Diagnostic and Therapeutic Particularities of Symptomatic Melanoma Brain Metastases from Case Report to Literature Review.

The recent introduction of immunotherapy and targeted therapy has substantially enriched the therapeutic landscape of metastatic melanoma. However, cerebral metastases remain unrelenting entities with atypical metabolic and genetic profiles compared to extracranial metastases, requiring combined approaches with local ablative treatment to alleviate symptoms, prevent recurrence and restore patients' biological and psychological resources for fighting malignancy. This paper aims to provide the latest scientific evidence about the rationale and timing of treatment, emphasizing the complementary roles of surgery, radiotherapy, and systemic therapy in eradicating brain metastases, with a special focus on the distinct response of intracranial and extracranial disease, which are regarded as separate molecular entities. To illustrate the complexity of designing individualized therapeutic schemes, we report a case of delayed BRAF-mutant diagnosis, an aggressive forearm melanoma, in a presumed psychiatric patient whose symptoms were caused by cerebral melanoma metastases. The decision to administer molecularly targeted therapy was dictated by the urgency of diminishing the tumor burden for symptom control, due to potentially life-threatening complications caused by the flourishing of extracranial disease in locations rarely reported in living patients, further proving the necessity of multidisciplinary management.

Confronting a New Challenge in Plastic Surgery: MDR Infections in Patients with Chronic Wounds.

BACKGROUND: The presence of a wound can be anywhere from non-problematic to life-threatening on a severity spectrum, with bacterial infection and resistance playing a major role in the development of chronicity, delaying wound healing. Wound colonization with multiple organisms and the limited number of effective antibiotics place a heavy burden on the healthcare system, with patients going through multiple surgeries during a prolonged hospitalization time. By analyzing the resistance patterns of pluri-bacterial populations and the approach used in managing complex cases, we aim to improve the protocols applied in caring for chronic wounds in our practice and share our experiences and observations. METHODS: We designed a retrospective study on 212 diabetic and non-diabetic patients, aiming to evaluate the course of chronic wound treatment in our practice. We focused on the impact that MDR bacteria and diabetes have on surgical outcomes and their role in the healing process. RESULTS: Patients who received empiric antibiotic therapy before being admitted eventually presented with multiple MDR bacteria compared to those who did not receive antibiotics (p = 0.014). The presence of at least one MDR bacteria in the wound bed was associated with ulcers reaching bone (p = 0.02) and was positively correlated with the number of surgeries performed (p < 0.001). Diabetes played a significant role in surgery-related complications (p = 0.02) and hospitalization time (p < 0.001). CONCLUSIONS: Proper management of chronic wounds requires a comprehensive, multidisciplinary approach and a thorough understanding of antibiotic usage. To address this need, we have developed and implemented a chronic wound treatment protocol in our clinic, with the goal of discharging patients once their ulcers have been treated and closed. A key summary of the protocol presented is to reduce the incidence of MDR bacteria and improve the patient's quality of life.

Exploring an Innovative Approach: Integrating Negative-Pressure Wound Therapy with Silver Nanoparticle Dressings in Skin Graft Procedures.

BACKGROUND: Skin grafting is a helpful instrument in a plastic surgeon's arsenal. Several types of dressings were designed to facilitate the process of graft integration. Negative-pressure wound therapy is a proven dressing method, enhancing graft survival through several mechanisms: aspiration of secretions, stimulation of neoangiogenesis, and promotion of an anti-inflammatory environment. Silver nanoparticle dressings also bring multiple benefits by bearing an antimicrobial effect and providing a humid medium, which are favorable for epithelialization. The combination of NPWT (negative-pressure wound therapy) with AgNPs (silver nanoparticles) has not been widely studied. MATERIALS AND METHODS: This study aimed to compare the outcomes of silver nanoparticle sheets with the combination of negative-pressure wound therapy and silver nanoparticle dressings. We conducted a comparative prospective study on 80 patients admitted to the Plastic Surgery Department of "Prof. Dr. Agrippa Ionescu" Emergency Clinical Hospital between 1st of January 2020 and 31st of December 2022. The study population was randomized to receive either silver nanoparticle dressings or negative-pressure wound therapy (NPWT) combined with silver nanoparticle dressings. Various parameters were monitored, including patient comorbidities and graft-related data such as defect etiology, graft integration, and graft size. Dressings were changed, and graft status was evaluated at 7, 10, and 14 days postoperatively. Additionally, baseline C-reactive protein (CRP) levels were measured before surgery and 7, 10, and 14 days postoperatively. RESULTS: The study demonstrated an enhanced integration of skin grafts at all evaluation stages when employing NPWT combined with AgNPs, particularly evident 10 days post operation. Significant variations in graft integration were also observed based on factors such as diabetes, cardiovascular disease, graft size, or the origin of the grafted defect. Moreover, dynamic C-reactive protein monitoring showed a statistically significant decrease in CRP levels 10 days post operation among patients treated with NPWT in conjunction with silver dressing, consistent with the nearly complete integration of skin grafts at this evaluation threshold. CONCLUSION: Several factors influence the postoperative evolution of split-skin grafts. Postoperative dressings target local factors to enhance graft integration further. Our research demonstrated that the innovative combination of NPWT-assisted dressings, complemented by a silver nanoparticle sheet, resulted in improved benefits for graft integration and the alleviation of systemic inflammation.

Extremely Rare Type of Breast Cancer-Dedifferentiated Breast Liposarcoma-Diagnosis and Treatment.

Primary liposarcoma of the breast is an uncommon soft tissue malignant tumor, comprising only 0.003% of all malignant breast tumors. The main differential diagnosis of this mass consists of malignant phyllodes tumor and metaplastic breast carcinoma. The objective of this paper is to report a case of dedifferentiated breast liposarcoma, therapeutic approach and outcome. We present a case of a 79-year-old woman complaining of a large mass in her left breast which had increased in size over the last 6 months. Physical examination revealed an enlarged left breast, and a total body CT scan showed a large tumor in contact with the musculature of the anterior thoracic wall, with no metastatic lesions. The histopathology report of a fine needle biopsy described a high-grade sarcoma. The Oncological Tumor Board recommended neoadjuvant radiotherapy sessions and reevaluation by MRI and CT scans. The patient underwent radical mastectomy with latissimus dorsi myo-cutaneous flap reconstruction. The final histopathology diagnosis was a grade 3 dedifferentiated liposarcoma (FNCLCC), with certain response to radiotherapy and positive MDM2, CDK4 markers. The postoperative period was uneventful; 12 months after surgery, the follow-up CT scan showed multiple pulmonary lesions with metastatic characteristics. Liposarcoma is a very rare type of breast cancer, and the most important treatment for breast sarcoma is surgery, the role of axillary lymph node removal, chemotherapy and radiotherapy still being controversial. Considering such cases are scarce and the development of surgical guidelines is difficult, reporting any new case is crucial.

Fabrication and Characterization of Porous Diopside/Akermanite Ceramics with Prospective Tissue Engineering Applications.

Tissue engineering requires new materials that can be used to replace damaged bone parts. Since hydroxyapatite, currently widely used, has low mechanical resistance, silicate ceramics can represent an alternative. The aim of this study was to obtain porous ceramics based on diopside (CaMgSi2O6) and akermanite (Ca2MgSi2O7) obtained at low sintering temperatures. The powder synthesized by the sol-gel method was pressed in the presence of a porogenic agent represented by commercial sucrose in order to create the desired porosity. The ceramic bodies obtained after sintering thermal treatment at 1050 °C and 1250 °C, respectively, were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR) to determine the chemical composition. The open porosity was situated between 32.5 and 34.6%, and the compressive strength had a maximum value of 11.4 MPa for the samples sintered at 1250 °C in the presence of a 20% wt porogenic agent. A cell viability above 70% and the rapid development of an apatitic phase layer make these materials good candidates for use in hard tissue engineering.

Fabrication and Characterisation of Calcium Sulphate Hemihydrate Enhanced with Zn- or B-Doped Hydroxyapatite Nanoparticles for Hard Tissue Restoration.

A composite based on calcium sulphate hemihydrate enhanced with Zn- or B-doped hydroxyapatite nanoparticles was fabricated and evaluated for bone graft applications. The investigations of their structural and morphological properties were performed by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and energy dispersive X-ray (EDX) spectroscopy techniques. To study the bioactive properties of the obtained composites, soaking tests in simulated body fluid (SBF) were performed. The results showed that the addition of 2% Zn results in an increase of 2.27% in crystallinity, while the addition of boron causes an increase of 5.61% compared to the undoped HAp sample. The crystallite size was found to be 10.69 ± 1.59 nm for HAp@B, and in the case of HAp@Zn, the size reaches 16.63 ± 1.83 nm, compared to HAp, whose crystallite size value was 19.44 ± 3.13 nm. The mechanical resistance of the samples doped with zinc was the highest and decreased by about 6% after immersion in SBF. Mixing HAp nanoparticles with gypsum improved cell viability compared to HAp for all concentrations (except for 200 µg/mL). Cell density decreased with increasing nanoparticle concentration, compared to gypsum, where the cell density was not significantly affected. The degree of cellular differentiation of osteoblast-type cells was more accentuated in the case of samples treated with G+HAp@B nanoparticles compared to HAp@B. Cell viability in these samples decreased inversely proportionally to the concentration of administered nanoparticles. From the point of view of cell density, this confirmed the quantitative data.

Prognosis Predictive Markers in Patients with Chronic Obstructive Pulmonary Disease and COVID-19.

Some studies have reported that chronic respiratory illnesses in patients with COVID-19 result in an increase in hospitalization and death rates, while other studies reported to the contrary. The present research aims to determine if a predictive model (developed by combing different clinical, imaging, or blood markers) could be established for patients with both chronic obstructive pulmonary disease (COPD) and COVID-19, in order to be able to foresee the outcomes of these patients. A prospective observational cohort of 165 patients with both diseases was analyzed in terms of clinical characteristics, blood tests, and chest computed tomography results. The beta-coefficients from the logistic regression were used to create a score based on the significant identified markers for poor outcomes (transfers to an intensive care unit (ICU) for mechanical ventilation, or death). The severity of COVID-19, renal failure, diabetes, smoking status (current or previous), the requirement for oxygen therapy upon admission, high lactate dehydrogenase (LDH) and C-reactive protein level (CRP readings), and low eosinophil and lymphocyte counts were all identified as being indicators of a poor prognosis. Higher mortality was linked to the occurrence of renal failure, the number of affected lobes, the need for oxygen therapy upon hospital admission, high LDH, and low lymphocyte levels. Patients had an 86.4% chance of dying if their mortality scores were -2.80 or lower, based on the predictive model. The factors that were linked to a poor prognosis in patients who had both COPD and COVID-19 were the same as those that were linked to a poor prognosis in patients who had only COVID-19.

To Protect or to Kill? Environmental Contingent Self-Worth Moderates Death Prime Effects on Animal-Based Attitudes.

Lifshin et al. found that death primes increased support for killing animals, suggesting that the killing of animals serves a terror management function. The present research adds to this by suggesting that protecting animals can also serve a terror management function when people see such behaviors as culturally valuable. In three studies (N = 765), environmental contingent self-worth (ECSW) moderated the effect of death primes on attitudes toward animals. Attitudes toward animals also mediated the effect of a death prime on increased power-based invulnerability for those with low ECSW and decreased power-based invulnerability for those with high ECSW (Study 3). Finally, we found little support that death primes influenced beliefs regarding human-animal superiority (Study 1 and 2) or similarity (Study 2). Our findings therefore provide partial support for past terror management research and further the understanding regarding how to promote more benevolent human-animal relations.

Composite Fibers Based on Polycaprolactone and Calcium Magnesium Silicate Powders for Tissue Engineering Applications.

The present work reports the synthesis and characterization of polycaprolactone fibers loaded with particulate calcium magnesium silicates, to form composite materials with bioresorbable and bioactive properties. The inorganic powders were achieved through a sol-gel method, starting from the compositions of diopside, akermanite, and merwinite, three mineral phases with suitable features for the field of hard tissue engineering. The fibrous composites were fabricated by electrospinning polymeric solutions with a content of 16% polycaprolactone and 5 or 10% inorganic powder. The physico-chemical evaluation from compositional and morphological points of view was followed by the biological assessment of powder bioactivity and scaffold biocompatibility. SEM investigation highlighted a significant reduction in fiber diameter, from around 3 µm to less than 100 nm after the loading stage, while EDX and FTIR spectra confirmed the existence of embedded mineral entities. The silicate phases were found be highly bioactive after 4 weeks of immersion in SBF, enriching the potential of the polymeric host that provides only biocompatibility and bioresorbability. Moreover, the cellular tests indicated a slight decrease in cell viability over the short-term, a compromise that can be accepted if the overall benefits of such multifunctional composites are considered.

Synthesis and Characterization of Porous Forsterite Ceramics with Prospective Tissue Engineering Applications.

Due to the urgent need to develop and improve biomaterials, the present article proposes a new strategy to obtain porous scaffolds based on forsterite (Mg2SiO4) for bone tissue regeneration. The main objective is to restore and improve bone function, providing a stable environment for regeneration. The usage of magnesium silicate relies on its mechanical properties being superior to hydroxyapatite and, in general, to calcium phosphates, as well as its high biocompatibility, and antibacterial properties. Mg2SiO4 powder was obtained using the sol-gel method, which was calcinated at 800 °C for 2 h; then, part of the powder was further used to make porous ceramics by mixing it with a porogenic agent (e.g., sucrose). The raw ceramic bodies were subjected to two sintering treatments, at 1250 or 1320 °C, and the characterization results were discussed comparatively. The porogenic agent did not influence the identified phases or the samples' crystallinity and was efficiently removed during the heat treatment. Moreover, the effect of the porogenic agent no longer seems significant after sintering at 1250 °C; the difference in porosity between the two ceramics was negligible. When analysing the in vitro cytotoxicity of the samples, the ones that were porous and treated at 1320 °C showed slightly better cell viability, with the cells appearing to adhere more easily to their surface.

Branched polyethyleneimine: CHARMM force field and molecular dynamics simulations.

Polyethyleneimine (PEI), one of the non-viral vectors of great interest for gene delivery, was investigated at all-atom level, with particular emphasis on its branched form. We report the extension of our previously published CHARMM force field (FF) for linear PEI, with parameters optimized specifically for branched configurations. A new residue type for the branch connector is introduced and the charges and bonded parameters are derived from ab initio calculations based on a model polymer. The new FF is validated by extensive molecular dynamics simulations of solvated branched PEIs of various protonation fractions and branch lengths. The gyration radii, end-to-end distances, and diffusion coefficients are compared with results for linear PEIs of similar molecular weights and protonation patterns. Solvated complexes of DNA with (linear/branched) PEI were also investigated to determine favorable attachment conformations. The parametrized atomistic force field is suitable for simulations of PEI with arbitrary branching pattern, protonation, and size, and is expected to provide relevant insights regarding optimal conditions for DNA-PEI complex formation.

Processing of Calcium Magnesium Silicates by the Sol-Gel Route.

In this work, calcium magnesium silicate ceramics were processed through the sol-gel method in order to study the crystalline and morphological properties of the resulting materials in correlation with the compositional and thermal parameters. Tetraethyl orthosilicate and calcium/magnesium nitrates were employed as sources of cations, in ratios specific to diopside, akermanite and merwinite; they were further subjected to gelation, calcination (600 °C) and thermal treatments at different temperatures (800, 1000 and 1300 °C). The properties of the intermediate and final materials were investigated by thermal analysis, scanning electron microscopy, energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction and Rietveld refinement. Such ceramics represent suitable candidates for tissue engineering applications that require porosity and bioactivity.

Investigation of Retinal Microcirculation in Diabetic Patients Using Adaptive Optics Ophthalmoscopy and Optical Coherence Angiography.

The current research approaches the retinal microvasculature of healthy volunteers (17 subjects), patients with diabetes mellitus without retinopathy (19 subjects), and of diabetic patients with nonproliferative (17 subjects) and proliferative (21 subjects) diabetic retinopathy, by using adaptive optics ophthalmoscopy and optical coherence ophthalmoscopy angiography. For each imaging technique, several vascular parameters have been calculated in order to achieve a comparative analysis of these imaging biomarkers between the four studied groups. The results suggest that diabetic patients with or without diabetic retinopathy prove signs of retinal arteriole structural alterations, mainly showed by altered values of wall to lumen ratio, calculated for the superior or inferior temporal branch of the central retinal artery, near the optic nerve head, and significant changes of the vascular density in the retinal superficial capillary plexus. Both adaptive optics ophthalmoscopy and optical coherence ophthalmoscopy angiography are providing useful information about the retinal microvasculature from early onset of diabetic disease, having a promising diagnostic and prognostic role in the future.

Chitosan Functionalized Magnetic Nanoparticles to Provide Neural Regeneration and Recovery after Experimental Model Induced Peripheral Nerve Injury.

(1) Background: Peripheral nerve injuries have a great impact on a patient's quality of life and a generally poor outcome regarding functional recovery. Lately, studies have focused on different types of nanoparticles and various natural substances for the treatment of peripheral nerve injuries. This is the case of chitosan, a natural compound from the crustaceans' exoskeleton. The present study proposes to combine chitosan benefic properties to the nanoparticles' ability to transport different substances to specific locations and evaluate the effects of magnetic nanoparticles functionalized with chitosan (CMNPs) on peripheral nerve injuries' rehabilitation by using an in vivo experimental model. (2) Methods: CMNPs treatment was administrated daily, orally, for 21 days to rats subjected to right sciatic nerve lesion and compared to the control group (no treatment) by analyzing the sciatic functional index, pain level, body weight, serum nerve growth factor levels and histology, TEM and EDX analysis at different times during the study. (3) Results: Animals treated with CMNPs had a statistically significant functional outcome compared to the control group regarding: sciatic functional index, pain-like behavior, total body weight, which were confirmed by the histological and TEM images. (4) Conclusions: The results of the study suggest that CMNPs appear to be a promising treatment method for peripheral nerve injuries.

Wegener's granulomatosis with orbital involvement: case report and literature review.

Objective: To describe the chronology and the extent of orbital involvement in a case of granulomatosis with polyangiitis. Methods: Descriptive case report and literature review. Results: A 45-year-old patient, formerly diagnosed with granulomatosis with polyangiitis due to otorhinolaryngologic manifestations, pulmonary lesions, renal impairment, left knee arthritis and high blood levels of antineutrophil cytoplasmic antibodies, addressed the Ophthalmology Department in November 2020, having the following complaints: left eye mild retro-orbital discomfort, proptosis and epiphora. On examination, Snellen's best corrected visual acuity was 6/ 6 in both eyes. The anterior segment of the left eye displayed significant changes: proptosis, upper lid swelling, ptosis, slightly decreased ocular motility, mild conjunctival hyperemia and chemosis, thinning of sclera in the upper quadrant and mild posterior subcapsular cataract. Left eye funduscopy revealed a slightly elevated optic disc, with indistinct margins in the nasal quadrant. Spectral-domain optical coherence tomography (OCT) of the optic nerve confirmed the clinical findings, illustrating an increase in the retinal nerve fiber layers thickness in the nasal quadrant, with no corresponding visual field defect. The orbit magnetic resonance imaging (MRI) unveiled an intraconal mass surrounding the optic nerve on its entire intra-orbital path, confirming the diagnosis of left orbital granuloma. Conclusion: Considering the relapsing disease and the orbital involvement, the patient is currently a candidate for rituximab, a monoclonal antibody against CD20. Abbreviations: AAV = ANCA associated vasculitides, ANCA = antineutrophil cytoplasmic antibody, AOM = acute otitis media, BCVA = best corrected visual acuity, CRP = C-reactive protein, CT = computerized tomography, EGPA = eosinophilic granulomatosis with polyangiitis, ENT = otorhinolaryngology/ ear-nose-throat, ESR = erythrocyte sedimentation rate, GPA = granulomatosis with polyangiitis, LE = left eye, MPA = microscopic polyangiitis, MRI = magnetic resonance imaging, OCT = optical coherence tomography, RE = right eye, RNFL = retinal nerve fiber layers, TNF = tumor necrosis factor, WG = Wegener's granulomatosis.

Essential Roles of Cohesin STAG2 in Mouse Embryonic Development and Adult Tissue Homeostasis.

Cohesin mediates sister chromatid cohesion and 3D genome folding. Two versions of the complex carrying STAG1 or STAG2 coexist in somatic vertebrate cells. STAG2 is commonly mutated in cancer, and germline mutations have been identified in cohesinopathy patients. To better understand the underlying pathogenic mechanisms, we report the consequences of Stag2 ablation in mice. STAG2 is largely dispensable in adults, and its tissue-wide inactivation does not lead to tumors but reduces fitness and affects both hematopoiesis and intestinal homeostasis. STAG2 is also dispensable for murine embryonic fibroblasts in vitro. In contrast, Stag2-null embryos die by mid-gestation and show global developmental delay and defective heart morphogenesis, most prominently in structures derived from secondary heart field progenitors. Both decreased proliferation and altered transcription of tissue-specific genes contribute to these defects. Our results provide compelling evidence on cell- and tissue-specific roles of different cohesin complexes and how their dysfunction contributes to disease.

Martini Force Field for Protonated Polyethyleneimine.

Polyethyleneimine (PEI), one of the most widely used nonviral gene carriers, was investigated in the presented work at coarse-grained (CG) level. The main focus was on elaborating a realistic CG force field (FF) aimed to reproduce dynamic structural features of protonated PEI chains and, furthermore, to enable massive simulations of DNA-PEI complex formation and condensation. We parametrized CG Martini FF models for PEI in polarizable and nonpolarizable water by applying Boltzmann inversion techniques to all-atom (AA) probability distributions for distances, angles, and dihedrals of entire monomers. The fine-tuning of the FFs was achieved by fitting simulated CG gyration radii and end-to-end distances to their AA counterparts. The developed Martini FF models are shown to be well suited for realistic large-scale simulations of size/protonation-dependent behavior of solvated PEI chains, either individually or as part of DNA-PEI systems. © 2019 Wiley Periodicals, Inc.

Is Scientific Medical Literature Related to Endometriosis Treatment Evidence-Based? A Systematic Review on Methodological Quality of Randomized Clinical Trials.

Background and objectives: Informed decision-making requires the ability to identify and integrate high-quality scientific evidence in daily practice. We aimed to assess whether randomized controlled trials (RCTs) on endometriosis therapy follow methodological criteria corresponding to the RCTs' specific level in the hierarchy of evidence in such details to allow the reproduction and replication of the study. Materials and Methods: Using the keywords "therapy" and "endometriosis" and "efficacy" three bibliographic databases were searched for English written scientific articles published from 1 January 2008 to 3 March 2018. Only the randomized clinical trials (RCTs) were evaluated in terms of whether they provided the appropriate level of scientific evidence, equivalent to level 1, degree 1b in the hierarchy of evidence. A list of criteria to ensure study replication and reproduction, considering CONSORT guideline and MECIR standards, was developed and used to evaluate RCTs' methodological soundness, and scores were granted. Three types of bias, namely selection bias (random sequence generation and allocation concealment), detection bias (blinding of outcome assessment), and attrition bias (incomplete outcome data) were also evaluated. Results: We found 387 articles on endometriosis therapy, of which 38 were RCTs: 30 double-blinded RCTs and 8 open-label RCTs. No article achieved the maximum score according to the evaluated methodological criteria. Even though 73.3% of the double-blinded RCTs had clear title, abstract, introduction, and objectives, only 13.3% provided precise information regarding experimental design and randomization, and also showed a low risk of bias. The blinding method was poorly reported in 43.3% of the double-blinded RCTs, while allocation concealment and random sequence generation were inadequate in 33.3% of them. Conclusions: None of the evaluated RCTs met all the methodological criteria, none had only a low risk of bias and provided sufficient details on methods and randomization to allow for the reproduction and replication of the study. Consequently, the appropriate level of scientific evidence (level 1, degree 1b) could not be granted. On endometriosis therapy, this study evaluated the quality of reporting in RCTs and not the quality of how the studies were performed.

CHARMM force field for protonated polyethyleneimine.

We present a revised version of our previously published atomistic Chemistry at Harvard Macromolecular Mechanics (CHARMM) force field for polyethyleneimine (PEI). It is based on new residue types (with symmetric CNC backbone), whose integer charges and bonded parameters are derived from ab initio calculations on an enlarged set of model polymers. The force field is validated by extensive molecular dynamics simulations on solvated PEI chains of various lengths and protonation patterns. The profiles of the gyration radius, end-to-end distance, and diffusion coefficient fine-tune our previous results, while the simulated diffusion coefficients excellently reproduce experimental findings. The developed CHARMM force field is suitable for realistic atomistic simulations of size/protonation-dependent behavior of PEI chains, either individually or composing polyplexes, but also provides reliable all-atom distributions for deriving coarse-grained force fields for PEI. © 2018 Wiley Periodicals, Inc.

Diacylglycerol Kinase ζ Limits Cytokine-dependent Expansion of CD8+ T Cells with Broad Antitumor Capacity.

Interleukin-2 and -15 drive expansion/differentiation of cytotoxic CD8+ T cells that eliminate targets via antigen-independent killing. This property is clinically relevant for the improvement of T cell-based antitumor therapies. Diacylglycerol kinase α and ζ (DGKα/ζ) metabolize the diacylglycerol generated following antigen recognition by T lymphocytes. Enhanced expression of these two lipid kinases in tumor-infiltrating CD8+ T cells promotes a hyporesponsive state that contributes to tumor immune escape. Inhibition of these two enzymes might thus be of interest for potentiating conventional antigen-directed tumor elimination. In this study, we sought to characterize the contribution of DGKα and ζ to antigen-independent cytotoxic functions of CD8+ T cells. Analysis of DGKζ-deficient mice showed an increase in bystander memory-like CD8+ T cell populations not observed in DGKα-deficient mice. We demonstrate that DGKζ limits cytokine responses in an antigen-independent manner. Cytokine-specific expansion of DGKζ-deficient CD8+ T cells promoted enhanced differentiation of innate-like cytotoxic cells in vitro, and correlated with the more potent in vivo anti-tumor responses of DGKζ-deficient mice engrafted with the murine A20 lymphoma. Our studies reveal a isoform-specific function for DGKζ downstream of IL-2/IL-15-mediated expansion of innate-like cytotoxic T cells, Pharmacological manipulation of DGKζ activity is of therapeutic interest for cytokine-directed anti-tumor treatments.