Modified R-BAC plus BTK inhibitor regimen in newly diagnosed young patients with mantle cell lymphoma: a real-world retrospective study.

To explore the optimal treatment for young patients with untreated mantle cell lymphoma (MCL), we compared the efficacy and safety of R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/rituximab, dexamethasone, cytarabine and cisplatin) and R-BAP (rituximab, bendamustine, cytarabine, and prednisone) plus BTK (Bruton's tyrosine kinase) inhibitors in newly diagnosed patients. Eighty-three young patients (≤ 65 years old) with newly diagnosed MCL admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2014, to June 1, 2023, using R-CHOP/R-DHAP or R-BAP plus BTK inhibitor were assessed in this study. The median age at presentation was 60 (42-65) years in 83 patients, including 64 males and 19 females; 59 were treated with R-CHOP/R-DHAP regimen chemotherapy, and 24 were treated with R-BAP in combination with the BTK inhibitor regimen. The median follow-up was 17 months (2-86 months) in 83 patients, and the median PFS (progression-free survival) time was not reached. The CRR (complete response rate) of the R-BAP group was higher than that of the R-CHOP/R-DHAP group (87.5% vs. 54.2%, P = 0.005). The ORR (overall response rate) was not significantly different between the two groups (ORR: 91.7% vs. 84.7%, P = 0.497). The PFS (progression-free survival) of the R-BAP group was longer than that of the R-CHOP/R-DHAP group (P = 0.013), whereas OS was not significantly different between the two groups (P = 0.499). The most common adverse effect in both groups was hematotoxicity, with a higher incidence of grade 3-4 lymphopenia and grade 3-4 thrombocytopenia in the R-BAP group than in the R-CHOP/R-DHAP group (P = 0.015 and P = 0.039). Male sex (HR = 4.257, P = 0.013), LDH (lactate dehydrogenase) ≥ 245 U/L (HR = 3.221, P = 0.012), pleomorphic-blastoid (HR = 2.802, P = 0.043) and R-CHOP/R-DHAP regimen (HR = 7.704, P = 0.047) were independent risk factors for PFS. Ki67 ≥ 30% (HR = 8.539, P = 0.005) was an independent risk factor for OS. First-line treatment with R-BAP in combination with BTK inhibitor improved CRR and prolonged PFS in young patients with mantle cell lymphoma and adverse events were tolerable.

Dihydroxyacetone phosphate accumulation leads to podocyte pyroptosis in diabetic kidney disease.

Diabetic kidney disease (DKD) can lead to accumulation of glucose upstream metabolites due to dysfunctional glycolysis. But the effects of accumulated glycolysis metabolites on podocytes in DKD remain unknown. The present study examined the effect of dihydroxyacetone phosphate (DHAP) on high glucose induced podocyte pyroptosis. By metabolomics, levels of DHAP, GAP, glucose-6-phosphate and fructose 1, 6-bisphosphate were significantly increased in glomeruli of db/db mice. Furthermore, the expression of LDHA and PKM2 were decreased. mRNA sequencing showed upregulation of pyroptosis-related genes (Nlrp3, Casp1, etc.). Targeted metabolomics demonstrated higher level of DHAP in HG-treated podocytes. In vitro, ALDOB expression in HG-treated podocytes was significantly increased. siALDOB-transfected podocytes showed less DHAP level, mTORC1 activation, reactive oxygen species (ROS) production, and pyroptosis, while overexpression of ALDOB had opposite effects. Furthermore, GAP had no effect on mTORC1 activation, and mTORC1 inhibitor rapamycin alleviated ROS production and pyroptosis in HG-stimulated podocytes. Our findings demonstrate that DHAP represents a critical metabolic product for pyroptosis in HG-stimulated podocytes through regulation of mTORC1 pathway. In addition, the results provide evidence that podocyte injury in DKD may be treated by reducing DHAP.

Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression.

Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.

Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.

Triosephosphate isomerase deficiency (TPI Df) is a rare, aggressive genetic disease that typically affects young children and currently has no established treatment. TPI Df is characterized by hemolytic anemia, progressive neuromuscular degeneration, and a markedly reduced lifespan. The disease has predominately been studied using invertebrate and in vitro models, which lack key aspects of the human disease. While other groups have generated mammalian Tpi1 mutant strains, specifically with the mouse mus musculus, these do not recapitulate key characteristic phenotypes of the human disease. Reported here is the generation of a novel murine model of TPI Df. CRISPR-Cas9 was utilized to engineer the most common human disease-causing mutation, Tpi1 E105D , and Tpi1 null mice were also isolated as a frame-shifting deletion. Tpi1 E105D/null mice experience a markedly shortened lifespan, postural abnormalities consistent with extensive neuromuscular dysfunction, hemolytic anemia, pathological changes in spleen, and decreased body weight. There is a ∼95% reduction in TPI protein levels in Tpi1 E105D/null animals compared to wild-type littermates, consistent with decreased TPI protein stability, a known cause of TPI Df. This work illustrates the capability of Tpi1 E105D/null mice to serve as a mammalian model of human TPI Df. This work will allow for advancement in the study of TPI Df within a model with physiology similar to humans. The development of the model reported here will enable mechanistic studies of disease pathogenesis and, importantly, efficacy testing in a mammalian system for emerging TPI Df treatments.

Unusually swift response of relapsed Burkitt leukemia to R-DHAP.

Burkitt leukemia (BL) represents a highly aggressive lymphoma characterized by proliferation rates of around 100%, and a frequent spread into the central nervous system. If standard frontline chemotherapy fails, the prognosis is usually dismal, and reports on successful effective salvage therapy strategies for patients with relapsed/refractory BL are scant. Here, we report on a 40-year-old female patient who suffered an early relapse of BL three months after the completion of frontline chemoimmunotherapy. Strikingly, after only one cycle of R-DHAP chemotherapy, the patient showed CR of BL enabling swift transition to a consolidating allogeneic stem cell transplantation. A 40-year-old previously healthy woman presented to the hospital with fatigue and incessant epistaxis, and a diagnosis of BL was made upon histological examination of a bone marrow biopsy. Treatment was initiated according to the GMALL 2002 B-NHL/ALL protocol, which could induce complete molecular remission. Nevertheless, three months after chemotherapy, the patient exhibited BL relapse in the bone marrow, and on Fluorodeoxyglucose (FDG)-PET-imaging. The relapse therapy was started with R-DHAP, and after only one cycle, the patient once again entered complete remission (CR) paving the way for allogeneic stem cell transplantation. Unfortunately, the patient again relapsed five months after transplantation prompting salvage therapy with R-DHAC and the execution of the second stem cell transplantation. However, one month after the second transplantation the patient presented with chemorefractory meningeosis leukemia resulting in the initiation of palliative care treatment. In summary, we report on rapid CR of relapsed BL after a single cycle of rituximab-DHAP. Given a paucity of clinical trials on the treatment of patients with r/r BL, we intend to highlight the potential efficacy of rituximab-DHAP as salvage therapy in those patients.

Dissecting carbon metabolism of Yarrowia lipolytica type strain W29 using genome-scale metabolic modelling.

Yarrowia lipolytica is a widely-used chassis cell in biotechnological applications. It has recently gained extensive research interest owing to its extraordinary ability of producing industrially valuable biochemicals from a variety of carbon sources. Genome-scale metabolic models (GSMMs) enable analyses of cellular metabolism for engineering various industrial hosts. In the present study, we developed a high-quality GSMM iYli21 for Y. lipolytica type strain W29 by extensive manual curation with Biolog experimental data. The model showed a high accuracy of 85.7% in predicting nutrient utilization. Transcriptomics data were integrated to delineate cellular metabolism of utilizing six individual metabolites as sole carbon sources. Comparisons showed that 302 reactions were commonly used, including those from TCA cycle, oxidative phosphorylation, and purine metabolism for energy and material supply. Whereas glycolytic reactions were employed only when glucose and glycerol used as sole carbon sources, gluconeogenesis and fatty acid oxidation reactions were specifically employed when fatty acid, alkane and glycerolipid were the sole carbon sources. Further test of 46 substrates for generating 5 products showed that hexanoate outcompeted other compounds in terms of maximum theoretical yield owing to the lowest carbon loss for energy supply. This newly generated model iYli21 will be a valuable tool in dissecting metabolic mechanism and guiding metabolic engineering of this important industrial cell factory.

Characterization of xanthine oxidase inhibitory activities of phenols from pickled radish with molecular simulation.

Pickled radish is a general source of natural bioactive compounds that include phenols. Here, we used molecular docking, fluorescence quenching, circular dichroism spectroscopy and molecular dynamics simulations to identify potential inhibitors against xanthine oxidase from a library of pickled radish compounds. The most effective compounds were selected for validation through in vitro experiments including enzyme activity inhibition tests, and cell-based assays. Molecular docking results revealed that 2,6-Dihydroxyacetophenone, 4-Hydroxyphenethyl alcohol, and 4-Hydroxybenzaldehyde exhibited significant effects on xanthine oxidase inhibition. Three phenols have varying degrees of inhibition on xanthine oxidase, which is driven by hydrophobic interactions and hydrogen bonds and affects the secondary structure and hydrophobic homeostasis of xanthine oxidase. The stability of xanthine oxidase inhibition by three phenols was analyzed by molecular dynamics simulation. Finally, cellular experiments confirmed that three phenols reduced uric acid levels by inhibiting the xanthine oxidase enzyme activity of BRL 3A cells.

Ibrutinib Associated with Rituximab-Platinum Salt-Based Immunochemotherapy in B-Cell Lymphomas: Results of a Phase 1b-II Study of the LYSA Group.

In the post-rituximab era, patients with relapsed/refractory non-Hodgkin B-cell lymphoma (R/R B-NHL) responding to a platinum salt-based salvage regimen can potentially be cured after intensification followed by autologous stem cell transplantation, with the quality of the response to salvage predicting survival. The Bruton tyrosine kinase inhibitor ibrutinib, given as monotherapy or combined with other molecules, has proven effective in numerous B-cell lymphomas. To evaluate the safety of the combination of ibrutinib, rituximab, dexamethasone, and cytarabine with either cisplatin (R-DHAP) or oxaliplatin (R-DHAOx), we conducted a multicenter Phase 1b-II study in transplant-eligible R/R B-NHL patients, with ibrutinib given using a 3-by-3 dose-escalation design. The combination of R-DHAP and ibrutinib (given from Day 1 to Day 21 of each cycle) was associated with dose-limiting hematological, infectious, and renal toxicities, while we were unable to reach a dose to recommend for Phase II. R-DHAOx could only be combined with a daily dosage of 280 mg ibrutinib when administered continuously. R-DHAP combined with intermittent ibrutinib administration (from Day 5 to Day 18) was found to be highly toxic. On the other hand, when this administration schedule was combined with R-DHAOx, ibrutinib dosing could be increased up to 560 mg but with relevant toxicities. Despite a strong rationale for combining ibrutinib and R-DHAP/R-DHAOx, as both target lymphoma B-cells by different mechanisms, this approach was limited by significant toxicities.

Selection of the mobilization regimen in lymphoma patients: A retrospective cohort study.

BACKGROUND AND OBJECTIVES: Consolidation with autologous stem cell transplantation (ASCT) is recommended for patients with recurrent or refractory lymphoma after salvage chemotherapy. Stem cells which will be used in ASCT are provided by mobilization using granulocyte colony stimulation factor (G-CSF) or chemotherapy plus G-CSF. The aim of this study was to compare the effect of various mobilization regimens on the clinical parameters of lymphoma patients. MATERIALS AND METHODS: Mobilization interventions of lymphoma patients were analysed retrospectively. The patients were divided into 3 groups according to the mobilization method implemented to collect stem cells before ASCT, (Group 1: Salvage chemotherapy plus G-CSF, Group 2: Cyclophosphamide plus G-CSF, Group 3: G-CSF alone). RESULTS: Analysis of CD34+ cell counts of the 3 groups revealed a significant difference (p < 0.001). Although the number of CD34+ cells collected were different, the neutrophil and platelet engraftment of the 3 groups were similar (p > 0.05). Furthermore, the results were similar in the separate analysis of NHL and HL patients. While the mobilization success rate in group 1 was 97.8 %, it was 90.2 % in group 3. This difference showed a certain trend towards statistical significance (p = 0.074). Patients who received DHAP plus G-CSF had a higher CD34+ count, while neutrophil engraftment was shorter than with ESHAP plus G-CSF (p < 0.05). CONCLUSION: Although the success rate of mobilization and number of CD34+ cell collected were higher in the salvage chemotherapy plus G-CSF than G-CSF alone, G-CSF alone group provided similar neutrophil and thrombocyte engraftment in most lymphoma patients.

Combination of Decitabine and a Modified Regimen of Cisplatin, Cytarabine and Dexamethasone: A Potential Salvage Regimen for Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Treatment Failure.

OBJECTIVE: The prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R-DLBCL) after second-line treatment failure is extremely poor. This study prospectively observed the efficacy and safety of decitabine with a modified cisplatin, cytarabine, and dexamethasone (DHAP) regimen in R/R-DLBCL patients who failed second-line treatment. METHODS: Twenty-one R/R-DLBCL patients were enrolled and treated with decitabine and a modified DHAP regimen. The primary endpoints were overall response rate (ORR) and safety. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: ORR reached 50% (complete response rate, 35%), five patients (25%) had stable disease (SD) with disease control rate (DCR) of 75%. Subgroup analysis revealed patients over fifty years old had a higher complete response rate compared to younger patients (P = 0.005), and relapsed patients had a better complete response rate than refractory patients (P = 0.031). Median PFS was 7 months (95% confidence interval, 5.1-8.9 months). Median OS was not achieved. One-year OS was 59.0% (95% CI, 35.5%-82.5%), and two-year OS was 51.6% (95% confidence interval, 26.9%-76.3%). The main adverse events (AEs) were grade 3/4 hematologic toxicities such as neutropenia (90%), anemia (50%), and thrombocytopenia (70%). Other main non-hematologic AEs were grade 1/2 nausea/vomiting (40%) and infection (50%). No renal toxicity or treatment-related death occurred. CONCLUSION: Decitabine with a modified DHAP regimen can improve the treatment response and prognosis of R/R-DLBCL patients with good tolerance to AEs, suggesting this regimen has potential as a possible new treatment option for R/R-DLBCL patients after second-line treatment failure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03579082.

5-Deoxyadenosine Metabolism: More than "Waste Disposal".

5-Deoxyadenosine (5dAdo) is a by-product of many radical SAM enzyme reactions in all domains of life, and an inhibitor of the radical SAM enzymes themselves. Hence, pathways to recycle or dispose of this toxic by-product must exist but remain largely unexplored. In this review, we discuss the current knowledge about canonical and atypical 5dAdo salvage pathways that have been characterized in the last years. We highlight studies that report on how, in certain organisms, the salvage of 5dAdo via specific pathways can confer a growth advantage by providing either intermediates for the synthesis of secondary metabolites or a carbon source for the synthesis of metabolites of the central carbon metabolism. Yet, an alternative recycling route exists in organisms that use 5dAdo as a substrate to synthesize and excrete 7-deoxysedoheptulose, an allelopathic inhibitor of one enzyme of the shikimate pathway, thereby competing for their own niche. Remarkably, most steps of 5dAdo salvage are the result of the activity of promiscuous enzymes. This strategy enables even organisms with a small genome to synthesize bioactive compounds which they can deploy under certain conditions to gain a competitive growth advantage. We conclude emphasizing that, unexpectedly, 5dAdo salvage pathways seem not to be ubiquitously present, raising questions about the fate of such a toxic by-product in those species. This observation also suggests that additional 5dAdo salvage pathways, possibly relying on the activity of promiscuous enzymes, may exist. The future challenge will be to bring to light these "cryptic" 5dAdo recycling pathways.

The presence of 3-hydroxypropionate and 1,3-propanediol suggests an alternative path for conversion of glycerol to Acetyl-CoA.

BACKGROUND: In our recent study using [U-13C3]glycerol, a small subset of hamsters showed an unusual profile of glycerol metabolism: negligible gluconeogenesis from glycerol plus conversion of glycerol to 1,3-propanediol (1,3PDO) and 3-hydroxypropionate (3HP) which were detected in the liver and blood. The purpose of the current study is to evaluate the association of these unusual glycerol products with other biochemical processes in the liver. METHODS: Fasted hamsters received acetaminophen (400 mg/kg; n = 16) or saline (n = 10) intraperitoneally. After waiting 2 h, all the animals received [U-13C3]glycerol intraperitoneally. Liver and blood were harvested 1 h after the glycerol injection for NMR analysis and gene expression assays. RESULTS: 1,3PDO and 3HP derived from [U-13C3]glycerol were detected in the liver and plasma of eight hamsters (two controls and six hamsters with acetaminophen treatment). Glycerol metabolism in the liver of these animals differed substantially from conventional metabolic pathways. [U-13C3]glycerol was metabolized to acetyl-CoA as evidenced with downstream products detected in glutamate and ß-hydroxybutyrate, yet 13C labeling in pyruvate and glucose was minimal (p < 0.001, 13C labeling difference in each metabolite). Expression of aldehyde dehydrogenases was enhanced in hamster livers with 1,3PDO and 3HP (p < 0.05). CONCLUSION: Detection of 1,3PDO and 3HP in the hamster liver was associated with unorthodox metabolism of glycerol characterized by conversion of 3HP to acetyl-CoA followed by ketogenesis and oxidative metabolism through the TCA cycle. Additional mechanistic studies are needed to determine the causes of unusual glycerol metabolism in a subset of these hamsters.

Chronic systemic exposure to IL6 leads to deregulation of glycolysis and fat accumulation in the zebrafish liver.

Inflammation is a constant in Non-Alcoholic Fatty Liver Disease (NAFLD), although their relationship is unclear. In a transgenic zebrafish system with chronic systemic overexpression of human IL6 (IL6-OE) we show that inflammation can cause intra-hepatic accumulation of triglycerides. Transcriptomics and proteomics analysis of the IL6-OE liver revealed a deregulation of glycolysis/gluconeogenesis pathway, especially a striking down regulation of the glycolytic enzyme aldolase b. Metabolomics analysis by mass spectrometry showed accumulation of hexose monophosphates and their derivatives, which can act as precursors for triglyceride synthesis. Our results suggest that IL6-driven repression of glycolysis/gluconeogenesis, specifically aldolase b, may be a novel mechanism for fatty liver. This mechanism may be relevant for NAFLD in lean individuals, an emerging class of NAFLD prevalent more in Asian Indian populations.

Efficacy of Artemether-Lumefantrine on various Plasmodium falciparum Kelch 13 and Pfmdr1 genes isolated in Ghana.

INTRODUCTION: Artemether-Lumefantrine (A-L) remains the drug of choice for the treatment of uncomplicated malaria in Ghana. However, the pharmaco-activity of A-L has not been assessed on various Plasmodium falciparum Kelch 13 and Pfmdr1 genes. Therefore, this study sought to determine the therapeutic efficacy of A-L on P. falciparum parasites isolated from Ghana. METHODS: The clinical study was done in Ga West Municipality, Ghana, where 78 uncomplicated malaria patients were recruited with prior consent. The patients were treated orally with A-L according to national treatment guidelines. Baseline parasitaemia was determined before treatment and 8-hourly parasitaemia posttreatment were determined till initial clearance of parasitaemia and at days 7, 14, 21, and 28. Kelch 13 and Pfmdr1 genes were genotyped by sequencing using baseline samples. Parasite clearance characteristics were determined using Parasite Clearance Estimator beta 0.9 application. RESULTS: Five Kelch 13 (F446I, S466N, R539I, A578S, and A676S) and three Pfmdr1 mutations (N86Y, Y184F and D1246Y) were identified in 78 infected samples. About 8% of the samples contained two Pfmdr1 double mutations (N86Y & D1246Y and Y184F & N86Y). Additionally, three samples (3.8%) were found to contain both Kelch 13 mutations and Pfmdr1 wild type genes. In all patients, parasitaemia persisted within the first 24 h of A-L therapy. However, at hour 40, only two patients were parasitaemic while all patients were aparasitaemic at hour 48. The genotypic profiles of the two persistent parasites at hour 40 were F446I and D1246Y, and R539I, Y184F, and N86Y. The slope half-life of the former was 6.4 h while the latter was 6.9 h and their respective PCT99 were 47.9 h and 49.2 h as well as a clearance rate constants of 0.109 and 0.092 respectively. CONCLUSION: This study reports the effectiveness of A-L on various P. falciparum mutant alleles. However, continuous surveillance of Kelch 13 mutations and Pfmdr1 gene in Ghana and regular assessment of the therapeutic efficacy of A-L and other artemisinin derivatives is recommended.

The impact of overweight on renal toxicity in patients treated with dexamethasone, high-dose cytarabine, and cisplatin.

The combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is used as salvage chemotherapy for relapsed or refractory lymphoma. It includes the administration of cisplatin in a single dose of 100 mg/m2, and renal toxicity is a common adverse event. In this study, we retrospectively analyzed the risk factors for renal toxicity (≥ grade 2) in 74 patients who received DHAP as salvage chemotherapy. Regarding maximal renal toxicities, 38 (51.4%), 6 (8.1%), and 1 (1.4%) patients had grade 2, 3, and 4 toxicities, respectively. Multivariate analyses revealed that overweight (body mass index ≥ 25) was an independent predictive factor for renal toxicity of ≥ grade 2 (odds ratio [OR] 4.08, P = 0.032). A subgroup analysis for patients with diffuse large B cell lymphoma treated with DHAP as second-line therapy (n = 44) confirmed that overweight was an independent risk factor (OR 5.28, P = 0.049). In conclusion, we demonstrated that overweight was an independent risk factor for renal toxicity of ≥ grade 2 in patients who received DHAP. Further clinical studies will be needed to identify a method to decrease renal toxicities after the administration of cisplatin.

Modified DHAP regimen in the salvage treatment of refractory or relapsed lymphomas.

BACKGROUND: The combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is an established salvage regimen for lymphoma patients. We hypothesized that a modified administration schedule for cisplatin and cytarabine results in lower toxicity and improved efficacy. METHODS: We retrospectively analysed 119 patients with relapsed or refractory, aggressive, or indolent B-cell lymphomas, mantle-cell lymphomas, peripheral T-cell lymphomas, or Hodgkin's lymphomas who were treated with the modified DHAP (mDHAP) regimen (dexamethasone 40 mg 15 min-i.v. infusion, days 1-4; cytarabine 2 × 0.5 g/m2 1 h-i.v. infusion, days 1-4; cisplatin 25 mg/m2 24 h-i.v. infusion, days 1-4). Responding and eligible patients underwent stem-cell transplantation. RESULTS: In total, 185 treatment cycles were evaluable. Severe myelosuppression was the main toxicity occurring in 90% of the cycles. Febrile neutropenia or documented infection was found in less than 40%. Two patients died related to treatment (TRM, 1.7%). Nephrotoxicity did not exceed CTC grade 3, which occurred in four cycles only (2.2%). Complete (CR) or partial (PR) responses after mDHAP were documented in 16% and 39% (overall response rate 55%). Harvest of autologous stem cells was successful in 94 (79%) patients and 85 patients (71%) proceeded to stem-cell transplantation. The median overall and progression-free survival was 50.8 and 25.8 months. CONCLUSIONS: An improvement in efficacy could not be observed after modified DHAP regimen; however, manageable toxicity and reduced renal complications suggest further investigation. The study, however, also underlines the need for new concepts in the management of advanced and high-risk lymphomas.

Theoretical Calculations for Highly Selective Direct Heteroarylation Polymerization: New Nitrile-Substituted Dithienyl-Diketopyrrolopyrrole-Based Polymers.

Direct Heteroarylation Polymerization (DHAP) is becoming a valuable alternative to classical polymerization methods being used to synthesize π-conjugated polymers for organic electronics applications. In previous work, we showed that theoretical calculations on activation energy (Ea) of the C⁻H bonds were helpful to rationalize and predict the selectivity of the DHAP. For readers' convenience, we have gathered in this work all our previous theoretical calculations on Ea and performed new ones. Those theoretical calculations cover now most of the widely utilized electron-rich and electron-poor moieties studied in organic electronics like dithienyl-diketopyrrolopyrrole (DT-DPP) derivatives. Theoretical calculations reported herein show strong modulation of the Ea of C⁻H bond on DT-DPP when a bromine atom or strong electron withdrawing groups (such as fluorine or nitrile) are added to the thienyl moiety. Based on those theoretical calculations, new cyanated dithienyl-diketopyrrolopyrrole (CNDT-DPP) monomers and copolymers were prepared by DHAP and their electro-optical properties were compared with their non-fluorinated and fluorinated analogues.

Metabolic engineering pathways for rare sugars biosynthesis, physiological functionalities, and applications-a review.

Biomolecules like rare sugars and their derivatives are referred to as monosaccharides particularly uncommon in nature. Remarkably, many of them have various known physiological functions and biotechnological applications in cosmetics, nutrition, and pharmaceutical industries. Also, they can be exploited as starting materials for synthesizing fascinating natural bioproducts with significant biological activities. Regrettably, most of the rare sugars are quite expensive, and their synthetic chemical routes are both limited and economically unfeasible due to expensive raw materials. On the other hand, their production by enzymatic means often suffers from low space-time yields and high catalyst costs due to hasty enzyme denaturation/degradation. In this context, biosynthesis of rare sugars with industrial importance is receiving renowned scientific attention, across the globe. Moreover, the utilization of renewable resources as energy sources via microbial fermentation or microbial metabolic engineering has appeared a new tool. This article presents a comprehensive review of physiological functions and biotechnological applications of rare ketohexoses and aldohexoses, including D-psicose, D-tagatose, L-tagatose, D-sorbose, L-fructose, D-allose, L-glucose, D-gulose, L-talose, L-galactose, and L-fucose. Novel in-vivo recombination pathways based on aldolase and phosphatase for the biosynthesis of rare sugars, particularly D-psicose and D-sorbose using robust microbial strains are also deliberated.

Recent advances in the synthesis of rare sugars using DHAP-dependent aldolases.

The occurrence rates of non-communicable diseases like obesity, diabetes and hyperlipidemia have increased remarkably due to excessive consumption of a high-energy diet. Rare sugars therefore have become increasingly attractive owing to their unique nutritional properties. In the past two decades, various rare sugars have been successfully prepared guided by the "Izumoring strategy". As a valuable complement to the Izumoring approach, the controllable dihydroxyacetone phosphate (DHAP)-dependent aldolases have generally predictable regio- and stereoselectivity, which makes them powerful tools in C-C bond construction and rare sugar production. However, the main disadvantage for this group of aldolases is their strict substrate specificity toward the donor molecule DHAP, a very expensive and relatively unstable compound. Among the current methods involving DHAP, the one that couples DHAP production from inexpensive starting materials (for instance, glycerol, DL-glycerol 3-phosphate, dihydroxyacetone, and glucose) with aldol condensation appears to be the most promising. This review thus focuses on recent advances in the application of L-rhamnulose-1-phosphate aldolase (RhaD), L-fuculose-1-phosphate aldolase (FucA), and D-fructose-1,6-bisphosphate aldolase (FruA) for rare sugar synthesis in vitro and in vivo, while illustrating strategies for supplying DHAP in efficient and economical ways.