first clinical trial in MCL patients was performed using 250 mg of temsirolimus weekly for 6–12 cycles. The overall response rate was 38%; the median time to progression was 6.5 months, median overall survival was 12 months, and the median duration of response was 6.9 months. At lower dose (25 mg/week), the overall response rate was 41%, median overall survival was 14 months, and time to progression was 6 months. In another trial, 162 patients were randomly assigned to receive temsirolimus at 2 different doses (175 mg/week for 3 weeks, then 75 mg or 25 mg/week) or a treatment chosen by the investigator among the most frequently adopted single agents for treatment of relapsed MCL. Patients treated with 175/75 mg of temsirolimus had significantly higher response rates and longer progression-free survival than those treated with investigator’s choice therapy. These data support the use of mTOR inhibitors for the treatment of MCL, probably in combination with other agents, such as antiangiogenic drugs or histone acetylase inhibitors

Semiparametric finite mixture of regression models with Bayesian P-splines

Mixture models provide a useful tool to account for unobserved heterogeneity and are at the basis of many model-based clustering methods. To gain additional flexibility, some model parameters can be expressed as functions of concomitant covariates. In this Paper, a semiparametric finite mixture of regression models is defined, with concomitant information assumed to influence both the component weights and the conditional means. In particular, linear predictors are replaced with smooth functions of the covariate considered by resorting to cubic splines. An estimation procedure within the Bayesian paradigm is suggested, where smoothness of the covariate effects is controlled by suitable choices for the prior distributions of the spline coefficients. A data augmentation scheme based on difference random utility models is exploited to describe the mixture weights as functions of the covariate. The performance of the proposed methodology is investigated via simulation experiments and two real-world datasets, one about baseball salaries and the other concerning nitrogen oxide in engine exhaust

Two steps one pot process for the conversion of dimethylfuran to pyrrole compounds with almost null E factor

The replacement of the oil-based chemicals with those derived from biomasses is one of the most exciting challenges of the last decades. For example, 1,4-dicarbonyl compounds have a great importance in chemical synthesis, thanks to their high chemoselectivity and there is an increasing interest for preparing them from biomasses. In particular, 2,5-hexanedione could be synthesized starting from lignocellulosic sources, through the acid-ring opening reaction of 2,5-dimethylfuran as the bio-based feedstock.[1] The reaction of 2,5-hexanedione and a generic primary amine leads to pyrrole compounds. Many examples have been reported by some of the authors.[2] In this work a sustainable process for the preparation of pyrrole compounds starting from a bio-based reagent has been developed. The selected starting material was 2,5-dimethyl furan. In this work, the ring opening reaction of 2,5-dimethylfuran was optimized by tuning parameters such as the amount of water, type and amount of acid, time and temperature. 2,5-hexanedione was obtained with a high yield (95%) without the need of purification. Then, different primary amines, in particular biosourced, have been used to prepare a variety of pyrrole compounds, with high yield (at least 90%) and with high carbon efficiency, without producing waste. The pyrrole compounds have then been used for the functionalization of a nanosized graphite, promoting the exfoliation to few layers graphene

Polyether from a biobased Janus molecule as surfactant for carbon nanotubes

A new polyether (PE) was prepared from a biobased Janus molecule, 2-(2,5-dimethyl-1H-pyrrol-1-yl)-1,3- propanediol (serinol pyrrole, SP). SP was synthesized with very high yield (about 96%) and high atom efficiency (about 80%) by reacting a biosourced molecule, such as serinol, with 2,5-hexanedione in the absence of solvent or catalyst. The reaction of SP with 1,6-dibromohexane led to PE oligomers, that were used as surfactants for multiwalled carbon nanotubes (MWCNT), in ecofriendly polar solvents such as acetone and ethyl acetate. The synergic interaction of aromatic rings and oxyalkylene sequences with the carbon allotrope led to dramatic improvement of surfactant efficiency: only 24% of SP based PE was extracted with ethyl acetate from the adduct with MWCNT, versus 98% of a typical pluronic surfactant. Suspensions of MWCNT-PE adducts in ethyl acetate were stable for months. High resolution transmission electron microscopy revealed a film of oligomers tightly adhered to MWCNT surface

A bio-sourced molecule as carbon black coupling agent in rubber compounds with low hysteresis

The prime application of rubber composites is represented by tire compounds. To achieve the desired tire performances an equilibrium between dynamic rigidity and hysteresis must be acquired. Amorphous precipitated silica is the preferred reinforcing filler to have low energy dissipations and thus low fuel consumption. Indeed, silica is characterized by nano dimensions and by the possibility of establishing chemical bonds with rubber chains allowing the achievement of high hysteresis at low temperatures, to promote wet traction, and low hysteresis at medium-high temperatures, for low fuel consumption. Carbon black (CB) is the main filler for tire compounds, but it does not have functional groups able to promote chemical bonds with the rubber matrix, though it would be highly desirable. In this work, a pyrrole compound (PyC) containing a thiol group, and which can be synthesized starting from bio-based building blocks was used to functionalize CB by the socalled “pyrrole methodology”. The thiol group was expected to react with the sulphurbased crosslinking system and/or with rubber chains, thus forming strong bonds with the rubber matrix. Results The synthesis of the PyC and the functionalization reaction were characterized by high atom efficiency. A poly(styrene-co-butadiene) copolymer from anionic solution polymerization was used as the main rubber for the compound preparation. The crosslinked composite material filled with functionalized CB revealed substantial improvements with respect to the composite with pristine CB, in particular: high rigidity and low hysteresis at high temperature. Composite properties were even comparable to those of silica-based rubber composites. The formation of the expected rubber-filler chemical bond via the thiol group of the selected PyC was confirmed studying such functionalizing agent in a squalene-based model compound. The results here reported pave the way to CB-based rubber composites with a low environmental impact

Outcome Prognostication of Acute Brain Injury using the Neurological Pupil Index (ORANGE) study: protocol for a prospective, observational, multicentre, international cohort study.

The pupillary examination is an important part of the neurological assessment, especially in the setting of acutely brain-injured patients, and pupillary abnormalities are associated with poor outcomes. Currently, the pupillary examination is based on a visual, subjective and frequently inaccurate estimation. The use of automated infrared pupillometry to measure the pupillary light reflex can precisely quantify subtle changes in pupillary functions. The study aimed to evaluate the association between abnormal pupillary function, assessed by the Neurological Pupil Index (NPi), and long-term outcomes in patients with acute brain injury (ABI). The Outcome Prognostication of Acute Brain Injury using the Neurological Pupil Index study is a prospective, observational study including adult patients with ABI requiring admission at the intensive care unit. We aimed to recruit at least 420 patients including those suffering from traumatic brain injury or haemorrhagic strokes, over 12 months. The primary aim was to assess the relationship between NPi and 6-month mortality or poor neurological outcome, measured by the Extended Glasgow Outcome Score (GOS-E, poor outcome=GOS-E 1-4). Supervised and unsupervised methods and latent class mixed models will be used to identify patterns of NPi trajectories and Cox and logistic model to evaluate their association with outcome. The study has been approved by the institutional review board (Comitato Etico Brianza) on 16 July 2020. Approved protocol V.4.0 dated 10 March 2020. The results of this study will be published in peer-reviewed journals and presented at conferences. NCT04490005

Monitoring Chronic Myeloid Leukemia: How Molecular Tools May Drive Therapeutic Approaches

More than 15 years ago, imatinib entered into the clinical practice as a “magic bullet”; from that point on, the prognosis of patients affected by chronic myeloid leukemia (CML) became comparable to that of aged-matched healthy subjects. The aims of treatment with tyrosine kinase inhibitors (TKIs) are for complete hematological response after 3 months of treatment, complete cytogenetic response after 6 months, and a reduction of the molecular disease of at least 3 logs after 12 months. Patients who do not reach their goal can switch to another TKI. Thus, the molecular monitoring of response is the main consideration of management of CML patients. Moreover, cases in deep and persistent molecular response can tempt the physician to interrupt treatment, and this “dream” is possible due to the quantitative PCR. After great international effort, today the BCR-ABL1 expression obtained in each laboratory is standardized and expressed as “international scale.” This aim has been reached after the establishment of the EUTOS program (in Europe) and the LabNet network (in Italy), the platforms where biologists meet clinicians. In the field of quantitative PCR, the digital PCR is now a new and promising, sensitive and accurate tool. Some authors reported that digital PCR is able to better classify patients in precise “molecular classes,” which could lead to a better identification of those cases that will benefit from the interruption of therapy. In addition, digital PCR can be used to identify a point mutation in the ABL1 domain, mutations that are often responsible for the TKI resistance. In the field of resistance, a prominent role is played by the NGS that enables identification of any mutation in ABL1 domain, even at sub-clonal levels. This manuscript reviews how the molecular tools can lead the management of CML patients, focusing on the more recent technical advances