Tumor-associated macrophages (TAMs) usually express an M2 phenotype, which enables them to perform immunosuppressive and tumor-promoting functions. Reprogramming these TAMs toward an M1 phenotype ...could thwart their pro-cancer activities and unleash anti-tumor immunity, but efforts to accomplish this are nonspecific and elicit systemic inflammation. Here we describe a targeted nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. We demonstrate in models of ovarian cancer, melanoma, and glioblastoma that infusions of nanoparticles formulated with mRNAs encoding interferon regulatory factor 5 in combination with its activating kinase IKKβ reverse the immunosuppressive, tumor-supporting state of TAMs and reprogram them to a phenotype that induces anti-tumor immunity and promotes tumor regression. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this immunotherapy could enable physicians to obviate suppressive tumors while avoiding systemic treatments that disrupt immune homeostasis.
The term “transnational” is appropriate to describe the globalized Brotherhood of the Cross and Star movement, and as such the term transnational will be used interchangeably for BCS tendencies ...towards traversing local-global terrain in this research paper. In the past, it has been falsely claimed that African Christianity was founded by and for Africans. African Christianity experts today refute this idea because the faith has spread successfully over the globe. This opinion also applies to BCS, an organization that has gained widespread acceptance globally. It achieves this by developing itself as a global organization, employing cutting-edge information technology, transferring missions and miracles, evangelizing abroad, and visiting foreign communities with the leader of the BCS. Thus, the paper takes into account
BCS tendencies toward globalization and further presents BCS as a worldwide movement. This paper critically used of qualitative method, involving historical, and theoretical, methods. Data was sourced mostly from library materials, oral interviews, participant and personal observations, as well as the internet and views of renowned scholars in religion, African Independent Church Movement, African Christianity in the Diaspora, and sociology of religion. This research concludes that a religion, as it moves to aa foreign territory, becomes an umbrella for cultural identity, a means of connecting to the home country for immigrant members and it additionally serves as a medium of survival for indigenous members.
Big data in drug development may not satisfactorily address the demands of precision medicine in a rare disease population, making the use of smaller clinical trials necessary. Consequently, the use ...of innovative design and analysis of these clinical trials using model-informed approaches have become indispensable. This requires informative exposure-outcome analysis, together with formal statistical analysis, which should include the strength of evidence for a study outcome. We demonstrate how knowledge can be gained, with supporting strength of evidence, from a small (data) clinical trial with a low dose of blarcamesine in the treatment of Rett syndrome (RTT). Based on a small data paradigm, pharmacometrics item response theory modeling and Bayes factor analysis were used to show that blarcamesine is efficacious in RTT.
Brain metastasis is the most common type of intracranial tumor. The contemporary management of brain metastasis is a challenging issue and traditionally has carried a poor prognosis as these lesions ...typically occur in the setting of advanced cancer. However, improvement in systemic therapy, advances in radiation techniques and multimodal therapy tailored to the individual patient, has given hope to this patient population. Surgical resection has a well-established role in the management of brain metastasis. Here we discuss the evolving role of surgery in the treatment of this diverse patient population.
Gentamicin and amikacin are aminoglycoside antibiotics which are renally excreted and known to be nephrotoxic. Estimate of glomerular filtration rate (eGFR) per body surface area is lower in neonates ...than in adults and exposure to these drugs could lead to more suppression in kidney function. The aim of this study was to determine maximum and minimum plasma concentrations (C
and C
), time to reach C
levels of gentamicin and amikacin, and to assess eGFR in preterm and term neonates.
Two groups of patients were recruited, 44 neonates receiving gentamicin (5 mg/kg/24 h) and 35 neonates receiving amikacin (15 mg/kg/24 h) by slow intravenous injection. Patients on amikacin had been on gentamicin before being switched to amikacin. Two blood samples were drawn for the determination of the maximum and minimum plasma concentration. Primary outcomes were determination of C
, C
, and the time it took to clear the aminoglycoside to a plasma concentration below the toxicity threshold (gentamicin: < 1 mcg/mL; amikacin: < 5 mcg/mL.
Therapeutic range for C
of gentamicin (15-25 mcg/mL) or amikacin (30-40 mcg/mL) was achieved in only 27.3 and 2.9% of neonates, respectively. Percentage of neonates reaching plasma concentrations below the toxicity threshold within the 24-hour dosing interval was 72.7% for gentamicin and 97.1% for amikacin. Positive correlation between gentamicin clearance and postnatal age borderline statistical significance (p = 0.007), while the correlation between amikacin clearance and postnatal age was poor and not statistically significant (r
= - 0.30, p = 0.971).
Although eGFR decreased significantly as a function of postnatal age in neonates receiving amikacin, the majority (91.4%) of these neonates were able to clear the drug to < 5 mcg/mL within a 24-hour dosing interval.
•An efficacious pediatric clobazam (CLB) dosing regimen identified by PopPK modeling.•Evaluation/validation showed the model adequately described CLB and N-CLB PK data.•Model simulation of CLB (1.5 ...and 2.0 mg/kg) showed levels associated with efficacy.•CLB 1.5 and 2.0 mg/kg may lead to efficacious drug levels in patients ≥16 months.•Similar PopPK modeling may be useful in other hard-to-recruit patient populations.
: To describe the use of a population pharmacokinetic (PopPK) model incorporating weight and ontogeny to identify effective clobazam (CLB) dosing for use in a clinical trial in pediatric patients with Dravet syndrome.
: Pharmacokinetic data were combined from 3 CLB trials (OV-1012, OV-1017, and study 301) and a simulated study (study 401) for a total of 1306 CLB and 1305 N-desmethyl clobazam (N-CLB) samples from 193 Lennox-Gastaut syndrome patients and healthy subjects aged 6 months to 45 years. A structured approach based on US Food and Drug Administration guidance and pharmacometric knowledge discovery was developed using a nonlinear mixed-effects approach. Graphing and fitting using logistical weight regression were used to identify covariates for inclusion in the final model, which was evaluated using goodness-of-fit criteria and validated using prediction-corrected visual predictive check (pcVPC). Using the final PopPK model, a simulation study determined CLB and N-CLB distributions after 4 weeks of 1.5 and 2.0 mg/kg CLB.
: The parameters of the final PopPK model were similar to previous reports. Fixed-effect parameters were precisely estimated, with no significant increase in NONMEM objective function value. Intersubject variability estimates were similar to previous reports, with <35% shrinkage associated with parameter variability, except for intercompartmental clearance and apparent volumes of distribution of peripheral compartments. Goodness-of-fit plots and pcVPC show that the model adequately described CLB and N-CLB data. The CLB/N-CLB ratio in virtual study subjects aged <3 years was 0.23 for 1.5 and 2.0 mg/kg and was 0.14 for subjects aged ≥3 years, which is 2 to 3 times those reported in a previous stiripentol/CLB/valproate study in which seizure improvement was reported.
: The PopPK model dosing parameters of 1.5 and 2.0 mg/kg are likely to result in efficacious concentrations of CLB and N-CLB in pediatric patients as young as 16 months. Dosages exceeding 1.5 mg/kg should be monitored for tolerability, particularly in patients aged <2 years, as there may be a higher incidence of sedation.
Histone methylation regulates normal stem cell fate decisions through a coordinated interplay between histone methyltransferases and demethylases at lineage specific genes. Malignant transformation ...is associated with aberrant accumulation of repressive histone modifications, such as polycomb mediated histone 3 lysine 27 (H3K27me3) resulting in a histone methylation mediated block to differentiation. The relevance, however, of histone demethylases in cancer remains less clear. We report that JMJD3, a H3K27me3 demethylase, is induced during differentiation of glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via chromatin dependent (INK4A/ARF locus activation) and chromatin independent (nuclear p53 protein stabilization) mechanisms. Our findings indicate that deregulation of JMJD3 may contribute to gliomagenesis via inhibition of the p53 pathway resulting in a block to terminal differentiation.
With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines ...recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. To determine factors influencing this variable response to SRS, we analyzed outcomes of brain metastases ≤3 cm diameter in patients with no prior systemic therapy treated with frame-based single-fraction SRS. Following SRS, 259 out of 1733 (15%) treated lesions demonstrated MRI findings concerning for local treatment failure (LTF), of which 202 /1733 (12%) demonstrated LTF and 54/1733 (3%) had an adverse radiation effect. Multivariate analysis demonstrated tumor size (>1.5 cm) and melanoma histology were associated with higher LTF rates. Our results demonstrate that brain metastases ≤3 cm are not uniformly responsive to SRS and suggest that prospective studies to evaluate the effect of SRS alone or in combination with surgery on brain metastases ≤3 cm matched by tumor size and histology are warranted. These studies will help establish multi-disciplinary treatment guidelines that improve local control while minimizing radiation necrosis during treatment of brain metastasis ≤3 cm.
Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3'-phosphatase and DNA 5'-kinase activities, which are required for processing termini of single- and ...double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. Functional and biochemical studies demonstrated these PNKP mutations significantly diminished DNA kinase/phosphatase activities, altered its cellular distribution, caused defective repair of DNA single/double stranded breaks, and were associated with a higher propensity for oncogenic transformation. Our findings indicate that specific PNKP mutations may contribute to tumor initiation within susceptible cells in the CNS by limiting DNA damage repair and increasing rates of spontaneous mutations resulting in pediatric glioma associated driver mutations such as ATRX and TP53.
Isocitrate dehydrogenase (IDH) mutations are cornerstone diagnostic features in glioma classification. IDH mutations are typically characterized by mutually exclusive amino acid substitutions in the ...genes encoding for the
and the
enzyme isoforms. We report our institutional case of a diffuse astrocytoma with progression to secondary glioblastoma and concurrent IDH1/IDH2 mutations. A 49-year-old male underwent a subtotal resection of a lobular lesion within the right insula in 2013, revealing a WHO grade 3 anaplastic oligoastrocytoma, IDH1 mutated, 1p19q intact. Symptomatic tumor progression was suspected in 2018, leading to a surgical tumor biopsy that demonstrated WHO grade 4
and
mutant diffuse astrocytoma. The patient subsequently underwent surgical resection followed by medical management and finally died in 2021. Although concurrent
mutations have been rarely reported in the current literature, further study is required to better define their impact on patients' prognoses and their response to targeted therapies.
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