Repurposing Kraft black Liquor as Reductant for Enhanced Lithium-Ion Battery Leaching.

The economic advantages of H2 SO4 make it the acid of choice for the hydrometallurgical treatment of waste lithium-ion batteries (LIBs). However, to facilitate the full dissolution of the higher valency metal oxides present in the cathode black mass, a suitable reducing agent is required. Herein, the application of industrial black liquor (BL) obtained from the Kraft pulping for papermaking is investigated as a renewable reducing agent for the enhanced leaching of transition metals from LIB powder with H2 SO4 . The addition of acidified BL to H2 SO4 significantly improved the leaching efficiency for a range of LIB cathode chemistries, with the strongest effect observed for manganese-rich active material. Focusing on NMC111 (LiMnx Coy Niz O2 ) material, a linear correlation between the BL concentration and the leaching yield of Mn was obtained, with the best overall leaching efficiencies being achieved for 2.0 mol L-1 H2 SO4 and 50 vol % of BL at 353 K. A quasi-total degradation of oxygenated and aromatic groups from the BL during NMC111 dissolution was observed after leaching, suggesting that these chemical groups are essential for LIB reduction. Finally, the leached transition metals could be easily recovered by pH adjustment and oxalic acid addition, closing the resource loop and fostering resource efficiency.

Gastroprotective activity and physicochemical analysis of carboxymethylated gum from Anadenanthera colubrina.

Biotechnological advancements require the physicochemical alteration of molecules to enhance their biological efficacy for the effective treatment of gastric ulcers. The study aimed to produce a polyelectrolytic compound from red angico gum (AG) by carboxymethylation, evaluate its physicochemical characteristics and investigate gastric protection against ethanol-induced ulcers. AG and carboxymethylated angico gum (CAG) were characterized by Fourier transform infrared spectroscopy, determination of the degree of substitution and gel permeation chromatography (GPC) and 13C NMR techniques. The results demonstrated that the modification of the polymer was satisfactory, presenting conformational changes e improving the interaction with the gastric mucosa. AG and CAG reduced macroscopic and microscopic damage such as edema, hemorrhage and cell loss caused by exposure of the mucosa to alcohol. Both demonstrated antioxidant activity in vitro, and in vivo, pretreatment with gums led to the restoration of superoxide dismutase and glutathione levels compared to the injured group. Concurrently, the levels of malondialdehyde and nitrite decreased. Atomic force microscopy showed that CAG presented better conformational properties of affinity and protection with the gastric mucosa compared to AG in the acidic pH. Based on our findings, it is suggested that this compound holds promise as a prospective product for future biotechnological applications.

Reusing wastewater from Coffea arabica processing to produce single-cell protein using Candida sorboxylosa: Optimizing of culture conditions.

Coffee is a crop of significant socioeconomic importance, and the reuse of agri-food by-products and biowaste has great potential across several industries. Coffee wastewater (CWW) is a valuable resource containing essential nutrients that can be utilized by Candida sorboxylosa for single-cell protein (SCP) production. This utilization contributes to mitigating the negative impacts of agro-industrial waste. The optimization of culture conditions using the design of experiments (DoE) technique is crucial in understanding the environmental factors influencing metabolite production. In our study, the DoE technique was employed to analyze culture conditions, including room temperature, pH 8.4, agitation at 200 rpm, a headspace of 60% (v/v), and an inoculum of 0.75 DO600nm over 28-h period. This approach resulted in a remarkable SCP yield of 64.4% and dry cell weight (DCW) of 2.26 g/L. It is noteworthy that there is no literature reporting SCP production under alkaline pH conditions in yeast. Interestingly, our work demonstrated that an alkaline pH of 8.4 significantly influenced SCP production by C. sorboxylosa. The DoE technique proved to be an efficient statistical tool for optimizing culture conditions, offering several advantages, such as: (i) conducting cultures at room temperature to minimize unnecessary energy consumption; (ii) reducing the incubation time from 46 to 28 h, thereby enhancing overall productivity; (iii) achieving 1.7-fold increase in SCP yield compared to previous basal production levels.

CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL.

ABSTRACT: CD19-negative relapse is a leading cause of treatment failure after chimeric antigen receptor (CAR) T-cell therapy for acute lymphoblastic leukemia. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral cotransduction with vectors encoding our previously described fast-off rate CD19 CAR (AUTO1) combined with a novel CD22 CAR capable of effective signaling at low antigen density. Twelve patients with advanced B-cell acute lymphoblastic leukemia were treated (CARPALL [Immunotherapy with CD19/22 CAR Redirected T Cells for High Risk/Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia] study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Of 12 patients, 10 (83%) achieved a measurable residual disease (MRD)-negative complete remission at 2 months after infusion. Of 10 responding patients, 5 had emergence of MRD (n = 2) or relapse (n = 3) with CD19- and CD22-expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months, there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95% confidence interval [CI], 41%-91%) at 6 and 12 months. The 6- and 12-month event-free survival rates were 75% (95% CI, 41%-91%) and 60% (95% CI, 23%-84%), respectively. These data suggest dual targeting with cotransduction may prevent antigen-negative relapse after CAR T-cell therapy.

Human metabolism and body composition: prospects for novel studies.

CONTEXT: Most articles on gut microbiota argue the importance of body composition assessment in patients; however, body composition assessments are fragile (ie, with methodological limitations) in the most recent studies. OBJECTIVE: To present two suggestions for further research using the human body composition assessment. METHODS: The methods used in this study are based on a Pinto et al article published in Nutrition Reviews. DATA EXTRACTION: On the basis of data.obtained from the PubMed, SCOPUS, LILACS, and Web of Science databases, Pinto et al provided a current survey of intermittent fasting protocols and an understanding of the outcomes to date in terms of the profile of the intestinal microbiota in obese organisms. DATA ANALYSIS: Of the 82 original articles identified from the databases, 35 were eliminated because of duplication and 32 were excluded for not meeting the inclusion criteria. Two additional articles found in a new search were added, yielding a total of 17 studies to be included in this review. Among the protocols, alternate-day fasting and time-restricted feeding were the most common, and they were shown to have different mechanisms of metabolic signaling. Time-restricted feeding influences body mass control and biochemical parameters by regulating the circadian system and improving satiety control systems by acting on leptin secretion. In contrast, alternate-day fasting leads to a reduction of ±75% of all energy consumption regardless of dietary composition, in addition to promoting hormonal adjustments that promote body mass control. Furthermore, both protocols could remodel the intestinal microbiota by changing the Firmicutes to Bacteroidetes ratio and increasing the abundance of strains such as Lactobacillus spp. and Akkermansia that have a protective effect on metabolism against the effects of body mass gain. CONCLUSION: Changes in adipose tissue (eg, body mass loss, control, gain) should be interpreted via the sum of skinfolds in absolute values, waist perimeter, and patients' body proportionality, because fat is just a fraction of the adipocyte (lipid).

Analysis of anthropometric and physical performance variables in U-17 soccer players.

Introduction: Soccer is considered a multifaceted collective sport, and to reach an elevated level, players must have moderate to high power, good agility, joint flexibility and muscle development. Also, players must be able to generate high torques during fast movements, which implies the development of different capacities, understood as multifactorial preparation. The objective was to analyse the effects of training (aerobic and continuous) on the leg power, fatigue levels, speed, agility, body fat, muscle mass and bone mass of these players. Methods: Seventy-two soccer players, male and under 17, from 4 teams participated. The teams performed 3 times a week training sessions of about 60-90 min each. Informed consent requests were given to their parents for authorisation to participate in this investigation. Data was collected in two different time points, about ten months apart. Specific tests were performed for each variable: the vertical jump with Bosco System for leg power, the T-Test for agility, the linear sprint test for speed and the RAST test for fatigue levels. A precision Tanita scale was used for the anthropometric tests such as body fat, muscle mass and bone mass. Statistical procedures were applied through the Wilcoxon test to compare the two time points of evaluation. Results: Improvements were found between evaluations regarding the level of anthropometric and physical fitness variables. Conclusions: The implemented training improved all the analysed variables with significant statistical values for leg power, speed, bone mass, muscle mass and fat mass.

Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.

Developmental and epileptic encephalopathies (DEEs) are a group of rare childhood disorders characterized by severe epilepsy and cognitive deficits. Numerous DEE genes have been discovered thanks to advances in genomic diagnosis, yet putative molecular links between these disorders are unknown. CDKL5 deficiency disorder (CDD, DEE2), one of the most common genetic epilepsies, is caused by loss-of-function mutations in the brain-enriched kinase CDKL5. To elucidate CDKL5 function, we looked for CDKL5 substrates using a SILAC-based phosphoproteomic screen. We identified the voltage-gated Ca2+ channel Cav2.3 (encoded by CACNA1E) as a physiological target of CDKL5 in mice and humans. Recombinant channel electrophysiology and interdisciplinary characterization of Cav2.3 phosphomutant mice revealed that loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability. Our results thus show that CDD is partly a channelopathy. The properties of unphosphorylated Cav2.3 closely resemble those described for CACNA1E gain-of-function mutations causing DEE69, a disorder sharing clinical features with CDD. We show that these two single-gene diseases are mechanistically related and could be ameliorated with Cav2.3 inhibitors.

Protective effect of alpha-ketoglutarate against water-immersion restraint stress-induced gastric mucosal damage in mice.

Gastric lesions have several aetiologies, among which stress is the most prominent. Therefore, identification of new therapies to prevent stress is of considerable importance. Alpha-ketoglutarate (α-kg) several beneficial effects and has shown promise in combating oxidative stress, inflammation, and premature aging. Thus, this study aimed to evaluate the protective effect of α-kg in a gastric damage model by water-immersion restraint stress (WIRS). Pretreatment with α-kg decreased stress-related histopathological scores of tissue oedema, cell loss, and inflammatory infiltration. The α-kg restored the percentage of type III collagen fibres. Mucin levels were preserved as well as the structure and area of the myenteric plexus ganglia were preserved after pretreatment with α-kg. Myeloperoxidase (MPO) levels and the expression of pro-inflammatory cytokines (TNF-α and IL-1ß) were also reduced following α-kg pretreatment. Decreased levels of glutathione (GSH) in the stress group were restored by α-kg. The omeprazole group was used as standard drug e also demonstrated improve on some parameters after the exposition to WIRS as inflammatory indexes, GSH and mucin. Through this, was possible to observe that α-kg can protect the gastric mucosa exposed to WIRS, preserve tissue architecture, reduce direct damage to the mucosa and inflammatory factors, stimulate the production of type III collagen and mucin, preserve the myenteric plexus ganglia, and maintain antioxidant potential. Due to, we indicate that α-kg has protective activity of the gastric mucosa, demonstrating its ability to prevent damage associated with gastric lesions caused by stress.

Expanding Cervical Cancer Screening in Mozambique: Challenges Associated With Diagnosing and Treating Cervical Cancer.

PURPOSE: Mozambique has one of the highest burdens of cervical cancer globally. Treatment options are few as most women present with advanced disease, and there are limited trained health professionals and health care resources. The objective of this study was to describe the outcomes of women diagnosed with invasive cancer as part of the Mozambican women undergoing cervical cancer screening with human papillomavirus (HPV) testing in conjunction with family planning services (MULHER) study. MATERIALS AND METHODS: Women age 30-49 years were prospectively enrolled in the MULHER study and offered screening with primary HPV testing followed by treatment of screen-positive women with thermal ablation or excision as appropriate. Women with cervical examination findings suspicious for cancer were referred to one of the three gynecologic oncologists in the country. RESULTS: Between January 2020 and January 2023, 9,014 women underwent cervical cancer screening and 30 women were diagnosed with cervical cancer. In this cohort, four patients (13.3%) had early-stage disease, 18 (60.0%) had locally advanced disease, one (3.3%) had distant metastatic disease, and seven (23.3%) did not have staging information available. Five patients (16.6%) died without receiving oncologic treatment, and seven patients (23.3%) are still awaiting treatment. Of the remaining 18 patients, three (17.6%) underwent surgery and four (23.5%) received radiotherapy. Eleven (36.7%) patients received only chemotherapy. CONCLUSION: As cervical screening programs are implemented in low-resource settings, there will likely be an increase in the number of women diagnosed with invasive cervical cancer. Our results in Mozambique demonstrate the need to increase access to advanced surgery, radiation, and palliative care services.

Testing a Model of Care for Patients on Immune Checkpoint Inhibitors Based on Electronic Patient-Reported Outcomes: Protocol for a Randomized Phase II Controlled Trial.

BACKGROUND: Management of severe symptomatic immune-related adverse events (IrAEs) related to immune checkpoint inhibitors (ICIs) can be facilitated by timely detection. As patients face a heterogeneous set of symptoms outside the clinical setting, remotely monitoring and assessing symptoms by using patient-reported outcomes (PROs) may result in shorter delays between symptom onset and clinician detection. OBJECTIVE: We assess the effect of a model of care for remote patient monitoring and symptom management based on PRO data on the time to detection of symptomatic IrAEs from symptom onset. The secondary objectives are to assess its effects on the time between symptomatic IrAE detection and intervention, IrAE grade (severity), health-related quality of life, self-efficacy, and overall survival at 6 months. METHODS: For this study, 198 patients with cancer receiving systemic treatment comprising ICIs exclusively will be recruited from 2 Swiss university hospitals. Patients are randomized (1:1) to a digital model of care (intervention) or usual care (control group). Patients are enrolled for 6 months, and they use an electronic app to complete weekly Functional Assessment of Cancer Therapy-General questionnaire and PROMIS (PROs Measurement Information System) Self-Efficacy to Manage Symptoms questionnaires. The intervention patient group completes a standard set of 37 items in a weekly PROs version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) questionnaire, and active symptoms are reassessed daily for the first 3 months by using a modified 24-hour recall period. Patients can add items from the full PRO-CTCAE item library to their questionnaire. Nurses call patients in the event of new or worsening symptoms and manage them by using a standardized triage algorithm based on the United Kingdom Oncology Nursing Society 24-hour triage tool. This algorithm provides guidance on deciding if patients should receive in-person care, if monitoring should be increased, or if self-management education should be reinforced. RESULTS: The Institut Suisse de Recherche Expérimentale sur le Cancer Foundation and Kaiku Health Ltd funded this study. Active recruitment began since November 2021 and is projected to conclude in November 2023. Trial results are expected to be published in the first quarter of 2024 and will be disseminated through publications submitted at international scientific conferences. CONCLUSIONS: This trial is among the first trials to use PRO data to directly influence routine care of patients treated with ICIs and addresses some limitations in previous studies. This trial collects a wider spectrum of self-reported symptom data daily. There are some methodological limitations brought by changes in evolving treatment standards for patients with cancer. This trial's results could entail further academic discussions on the challenges of diagnosing and managing symptoms associated with treatment remotely by providing further insights into the burden symptoms represent to patients and highlight the complexity of care procedures involved in managing symptomatic IrAEs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05530187; https://www.clinicaltrials.gov/study/NCT05530187. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48386.

Does sentinel node mapping impact morbidity and quality of life in endometrial cancer?

OBJECTIVES: To evaluate the prevalence of post-operative complications and quality of life (QoL) related to sentinel lymph node (SLN) biopsy vs systematic lymphadenectomy in endometrial cancer. METHODS: A prospective cohort included women with early-stage endometrial carcinoma who underwent lymph node staging, grouped as follows: SLN group (sentinel lymph node only) and SLN+LND group (sentinel lymph node biopsy with addition of systematic lymphadenectomy). The patients had at least 12 months of follow-up, and QoL was assessed by European Organization for Research and Treatment of Cervical Cancer Quality of Life Questionnaire 30 (EORTC-QLQ-C30) and EORTC-QLQ-Cx24. Lymphedema was also assessed by clinical evaluation and perimetry. RESULTS: 152 patients were included: 113 (74.3%) in the SLN group and 39 (25.7%) in the SLN+LND group. Intra-operative surgical complications occurred in 2 (1.3%) cases, and all belonged to SLN+LND group. Patients undergoing SLN+LND had higher overall complication rates than those undergoing SLN alone (33.3% vs 14.2%; p=0.011), even after adjusting for confound factors (OR=3.45, 95% CI 1.40 to 8.47; p=0.007). The SLN+LND group had longer surgical time (p=0.001) and need for admission to the intensive care unit (p=0.001). Moreover, the incidence of lymphocele was found in eight cases in the SLN+LND group (0 vs 20.5%; p<0.001). There were no differences in lymphedema rate after clinical evaluation and perimetry. However, the lymphedema score was highest when lymphedema was reported by clinical examination at 6 months (30.1 vs 7.8; p<0.001) and at 12 months (36.3 vs 6.0; p<0.001). Regarding the overall assessment of QoL, there was no difference between groups at 12 months of follow-up. CONCLUSIONS: There was a higher overall rate of complications for the group undergoing systematic lymphadenectomy, as well as higher rates of lymphocele and lymphedema according to the symptom score. No difference was found in overall QoL between SLN and SLN+LND groups.

Radiolabeled Human Serum Albumin Nanoparticles Co-Loaded with Methotrexate and Decorated with Trastuzumab for Breast Cancer Diagnosis.

Breast cancer is a leading cause of cancer-related mortality among women worldwide, with millions of new cases diagnosed yearly. Addressing the burden of breast cancer mortality requires a comprehensive approach involving early detection, accurate diagnosis, effective treatment, and equitable access to healthcare services. In this direction, nano-radiopharmaceuticals have shown potential for enhancing breast cancer diagnosis by combining the benefits of nanoparticles and radiopharmaceutical agents. These nanoscale formulations can provide improved imaging capabilities, increased targeting specificity, and enhanced sensitivity for detecting breast cancer lesions. In this study, we developed and evaluated a novel nano-radio radiopharmaceutical, technetium-99m ([99mTc]Tc)-labeled trastuzumab (TRZ)-decorated methotrexate (MTX)-loaded human serum albumin (HSA) nanoparticles ([99mTc]-TRZ-MTX-HSA), for the diagnosis of breast cancer. In this context, HSA and MTX-HSA nanoparticles were prepared. Conjugation of MTX-HSA nanoparticles with TRZ was performed using adsorption and covalent bonding methods. The prepared formulations were evaluated for particle size, PDI value, zeta (ζ) potential, scanning electron microscopy analysis, encapsulation efficiency, and loading capacity and cytotoxicity on MCF-7, 4T1, and MCF-10A cells. Finally, the nanoparticles were radiolabeled with [99mTc]Tc using the direct radiolabeling method, and cellular uptake was performed with the nano-radiopharmaceutical. The results showed the formation of spherical nanoparticles, with a particle size of 224.1 ± 2.46 nm, a PDI value of 0.09 ± 0.07, and a ζ potential value of -16.4 ± 0.53 mV. The encapsulation efficiency of MTX was found to be 32.46 ± 1.12%, and the amount of TRZ was 80.26 ± 1.96%. The labeling with [99mTc]Tc showed a high labeling efficiency (>99%). The cytotoxicity studies showed no effect, and the cellular uptake studies showed 97.54 ± 2.16% uptake in MCF-7 cells at the 120th min and were found to have a 3-fold higher uptake in cancer cells than in healthy cells. In conclusion, [99mTc]Tc-TRZ-MTX-HSA nanoparticles are promising for diagnosing breast cancer and evaluating the response to treatment in breast cancer patients.

Development of an eHealth-enhanced model of care for the monitoring and management of immune-related adverse events in patients treated with immune checkpoint inhibitors.

PURPOSE: The use of electronic patient-reported outcome (ePRO) data in routine care has been tied to direct patient benefits such as improved quality of care and symptom control and even overall survival. The modes of action behind such benefits are seldom described in detail. Here, we describe the development of a model of care leveraging ePRO data to monitor and manage symptoms of patients treated with immune checkpoint inhibitors. METHODS: Development was split into four stages: (1) identification of an underlying theoretical framework, (2) the selection of an ePRO measure (ePROM), (3) the adaptation of an electronic application to collect ePRO data, and (4) the description of an ePRO-oriented workflow. The model of care is currently evaluated in a bicentric longitudinal randomized controlled phase II trial, the IePRO study. RESULTS: The IePRO model of care is grounded in the eHealth Enhanced Chronic Care Model. Patients are prompted to report symptoms using an electronic mobile application. Triage nurses are alerted, review the reported symptoms, and contact patients in case of a new or worsening symptom. Nurses use the UKONS 24-hour telephone triage tool to issue patient management recommendations to the oncology team. Adapted care coordinating procedures facilitate team collaboration and provide patients with timely feedback. CONCLUSION: This report clarifies how components of care are created and modified to leverage ePRO to enhance care. The model describes a workflow that enables care teams to be proactive and provide patients with timely, multidisciplinary support to manage symptoms.

Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia.

In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists.