Prevalence of non-Hodgkin lymphoma patients at high-risk of failure after CAR T-cell therapy eligible for bridging radiation therapy.

Background and purpose: The aim of this study was to determine the prevalence of patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) meeting high-risk criteria for early relapse after CD19 CAR T-cell therapy (CART) who have disease encompassable in a standard radiation therapy (RT) plan (defined as <5 malignant lesions) and may benefit from bridging RT prior to CD19 CART. Materials and methods: This is a single-center, retrospective study of patients with R/R NHL who received CD19 CART from 2018 to 2022. Eligible patients had pre-apheresis radiologic studies available. All patients were classified by number of lesions and history of high-risk disease criteria: bulky disease ≥10 cm, ≥1 extranodal (EN) sites, LDH ≥normal, or ≥1 lesion with SUVmax ≥10. Results: A total of 81 patients with R/R NHL were evaluated. Based on our definition, 40 (49%) patients would have been eligible for bridging RT, including 38 patients who met high-risk criteria: 31 with ≥1 EN site, 19 had ≥1 lesion with SUVmax ≥10, 16 with bulky disease, and 3 with elevated LDH. At 3 months after CART, ORRs in high-risk patients with <5 lesions, ≥5 lesions, and no lesions on pre-apheresis studies were 76% (CR 69%, PR 7%), 70% (CR 60%, PR 10%), and 80% (CR 80%), respectively. Conclusion: Approximately 47% (38/81) of patients were classified as at high risk of relapse after CART with disease encompassable in a standard radiation plan and eligible for bridging RT studies.

Orthostatic testing for heart rate and heart rate variability monitoring in exercise science and practice.

Orthostatic testing, involving the transition from different body positions (e.g., from lying or sitting position to an upright or standing position), offers valuable insights into the autonomic nervous system (ANS) functioning and cardiovascular regulation reflected through complex adjustments in, e.g., measures of heart rate (HR) and heart rate variability (HRV). This narrative review explores the intricate physiological mechanisms underlying orthostatic stress responses and evaluates its significance for exercise science and sports practice. Into this matter, active orthostatic testing (e.g., active standing up) challenges the cardiovascular autonomic function in a different way than a passive tilt test. It is well documented that there is a transient reduction in blood pressure while standing up, leading to a reflex increase in HR and peripheral vasoconstriction. After that acute response systolic and diastolic blood pressures are usually slightly increased compared to supine lying body position. The ANS response to standing is initiated by instantaneous cardiac vagal withdrawal, followed by sympathetic activation and vagal reactivation over the first 25-30 heartbeats. Thus, HR increases immediately upon standing, peaking after 15-20 beats, and is less marked during passive tilting due to the lack of muscular activity. Standing also decreases vagally related HRV indices compared to the supine position. In overtrained endurance athletes, both parasympathetic and sympathetic activity are attenuated in supine and standing positions. Their response to standing is lower than in non-overtrained athletes, with a tendency for further decreased HRV as a sign of pronounced vagal withdrawal and, in some cases, decreased sympathetic excitability, indicating a potential overtraining state. However, as a significant main characteristic, it could be noted that additional pathophysiological conditions consist in a reduced responsiveness or counter-regulation of neural drive in ANS according to an excitatory stimulus, such as an orthostatic challenge. Hence, especially active orthostatic testing could provide additional information about HR(V) reactivity and recovery giving valuable insights into athletes' training status, fatigue levels, and adaptability to workload. Measuring while standing might also counteract the issue of parasympathetic saturation as a common phenomenon especially in well-trained endurance athletes. Data interpretation should be made within intra-individual data history in trend analysis accounting for inter-individual variations in acute responses during testing due to life and physical training stressors. Therefore, additional measures (e.g., psychometrical scales) are required to provide context for HR and HRV analysis interpretation. However, incidence of orthostatic intolerance should be evaluated on an individual level and must be taken into account when considering to implement orthostatic testing in specific subpopulations. Recommendations for standardized testing procedures and interpretation guidelines are developed with the overall aim of enhancing training and recovery strategies. Despite promising study findings in the above-mentioned applied fields, further research, thorough method comparison studies, and systematic reviews are needed to assess the overall perspective of orthostatic testing for training monitoring and fine-tuning of different populations in exercise science and training.

Mega-dose decitabine conditioning and prophylactic donor lymphocyte infusion for patients with relapsed/refractory AML with active disease at the time of allogeneic haematopoietic cell transplantation: A multicenter prospective phase II study.

Patients with relapsed/refractory acute myeloid leukaemia (R/R AML), especially those who failed in novel target agents are related to dismal survival. We developed a multi-institutional, single-arm, prospective phase II trial, to investigate intensified conditioning with 'Mega-Dose' decitabine (MegaDAC) following allogeneic haematopoietic cell transplantation (allo-HCT) for R/R AML. From 2019 to 2023, 70 heavily treated R/R AML patients in active disease were consecutively enrolled. Significantly, every patient (n = 18) harbouring specific mutations exhibited no response to their best available target agents (BATs). Moreover, 74.3% of the enrolled patients did not reach remission following venetoclax-based regimens. All patients underwent intravenous decitabine (400 mg/m2) along with busulfan and cyclophosphamide. Median follow-up was 26 months (8-65) after HCT. All engrafted patients achieved MRD negativity post-HCT, with a median 3.3-log reduction in recurrent genetic abnormalities. The regimen was well tolerated, without irreversible grades III-IV toxicity peri-engraftment. The estimated 2-year CIR was 29.6% (18.4%-41.7%) and the est-2-year NRM was 15.5% (7.8%-25.5%). The est-2-year LFS, OS, and GRFS were 55.0% (43.5%-69.4%), 58.6% (47.0%-73.0%), and 42.9% (31.9%-57.6%), respectively. Multivariate analysis showed that pre-HCT drug exposures had no significant impact on primary outcomes. MegaDAC is highlighted as an effective and safe option for R/R AML in the new era of targeted therapies.

High production of enantiopure (R,R)-2,3-butanediol from crude glycerol by Klebsiella pneumoniae with an engineered oxidative pathway and a two-stage agitation strategy.

BACKGROUND: (R,R)-2,3-butanediol (BDO) is employed in a variety of applications and is gaining prominence due to its unique physicochemical features. The use of glycerol as a carbon source for 2,3-BDO production in Klebsiella pneumoniae has been limited, since 1,3-propanediol (PDO) is generated during glycerol fermentation. RESULTS: In this study, the inactivation of the budC gene in K. pneumoniae increased the production rate of (R,R)-2,3-BDO from 21.92 ± 2.10 to 92.05 ± 1.20%. The major isomer form of K. pneumoniae (meso-2,3-BDO) was shifted to (R,R)-2,3-BDO. The purity of (R,R)-2,3-BDO was examined by agitation speed, and 98.54% of (R,R)-2,3-BDO was obtained at 500 rpm. However, as the cultivation period got longer, the purity of (R,R)-2,3-BDO declined. For this problem, a two-step agitation speed control strategy (adjusted from 500 to 400 rpm after 24 h) and over-expression of the dhaD gene involved in (R,R)-2,3-BDO biosynthesis were used. Nevertheless, the purity of (R,R)-2,3-BDO still gradually decreased over time. Finally, when pure glycerol was replaced with crude glycerol, the titer of 89.47 g/L of (R,R)-2,3-BDO (1.69 g/L of meso-2,3-BDO), productivity of 1.24 g/L/h, and yield of 0.35 g/g consumed crude glycerol was achieved while maintaining a purity of 98% or higher. CONCLUSIONS: This study is meaningful in that it demonstrated the highest production and productivity among studies in that produced (R,R)-2,3-BDO with a high purity in Klebsiella sp. strains. In addition, to the best of our knowledge, this is the first study to produce (R,R)-2,3-BDO using glycerol as the sole carbon source.

Rhodium-Catalyzed Enantioselective Intramolecular Hydroalkoxylation of Allenes and Application in the Total Synthesis of (R,R,R)-α-Tocopherol.

We report herein of a novel, enantioselective and rhodium- catalyzed cyclisation of allenyl alcohols towards chiral α-vinylic, cyclic ethers employing a rhodium/(R,R)-Me-ferrocelane catalyst. The corresponding chiral cyclic products were obtained in general high yields and enantioselectivities. The synthetic value of our obtained products was further exemplified by transformations of the allylic ether function. Furthermore, applying our newly developed method in our previously reported route towards the total synthesis of (R,R,R)-α-tocopherol, we accomplished a significantly improved 2nd generation synthesis of the chromane building providing a total number of 13 steps and an overall total yield of 27 %.

Exploring quantitative indices to characterize piano timbre with precision validated using measurement system analysis.

Aim: Timbre in piano performance plays a critical role in enhancing musical expression. However, timbre control in current piano performance education relies mostly on descriptive characterization, which involves large variations of interpretation. The current study aimed to mitigate the limitations by identifying quantitative indices with adequate precision to characterize piano timbre. Methods: A total of 24 sounds of G6 were recorded from 3 grand pianos, by 2 performers, and with 4 repetitions. The sounds were processed and analyzed with audio software for the frequencies and volumes of harmonic series in the spectrum curves. Ten quantitative timbre indices were calculated. Precision validation with statistical gage R&R analysis was conducted to gage the repeatability (between repetitions) and reproducibility (between performers) of the indices. The resultant percentage study variation (%SV) of an index must be ≤10% to be considered acceptable for characterizing piano timbre with enough precision. Results: Out of the 10 indices, 4 indices had acceptable precision in characterizing piano timbre with %SV ≤10%, including the square sum of relative volume (4.40%), the frequency-weighted arithmetic mean of relative volume (4.29%), the sum of relative volume (3.11%), and the frequency-weighted sum of relative volume (2.09%). The novel indices identified in the current research will provide valuable tools to advance the measurement and communication of timbre and advance music performance education.

Real-World Evidence of Relapsed/Refractory Mantle Cell Lymphoma Patients and Treatments: A Systematic Review.

Introduction: Mantle cell lymphoma (MCL) is an incurable disease with an aggressive clinical course, and most patients eventually relapse after chemotherapy. Targeted therapies developed for relapsed/refractory MCL have been approved based on clinical trial data. However, real-world setting data are scarce and scattered. Areas Covered: This systematic review aimed to collect, synthesize, and describe the characteristics and treatment outcomes of patients with relapsed/refractory MCL after receiving a second or subsequent line of therapy in the real-world setting. Expert Opinion: R/R MCL is clinically and biologically heterogeneous and still represents a therapeutic challenge, with high-risk and early relapsed patients remaining an unmet medical need. This systematic review is limited by the quality of the available data and the difficulty of comparing outcomes in R/R MCL due to the heterogeneity of the disease, but the results suggest that covalent BTKis should be positioned as second-line therapy, followed by CAR T-cells in BTK-i-relapsed patients. Chemo-free and combination therapies with established chemoimmunotherapy backbones in the relapsed and front-line settings have been recently developed, and front-line options are being improved to move targeted and cellular therapies to earlier lines, including front-line therapy, in elderly and younger fit patients. In the upcoming years, many new targeted agents will play an important role and will be incorporated to the routine practice as their sequence, and outcomes in unselected patients are determined.

Discovery of bitter masking compounds from Allspice (Pimenta dioica) using sensory guided isolation.

Bitter substances in functional foods and beverages can act as nutraceuticals, offering potential health benefits. However, their unpleasant sensory impact reduces the consumption of these foods. Consequently, the discovery of bitter masking compounds is crucial for enhancing the intake of bioactive compounds in functional foods and beverages. Bitter taste is mediated by TAS2Rs, a sub-family of G-protein-coupled receptors. TAS2R14 is especially pivotal in the perception of bitterness, as it is one of the most broadly tuned bitter receptors. In this study, allspice was extracted and purified to yield five single compounds based on sensory guided fractionation. The structures of each compound were determined based on nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HR-MS). In a sensory evaluation, compound 1 exhibited bitter masking activity against quinine. Molecular docking analysis revealed that compound 1 could act as an antagonist of the TAS2R14 bitter receptor.

Rituximab potentially improves clinical outcomes of CAR-T therapy for r/r B-ALL via sensitizing leukemia cells to CAR-T-mediated cytotoxicity and reducing CAR-T exhaustion.

PURPOSE: Despite chimeric antigen receptor (CAR) T-cell therapy has achieved great advances in recent year, approximately 50% of relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) patients treated with CAR-T experience relapse 6 months post CAR-T treatment. CD20 express on 30 to 50% of B-ALL, which makes CD20 Monoclonal Antibody as one of the potential therapy strategies to decrease the tumor burden and improve the efficacy of CAR-T therapy. Adding Rituximab to chemotherapy protocol had been demonstrated to improve the outcome for CD20-positive ALL. However, rare study explored the influence of Rituximab combined with CAR-T therapy. METHODS: We retrospectively analyzed 20 r/r B-ALL patients who received CAR-T therapy, all of whom had failed multiple lines of therapy. Before CAR-T infusion, we administered Rituximab to 10 patients with high CD20 expression at a dose of 375 mg/m2 for 1 day. Meanwhile, we selected 10 patients with the comparable features who underwent CAR-T treatment without Rituximab in the same period as the control group. In vitro, the surface molecule expression and killing of CAR-T post Rituximab-treated B-ALL cells co-incubated with CAR-T cells were detected by flow cytometry. RESULTS: The median follow-up of Rituximab and Control groups were 29.27 and 9.83 months. We found that adding Rituximab may confer a favorable prognosis compared with Control group. The 2-year overall survival (OS) and leukemia-free survival (LFS) rates both were longer in the Rituximab group (90% vs. 26.7%, p = 0.0342; 41.7% vs. 25%, p = 0.308). In vitro, we observed that Rituximab-treated tumour cells are more sensitive to CAR-T killing and a broad range of cytokines and chemokines were produced when Rituximab-treated Nalm-6 cells co-cultured with 19-22CAR-T cells, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). To investigate whether Rituximab has an effect on CAR-T persistence, we stimulated CAR-T cells repeatedly in vitro with Rituximab-treated Nalm-6 to evaluate the changes in CAR-T surface exhaustion molecules at different times. We found that the expression of exhaustion molecules (LAG-3, PD-1, TIM-3) on CAR-T cells were significantly lower in the Rituximab group than in the Control group. CONCLUSION: Rituximab combined with CAR-T therapy is effective for improving the long-term prognosis of B-ALL patients who have failed multiple lines of therapy. In vitro, we observed that rituximab potentially improves CAR-T efficacy by sensitizing ALL to CART-mediated cytotoxicity and reducing CAR-T exhaustion.

Optimizing Real-World Outcomes in High-Risk Relapsed/Refractory (r/r) FL with CAR-T Cell Therapy: A Vodcast and Case Example.

Follicular lymphoma (FL) is often considered a chronic disease with frequent relapses, shortening both response duration and survival after every relapse. Selecting the most appropriate therapy at the right time within the treatment timeline is key to optimize outcomes. The aim of this vodcast, featuring Dr. Kai Hübel, is to outline the severity of FL by referring to a patient case as well as highlight chimeric antigen receptor (CAR)-T cells as an effective therapy in relapsed/refractory (r/r) FL. The patient was in their early 50s, diagnosed with FL in the early 2010s and presented with a third relapse. The patient complained of night sweats and fatigue but was still capable of self-care (Eastern Cooperative Oncology Group Performance Status Scale 2). The patient received eight cycles of rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP), followed by irradiation and rituximab maintenance (first-line) and then received rituximab 4 × weekly, followed by rituximab maintenance (second-line). The patient relapsed during rituximab maintenance; the patient was rituximab refractory. The patient received six cycles of bendamustine/obinutuzumab followed by obinutuzumab maintenance. The patient relapsed during obinutuzumab maintenance, achieved a partial remission after irradiation and was switched to R/lenalidomide. Due to several high-risk features, CAR-T cell therapy was initiated. Dr. Hubel underlines how earlier treatment with CAR-T cell therapy would have been beneficial for this patient. Results of the ELARA trial as well as comparative studies have shown tisagenlecleucel to be more effective than standard of care in extensively pretreated r/r FL, including high-risk patients. In conclusion, CAR-T cell therapy is a promising therapy option for patients with multiply r/r FL. A vodcast feature is available for this article.

Efficacy and Safety of Children With Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia After Anti-CD19 CAR T-Cell Therapy Without Bridging Transplantation.

BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapies have demonstrated significant efficacy in achieving complete remission (CR) in pediatric patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, a considerable number of patients experience relapse within 1 year after CAR T-cell therapy, leading to an extremely poor prognosis, particularly in patients without bridging transplantation. MATERIALS AND METHODS: In our study, we investigated 42 children with R/R B-ALL who underwent anti-CD19 CAR T-cell therapy without bridging transplantation at our center. All patients were included in the response analysis and evaluated for survival and toxicity. RESULTS: The cohort that received the CAR T-cell infusion exhibited a 100% CR rate by day 28 (d28). The overall survival (OS) at 4 years was 61.3% ± 8.5%, and the event-free survival (EFS) was 55.9% ± 7.9%, with a median follow-up duration of 50.1 months. Minimal residual disease (MRD) ≥1% was associated with inferior outcomes, resulting in lower 4-year OS (P = .033) and EFS (P = .014) compared to MRD<1%. The incidences of grade ≥3 cytokine release syndrome (CRS) and neurotoxicity were 26.8% and 23.8%, respectively. Furthermore, MRD≥1% was identified as an independent factor associated with increased severity of CRS and occurrence of neurotoxicity. CONCLUSION: These findings suggest that reducing the pre-infusion MRD could serve as an effective treatment strategy to enhance the outcomes of CAR T-cell therapy.

CD19-Specific CAR-T Cell Treatment of 115 Children and Young Adults with Acute B Lymphoblastic Leukemia: Long-term Follow-up.

PURPOSE: Chemotherapy has been the primary treatment for patients with B-cell acute lymphoblastic leukemia (B-ALL). However, there are still patients who are not sensitive to chemotherapy, including those with refractory/relapse (R/R) disease and those experiencing minimal residual disease (MRD) re-emergence. Chimeric antigen receptor-T lymphocytes (CAR-T) therapy may provide a new treatment option for these patients. MATERIALS AND METHODS: Our institution conducted a single-arm prospective clinical trial (ChiCTR-OPN-17013507) using CAR-T-19 to treat R/R B-ALL and MRD re-emergent patients. One hundred and fifteen patients, aged 1-25 years (median age, 8 years), were enrolled, including 67 R/R and 48 MRD re-emergent CD19-positive B-ALL patients. RESULTS: All patients achieved morphologic complete remission (CR), and within 1 month after infusion, 111 out of 115 (96.5%) patients achieved MRD-negative CR. With a median follow-up time of 48.4 months, the estimated 4-year leukemia-free survival (LFS) rate and overall survival (OS) rate were 68.7%±4.5% and 70.7%±4.3%, respectively. There were no significant differences in long-term efficacy observed among patients with different disease statuses before infusion (4-year OS: MRD re-emergence vs. R/R B-ALL, 70.6%±6.6% vs. 66.5%±6.1%, p=0.755; 4-year LFS: MRD re-emergence vs. R/R B-ALL, 67.3%±7.0% vs. 63.8%±6.2%, p=0.704). R/R B-ALL patients bridging to transplantation after CAR-T treatment had a superior OS and LFS compared to those who did not. However, for MRD re-emergent patients, there was no significant difference in OS and LFS, regardless of whether they underwent hematopoietic stem cell transplantation or not. CONCLUSION: CD19 CAR-T therapy effectively and safely cures both R/R B-ALL and MRD re-emergent patients.

Simplified electrophysiological approach combining a point-of-care nerve conduction device and an electrocardiogram produces an accurate diagnosis of diabetic polyneuropathy.

AIMS/INTRODUCTION: This study aimed to investigate the diagnostic potential of two simplified tests, a point-of-care nerve conduction device (DPNCheck™) and a coefficient of variation of R-R intervals (CVR-R), as an alternative to traditional nerve conduction studies for the diagnosis of diabetic polyneuropathy (DPN) in patients with diabetes. MATERIALS AND METHODS: Inpatients with type 1 or type 2 diabetes (n = 167) were enrolled. The study population consisted of 101 men, with a mean age of 60.8 ± 14.8 years. DPN severity was assessed using traditional nerve conduction studies, and differentiated based on Baba's classification (BC). To examine the explanatory potential of variables in DPNCheck™ and CVR-R regarding the severity of DPN according to BC, a multiple regression analysis was carried out, followed by a receiver operating characteristic analysis. RESULTS: Based on BC, 61 participants (36.5% of the total) were categorized as having DPN severity of stage 2 or more. The multiple regression analysis yielded a predictive formula with high predictive power for DPN diagnosis (estimated severity of DPN in BC = 2.258 - 0.026 × nerve conduction velocity [m/s] - 0.594 × ln[sensory nerve action potential amplitude (µV)] + 0.528In[age(years)] - 0.178 × ln[CVR-R], r = 0.657). The area under the curve in receiver operating characteristic analysis was 0.880. Using the optimal cutoff value for DPN with severer than stage 2, the predictive formula showed good diagnostic efficacy: sensitivity of 83.6%, specificity of 79.2%, positive predictive value of 51.7% and negative predictive value of 76.1%. CONCLUSIONS: These findings suggest that DPN diagnosis using DPNCheck™ and CVR-R could improve diagnostic efficiency and accessibility for DPN assessment in patients with diabetes.

Evaluation of therapeutic effect and prognostic value of 18F-FDG PET/CT in different treatment nodes of DLBCL patients.

BACKGROUND: In the present study, we aimed to investigate the role of baseline (B), interim (I) and end-of-treatment (Eot) 18F-FDG PET/CT in assessing the prognosis of diffuse large B cell lymphoma (DLBCL), so as to identify patients who need intensive treatment at an early stage. METHODS: A total of 127 DLBCL patients (62 men; 65 women; median age 62 years) were retrospectively analyzed in this study. Baseline (n = 127), interim (n = 127, after 3-4 cycles) and end-of-treatment (n = 53, after 6-8 cycles) PET/CT images were re-evaluated; semi-quantitative parameters such as maximum standardized uptake value of lesion-to-liver ratio (SUVmax(LLR)) and lesion-to-mediastinum ratio (SUVmax(LMR)), total metabolic tumor volume (TMTV) and total metabolic tumor volume (TLG) were recorded. ΔTLG1 was the change of interim relative to baseline TLG (I to B), ΔTLG2 (Eot to B). ΔSUVmax and ΔTMTV were the same algorithm. The visual Deauville 5-point scale (D-5PS) has been adopted as the major criterion for PET evaluation. Visual analysis (VA) and semi-quantitative parameters were assessed for the ability to predict progression-free survival (PFS) and overall survival (OS) by using Kaplan-Meier method, cox regression and logistic regression analysis. When visual and semi-quantitative analysis are combined, the result is only positive if both are positive. RESULTS: At a median follow-up of 34 months, the median PFS and OS were 20 and 32 months. The survival curve analysis showed that advanced stage and IPI score with poor prognosis, ΔSUVmax(LLR)1 < 89.2%, ΔTMTV1 < 91.8% and ΔTLG1 < 98.8%, ΔSUVmax(LLR)2 < 86.4% were significantly related to the shortening of PFS in patient (p < 0.05). ΔSUVmax(LLR)1 < 83.2% and ΔTLG1 < 97.6% were significantly correlated with the shortening of OS in patients (p < 0.05). Visual analysis showed that incomplete metabolic remission at I-PET and Eot-PET increased the risk of progress and death. In terms of predicting recurrence by I-PET, the combination of visual and semi-quantitative parameters showed higher positive predictive value (PPV) and specificity than a single index. CONCLUSION: Three to four cycles of R-CHOP treatment may be a time point for early prediction of early recurrence/refractory (R/R) patients and active preemptive treatment. Combined visual analysis with semi-quantitative parameters of 18F-FDG PET/CT at interim can improve prognostic accuracy and may allow for more precise screening of patients requiring early intensive therapy.

Outcomes of allogeneic hematopoietic stem cell transplantation in R/R DLBCL patients with failure of CAR-T therapy.

From October 2017 to June 2022, we retrospectively report outcomes of R/R DLBCL patients with failure of CAR-T therapy, then receiving allo-HSCT. Among 10 patients, 5 were males and 5 females, with a median age of 43.5 (27-52) years. All patients were diagnosed refractory/relapsed diffuse large B cell lymphoma. The median time from CAR-T treatment to transplantation was 84.5 (31-370) days. The median follow-up was 21 (3-69) months. 5/10 patients attained CR and 1/10 patient attained PR during the follow up. The objective response rate (ORR) was 60%. The 1-year overall survival (OS) and progression-free survival (PFS) were 70% and 40%, respectively. At the time of the analysis, 6 patients were still living. During the follow up, four patients have died and the causes were disease relapses and progressions (2 patients), acute renal failure (1 patient), severe pulmonary infection (1 patient). Non-relapse was 20.0%.

A new R,R-RvD6 isomer with protective actions following corneal nerve injury.

The transparent cornea is the most densely innervated tissue in the body, primarily by sensory nerves originating from the trigeminal ganglia (TG). Damage to corneal nerves reduces sensitivity and tear secretion and results in dry eye. Consequently, ocular pain, for which no satisfactory therapies exist, arises in many cases. Treatment of injured corneas with pigment epithelium-derived factor (PEDF) combined with docosahexaenoic acid (DHA) stimulates nerve regeneration in models of refractive surgery, which damages nerves. The mechanism involves the synthesis of a stereoisomer of resolvin D6 (R,R-RvD6) formed after incorporating DHA into membrane lipids. Activation of a PEDF receptor (PEDF-R) with phospholipase activity releases DHA to synthesize the new resolvin isomer, which is secreted via tears. Topical treatment of mice corneas with R,R-RvD6 shows higher bioactivity in regenerating nerves and increasing sensitivity compared to PEDF+DHA. It also stimulates a transcriptome in the TG that modulates genes involved in ocular pain. Our studies suggest an important therapeutic role for R,R-RvD6 in regenerating corneal nerves and decreasing pain resulting from dry eye.

Cell-Engineered Recombinant α-Synuclein: A Gage R&R Validated Protocol.

α-Synuclein (α-Syn) misfolding and its presence in Lewy bodies are observed in almost all Parkinson's disease (PD) patients. Basic biomedical research would benefit from a quick, low-cost approach to purifying α-Syn and developing in vitro and in vivo models for PD. Several research groups utilize PFF-based models, yet the production of α-Syn PFFs is inconsistent, resulting in nonconclusive findings. Some research laboratories prepare recombinant α-Syn (r α-Syn) by molecular cloning to overexpress α-Syn with various purifying techniques. Laboratory-to-laboratory protocols cause considerable variability and sometimes contradictory findings. PD researchers spend more on protein than solving α-Syn's riddles. This article uncovered a novel method for expressing and purifying r α-Syn validated through gage reproducibility and repeatability (Gage R&R). For the production of r α-Syn, we have employed the ability of a high-cell-density-based expression system to overexpress protein in BL21(DE3). A simple, high-throughput, nonchromatographical purification protocol has been devised to facilitate research with higher reproducibility, which was validated through Gage R&R. A crossover experimental design was utilized, and the purified protein was characterized using orthogonal high-end analytical methods, which displayed higher similarity between the isolated r α-Syn. Batch-to-batch variability was the least for produced protein and hence can be utilized for exploring the iceberg of PD.

Metabolic parameters predict survival and toxicity in chimeric antigen receptor T-cell therapy-treated relapsed/refractory large B-cell lymphoma.

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for patients with relapsed/refractory large B-cell lymphoma (LBCL). However, data available concerning the impact of the prognostic value of quantitative 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) parameters on the CAR T-related outcomes and toxicities are limited. Therefore, we aimed to evaluate the predictive value of pre- and post-CAR T metabolic parameters on survival and toxicities following CAR T-cell therapy. Fifty-nine patients with PET/CT scans done pre-and post-CAR T infusion were retrospectively identified and analyzed in a single institution database of LBCL patients treated with commercial CD19-targeted CAR T-cell therapy. The median follow-up was 10.7 months [interquartile range (IQR): 2.6-25.5 months]. The overall response (complete response-CR and partial response) and CR rates post-CAR T were 76% (n = 45) and 53% (n = 31), respectively. On univariate analysis, low pre-CAR T total lesion glycolysis (TLG) and metabolic tumor volume (MTV) predicted improved overall response post-CAR T (OR = 4.7, p = 0.01, OR = 9.5, p = 0.03, respectively) and CR post-CAR T (OR = 12.4, p = 0.0004, OR = 10.9, p = 0.0001, respectively). High TLG pre-CAR T was correlated with cytokine release syndrome (CRS, OR = 3.25, p = 0.04). High MTV pre-CAR T was correlated with developing immune effector cell neurotoxicity syndrome (ICANS) events (OR = 4.3, p = 0.01), and high SUV pre-CAR T was associated with grade 3-4 neurological events (OR = 12, p = 0.01). High MTV/TLG/SUVmax post-CAR T were significantly associated with inferior Overall survival (OS). On multivariate analysis, high TLG pre-CAR T (HR = 2.4, p = 0.03), age ≥60 (HR = 2.7, p = 0.03), and bulky disease (≥5 cm) at the time of apheresis (HR = 2.5, p = 0.02) were identified to be independent prognostic factors for inferior PFS. High MTV post-CAR T was identified as the most prognostic factor associated with inferior OS.