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Neurology was consulted and performed an evaluation at bedside the morning after her arrival and obtained further history. Findings Serum laboratory studies Complete white blood count Unremarkable Inflammatory markers Unremarkable Electrolytes Unremarkable Renal function panel Unremarkable Liver function panel Unremarkable 1, 25 dihydroxyvitamin D 44 PCG/mL Vitamin B1 level 113 nMol/L (normal 70–180) Vitamin B6 level 6 mCg/L (normal 5–50) Vitamin B9 level 2.2 ng/mL (normal 2.7–20) Vitamin B12 339 PG/mL (normal 159–931) Methylmalonic acid 0.07 nMol/mL (normal <0.4) Thyroid function tests Normal Comprehensive drug screen (serum and urine) Negative Heavy metal screen Negative HIV 1&2 Ag antibody Nonreactive Rapid plasma reagin Nonreactive Urine study Pregnancy test Negative Lumbar puncture studies Opening pressure 12 cm H2O Cell indices Normal CSF specific oligoclonal bands Negative Autoimmune panels Serum autoantibodies Negative CSF autoantibodies Negative Neurodiagnostic studies CT head without contrast Normal Brain MRI with and without gadolinium Normal Cervical spine MRI with and without gadolinium Normal NCS Normal Electroencephalogram Normal Discussion Although our patient's thiamine level was in the lower limit of normal, we do not have a baseline level prior to her sleeve gastrectomy for comparison. Conflict of Interest The authors declare no conflicts of interest.

Background Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care. Methods Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 10 6 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3. Results After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients ( N  = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients ( N  = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 ( N  = 49) and matched historical controls ( N  = 40) was 25.4 and 5.5 months, respectively. Conclusions These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population. Trial Registration : NCT02614066.

The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small-molecule 6PGD inhibitors Physcion and its derivative S3, shows anticancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase, exhibit non-immune hemolytic anemia upon exposure to aspirin and various antimalarial drugs. Inspired by these clinical observations, we examined the anticancer potential of combined treatment with 6PGD inhibitors and antimalarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to antimalarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel antileukemia treatment without inducing hemolysis.

There is an increasing interest in the use of plant viruses as vehicles for anti-cancer therapy. In particular, the plant virus brome mosaic virus (BMV) and cowpea chlorotic mottle virus (CCMV) are novel potential nanocarriers for different therapies in nanomedicine. In this work, BMV and CCMV were loaded with a fluorophore and assayed on breast tumor cells. The viruses BMV and CCMV were internalized into breast tumor cells. Both viruses, BMV and CCMV, did not show cytotoxic effects on tumor cells in vitro. However, only BMV did not activate macrophages in vitro. This suggests that BMV is less immunogenic and may be a potential carrier for therapy delivery in tumor cells. Furthermore, BMV virus-like particles (VLPs) were efficiently loaded with small interfering RNA (siRNA) without packaging signal. The gene silencing was demonstrated by VLPs loaded with siGFP and tested on breast tumor cells that constitutively express the green fluorescent protein (GPF). After VLP-siGFP treatment, GFP expression was efficiently inhibited corroborating the cargo release inside tumor cells and the gene silencing. In addition, BMV VLP carring siAkt1 inhibited the tumor growth in mice. These results show the attractive potential of plant virus VLPs to deliver molecular therapy to tumor cells with low immunogenic response.

Safety concerns associated with foetal bovine serum (FBS) have restricted its translation into clinics. We hypothesised that platelet lysate (PL) can be utilised as a safe alternative to produce serum-free 3D-engineered skin. PL supported a short-term expansion of fibroblasts, with negligible replication-induced senescence and directed epidermal stratification. PL-expanded fibroblasts were phenotypically separated into three subpopulations of CD90 + FAP + , CD90 + FAP − and CD90 − FAP + , based on CD90 (reticular marker) and FAP (papillary marker) expression profile. PL drove the expansion of the intermediate CD90 +  FAP +  subpopulation in expense of reticular CD90 + FAP − , which may be less fibrotic once grafted. The 3D-engineered skin cultured in PL was analysed by immunofluorescence using specific markers. Detection of ColIV and LMN-511 confirmed basement membrane. K10 confirmed near native differentiation pattern of neo-epidermis. CD29- and K5-positive interfollicular stem cells were also sustained. Transmission and scanning electron microscopies detailed the ultrastructure of the neo-dermis and neo-epidermis. To elucidate the underlying mechanism of the effect of PL on skin maturation, growth factor contents in PL were measured, and TGF-β1 was identified as one of the most abundant. TGF-β1 neutralising antibody reduced the number of Ki67-positive proliferative cells, suggesting TGF-β1 plays a role in skin maturation. Moreover, the 3D-engineered skin was exposed to lucifer yellow on days 1, 3 and 5. Penetration of lucifer yellow into the skin was used as a semi-quantitative measure of improved barrier function over time. Our findings support the concept of PL as a safe and effective serum alternative for bioengineering skin for cell therapies.

Chromium-doped BiYO 3 powders were synthesized by the Pechini method at low temperature between 400 and 800 °C for 1 h. From the XRD results it was observed the coexistence between tetragonal and cubic phases for samples calcined at 400 °C for 1 h. Meanwhile, for samples calcined at 600 and 800 °C, a single cubic phase was observed. The powders consisted of agglomerates of nanocrystals as shown in the SEM and TEM images. The specific surface area was in the order of 3.01–7.74 m 2  g −1 , obtained from BET analysis. The band gap of BiYO 3 and Cr-doped BiYO 3 was < 2.21 eV which corroborates that these materials absorb light in the visible region of the electromagnetic spectrum. The photocatalytic decomposition of oxytetracycline was successfully achieved using Cr-doped BiYO 3 , where the best performance was obtained with BiY 0.98 Cr 0.02 O 3 ceramic powders calcined at 800 °C for 1 h. For this composition the removal of oxytetracycline after 240 min of visible light irradiation was 100% of degradation and 75% of mineralization. The photocatalytic process was driven by the photo-holes, as a negligible production of · OH radicals was observed in tests using scavengers. The photocatalytic activity of the BiY 0.995 Cr 0.005 O 3 and BiY 0.98 Cr 0.02 O 3 materials was corroborated under more realistic conditions, using tap water and trace concentration of the antibiotic. The high stability of the photocatalyst was observed through four consecutive reaction cycles. The results demonstrate that the Cr-doping has clearly improved the catalytic performance of BiYO 3 for degradation of oxytetracycline under visible light irradiation.

In recent years, progress has been made in understanding the pathological, genetic, and molecular heterogeneity of central nervous system (CNS) tumors. However, improvements in risk classification, prognosis, and treatment have not been sufficient. Currently, great importance has been placed to the tumor microenvironment and the immune system, which are very important components that influence the establishment and development of tumors. Toll-like receptors (TLRs) are innate immunite system sensors of a wide variety of molecules, such as those associated with microorganisms and danger signals. TLRs are expressed on many cells, including immune cells and nonimmune cells such as neurons and cancer cells. In the tumor microenvironment, activation of TLRs plays dual antitumoral (dendritic cells, cytotoxic T cells, and natural killer cells activation) and protumoral effects (tumor cell proliferation, survival, and resistance to chemotherapy) and constitutes an area of opportunities and challenges in the development of new therapeutic strategies. Several clinical trials have been carried out, and others are currently in process; however, the results obtained to date have been contradictory and have not led to a definitive position about the use of TLR agonists in adjuvant therapy during the treatment of central nervous system (CNS) tumors. In this review, we focus on recent advances in TLR agonists as immunotherapies for treatment of CNS tumors.

Background Photodynamic therapy is a promising cancer therapy modality but its application for deep-seated tumor is mainly hindered by the shallow penetration of visible light. X-ray-mediated photodynamic therapy (PDT) has gained a major attention owing to the limitless penetration of X-rays. However, substantial outcomes have still not been achieved due to the low luminescence efficiency of scintillating nanoparticles and weak energy transfer to the photosensitizer. The present work describes the development of Y 2.99 Pr 0.01 Al 5 O 12 -based (YP) mesoporous silica coated nanoparticles, multifunctionalized with protoporphyrin IX (PpIX) and folic acid (YPMS@PpIX@FA) for potential application in targeted deep PDT. Results A YP nanophosphor core was synthesized using the sol–gel method to be used as X-ray energy transducer and was then covered with a mesoporous silica layer. The luminescence analysis indicated a good spectral overlap between the PpIX and nanoscintillator at the Soret as well as Q-band region. The comparison of the emission spectra with or without PpIX showed signs of energy transfer, a prerequisite for deep PDT. In vitro studies showed the preferential uptake of the nanocomposite in cancer cells expressing the folate receptor Folr1 , validating the targeting efficiency. Direct activation of conjugated PpIX with UVA in vitro induced ROS production causing breast and prostate cancer cell death indicating that the PpIX retained its activity after conjugation to the nanocomposite. The in vivo toxicity analysis showed the good biocompatibility and non-immunogenic response of YPMS@PpIX@FA. Conclusion Our results indicate that YPMS@PpIX@FA nanocomposites are promising candidates for X-ray-mediated PDT of deep-seated tumors. The design of these nanoparticles allows the functionalization with exchangeable targeting ligands thus offering versatility, in order to target various cancer cells, expressing different molecular targets on their surface.

The biocidal properties of gecko skin and cicada wings have inspired the synthesis of synthetic surfaces decorated with high aspect ratio nanostructures that inactivate microorganisms. Here, we investigate the bactericidal activity of oriented zinc phthalocyanine (ZnPc) nanopillars grown using a simple pencil-drawn graphite templating technique. By varying the evaporation time, nanopillars initiated from graphite that was scribbled using a pencil onto silicon substrates were optimized to yield a high inactivation of the Gram-negative bacteria, Escherichia coli . We next adapted the procedure so that analogous nanopillars could be grown from pencil-drawn graphite scribbled onto stainless steel, flexible polyimide foil, and glass substrates. Time-dependent bacterial cytotoxicity studies indicate that the oriented nanopillars grown on all four substrates inactivated up to 97% of the E. coli quickly, in 15 min or less. These results suggest that organic nanostructures, which can be easily grown on a broad range of substrates hold potential as a new class of biocidal surfaces that kill microbes quickly and potentially, without spreading antibiotic-resistance genes.