Left out in the cold: Moving beyond hormonal therapy for the treatment of immunologically cold prostate cancer with CAR T cell immunotherapies.

Prostate cancer is primarily hormone-dependent, and medical treatments have focused on inhibiting androgen biosynthesis or signaling through various approaches. Despite significant advances with the introduction of androgen receptor signalling inhibitors (ARSIs), patients continue to progress to castration-resistant prostate cancer (CRPC), highlighting the need for targeted therapies that extend beyond hormonal blockade. Chimeric Antigen Receptor (CAR) T cells and other engineered immune cells represent a new generation of adoptive cellular therapies. While these therapies have significantly enhanced outcomes for patients with hematological malignancies, ongoing research is exploring the broader use of CAR T therapy in solid tumors, including advanced prostate cancer. In general, CAR T cell therapies are less effective against solid cancers with the immunosuppressive tumor microenvironment hindering T cell infiltration, activation and cytotoxicity following antigen recognition. In addition, inherent tumor heterogeneity exists in patients with advanced prostate cancer that may prevent durable therapeutic responses using single-target agents. These barriers must be overcome to inform clinical trial design and improve treatment efficacy. In this review, we discuss the innovative and rationally designed strategies under investigation to improve the clinical translation of cellular immunotherapy in prostate cancer and maximise therapeutic outcomes for these patients.

Low-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models.

Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (LeY)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, LeY CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although LeY CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.

Modeling the Impacts of Manure on Phosphorus Loss in Surface Runoff and Subsurface Drainage.

Simulation of phosphorus (P) transfer from manured agricultural lands to water bodies via surface runoff and subsurface drainage is potentially of great help in evaluating the risks and effects of eutrophication under a range of best management practice scenarios. However, it remains a challenge since few models are capable of providing a reasonably accurate prediction of P losses under manure treatment. The Environmental Policy Integrated Climate (EPIC) model was applied to simulate the impacts on dissolved reactive P (DRP) losses through surface runoff and subsurface drainage from a solid cattle manure-amended corn ( L.)-soybean [ (L.) Merr.] rotation on a clay loam soil (Vertisol) located in the Lake Erie region. Simulations of DRP loss in surface runoff and tile drainage were satisfactory; however, EPIC did not consider DRP loss directly from manure, weakening its accuracy in the prediction of DRP loss in surface runoff. Having previously drawn on EPIC-predicted surface runoff to initiate SurPhos (Surface Phosphorus and Runoff Model) predictions of DRP losses strictly in surface runoff, no comparison had been made of differences in manure application impacts on EPIC- or SurPhos-predicted DRP losses-accordingly, this was assessed. The SurPhos improved the estimation of DRP loss in surface runoff (Nash-Sutcliffe coefficient, 0.53), especially when large rain events occurred immediately after or within 6 wk of manure application. Generally, EPIC can capture the impacts of manure application on DRP loss in surface runoff and subsurface drainage; however, coupling of the EPIC and SurPhos models increased the accuracy of simulation of runoff DRP losses.

Caudal regression syndrome in a fetus of a glucokinase-maturity-onset diabetes of the young pregnancy.

BACKGROUND: Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is a form of diabetes caused by heterozygous inactivating mutations in the GCK gene. Affected individuals maintain their fasting glucose levels at a higher set point (5.4-8.3 mmol/l) than the general population. Hyperglycaemia in women with Type 1 or Type 2 diabetes is known to confer increased risk of fetal congenital abnormalities. The association between GCK-MODY and congenital abnormalities, however, remains uncertain. CASE REPORT: A 35-year-old woman in her third pregnancy was diagnosed with gestational diabetes at 13 weeks' gestation (fasting blood glucose 6.0 mmol/L, 1-h blood glucose 9.2 mmol/l, 2-h blood glucose 7.3 mmol/l). The morphology scan at 19+2 weeks' gestation showed a Type III sacral agenesis. The woman elected to terminate the pregnancy. Her postpartum oral glucose tolerance test was suggestive of GCK-MODY (fasting blood glucose 7.4 mmol/l, 1-h blood glucose 9.3 mmol/l, 2-h blood glucose 7.3 mmol/l). Mutation analysis of the GCK gene identified a novel heterozygous GCK missense mutation, p.V199M, classified as likely pathogenic, providing molecular confirmation of the suspected GCK-MODY diagnosis. DISCUSSION: Sacral agenesis is a rare form of sacral abnormality affecting 0.005% to 0.1% of pregnancies. It is a subtype of the caudal regression sequence, a cardinal feature of diabetic embryopathy. This case raises the question as to whether hyperglycaemia in GCK-MODY may increase the risk of fetal caudal regression syndrome as reported in women with pre-existing diabetes mellitus. Improved diagnostic rates of GCK-MODY, and MODY registers that include pregnancy outcomes, are important to further elucidate risk of congenital abnormalities in GCK-MODY.

Mitigating the photocurrent persistence of single ZnO nanowires for low noise photodetection applications.

In this work, we investigate the optoelectronic properties of zinc oxide (ZnO) nanowires, which are good candidates for applications based on integrated optics. Single ZnO nanowire photodetectors were fabricated with ohmic contacts. By taking current transient measurements in different atmospheres (oxygen, air, vacuum and argon), and at various temperatures, we point out the importance of surface effects on the electrical behaviour. Results confirm that oxygen chemisorption is responsible for the existence of a high photoconductive gain in these devices, and for the first time a two step process in the photocurrent rise transient is reported. A maximum gain of G = 7.8 × 107 is achieved. However, under certain conditions, the persistence of the photocurrent can last up to several hours and as such may prevent the device from operating at useful rates. From a knowledge of the photocurrent response mechanisms, we establish a method to restore the photodetector to its initial state, with very low dark current, by applying an appropriate gate voltage sequence. This advances the state of the art for these detectors towards commercial applications.

Polarisation-controlled single photon emission at high temperatures from InGaN quantum dots.

Solid-state single photon sources with polarisation control operating beyond the Peltier cooling barrier of 200 K are desirable for a variety of applications in quantum technology. Using a non-polar InGaN system, we report the successful realisation of single photon emission with a g(2)(0) of 0.21, a high polarisation degree of 0.80, a fixed polarisation axis determined by the underlying crystallography, and a GHz repetition rate with a radiative lifetime of 357 ps at 220 K in semiconductor quantum dots. The temperature insensitivity of these properties, together with the simple planar epitaxial growth method and absence of complex device geometries, demonstrates that fast single photon emission with polarisation control can be achieved in solid-state quantum dots above the Peltier temperature threshold, making this system a potential candidate for future on-chip applications in integrated systems.

Room-temperature exciton-polaritons with two-dimensional WS2.

Two-dimensional transition metal dichalcogenides exhibit strong optical transitions with significant potential for optoelectronic devices. In particular they are suited for cavity quantum electrodynamics in which strong coupling leads to polariton formation as a root to realisation of inversionless lasing, polariton condensation and superfluidity. Demonstrations of such strongly correlated phenomena to date have often relied on cryogenic temperatures, high excitation densities and were frequently impaired by strong material disorder. At room-temperature, experiments approaching the strong coupling regime with transition metal dichalcogenides have been reported, but well resolved exciton-polaritons have yet to be achieved. Here we report a study of monolayer WS2 coupled to an open Fabry-Perot cavity at room-temperature, in which polariton eigenstates are unambiguously displayed. In-situ tunability of the cavity length results in a maximal Rabi splitting of hΩRabi = 70 meV, exceeding the exciton linewidth. Our data are well described by a transfer matrix model appropriate for the large linewidth regime. This work provides a platform towards observing strongly correlated polariton phenomena in compact photonic devices for ambient temperature applications.

Towards witnessing quantum effects in complex molecules.

Whether many-body objects like organic molecules can exhibit full quantum behaviour, including entanglement, is an open fundamental question. We present a generic theoretical protocol for entangling two organic molecules, such as dibenzoterrylene in anthracene. The availability of organic dye molecules with two-level energy structures characterised by sharp and intense emission lines are characteristics that position them favourably as candidates for quantum information processing technologies involving single-photons. Quantum entanglement can in principle be generated between several organic molecules by carefully interfering their photoluminescence spectra. Major milestones have been achieved in the last 10 years showcasing entanglement in diverse systems including ions, cold atoms, superconductors, photons, quantum dots and NV-centres in diamond, but not yet in molecules.

Temperature dependence of the radiative recombination time in ZnO nanorods under an external magnetic field of 6 T.

The Temperature dependence of the exciton radiative decay time in ZnO nanorods has been investigated, which is associated with the density of states for the intra-relaxation of thermally excited excitons. The photoluminescence decay time was calibrated by using the photoluminescence intensity in order to obtain the radiative decay time. In the absence of an external magnetic field, we have confirmed that the radiative decay time increased with temperature in a similar manner to that seen in bulk material (∼ T1.5). Under an external magnetic field of 6 T parallel to the c-axis, we found that the power coefficient of the radiative decay time with temperature decreased (∼ T1.3) when compared to that in the absence of a magnetic field. This result can be attributed to an enhancement of the effective mass perpendicular to the magnetic field and a redshift of the center-of-mass exciton as a consequence of perturbation effects in the weak-field regime.

Confocal microphotoluminescence mapping of coupled and detuned states in photonic molecules.

We study the coupling of cavities defined by the local modulation of the waveguide width using confocal photoluminescence microscopy. We are able to spatially map the profile of the antisymmetric (antibonding) and symmetric (bonding) modes of a pair of strongly coupled cavities (photonic molecule) and follow the coupled cavity system from the strong coupling to the weak coupling regime in the presence of structural disorder. The effect of disorder on this photonic molecule is also investigated numerically with a finite-difference time-domain method and a semi-analytical approach, which enables us to quantify the light localization observed in either cavity as a function of detuning.

Posterior reversible encephalopathy syndrome induced by pazopanib for renal cell carcinoma.

WHAT IS KNOWN AND OBJECTIVE: Posterior reversible encephalopathy syndrome (PRES) can be the result of acute hypertension, eclampsia, renal failure and the use of immunosuppressive or cytotoxic agents. We report a case of PRES as a result of the use of pazopanib, a vascular endothelial growth factor inhibitor used for renal cell carcinoma (RCC). CASE SUMMARY: A 76-year-old man treated with RCC develops PRES shortly after the initiation of pazopanib. WHAT IS NEW AND CONCLUSION: There are no known reports of the association between PRES and pazopanib. We postulate that pazopanib can disrupt the normal endothelial function of the brain leading to the development of PRES.

Breaking through a roadblock in prostate cancer research: an update on human model systems.

Prostate cancer is a prevalent disease that affects the aging male population. Whilst there have been significant advances of our biological understanding of the disease, clinical translation of promising agents continues to lag behind. In part, this is due to a paucity of relevant experimental and pre-clinical models required to further develop effective prevention and therapeutic strategies. Genetically modified cell lines fail to entirely represent the genetic and molecular diversity of primary human specimens, particularly from localised disease. Furthermore, primary prostate cancer tissues are extremely difficult to grow in the laboratory and virtually all human models, whether they grow as xenografts in immune-deficient animals or as cell cultures, are genetically modified by the investigator or derived from patients with advanced metastatic disease. In this review, we discuss the latest advances and improvements to current methods of xenografting human primary prostate cancer, and their potential application to translational research.

The external Ballard examination does not accurately assess the gestational age of infants born at home in a rural community of The Gambia.

BACKGROUND: Accurate assessment of gestational age at birth is critical to the identification of neonates at high risk. In resource-poor settings, postnatal techniques are commonly used but may be difficult to apply and have not been well validated against ultrasound in community studies. The aim of this study was to evaluate postnatal assessment of gestational age in rural Africa using the external criteria of the Ballard examination against 1st/early 2nd-trimester ultrasound and date of last menstrual period. METHOD: In a sample of women from Kiang West, The Gambia (n=80), the precision of gestational age estimates using the external Ballard examination was compared with those derived from 1st and early 2nd-trimester ultrasound examination and date of last menstrual period. RESULTS: The incidence of preterm delivery was low at 2.5%. The external Ballard examination tended to underestimate gestational age by a mean (SD) of 15.6 (10.9) days compared with that derived from ultrasound and to underestimate by 15.4 (23.1) days compared with that derived from date of last menstrual period. The differences between the methods varied with gestation. CONCLUSION: In this rural, community-born population of infants, postnatal assessment of gestational age by external Ballard examination performed poorly compared with ultrasound and last menstrual period. No reliable gestational age could be derived from its estimate and it failed to detect a significant proportion of high-risk infants. The development of an accurate but simple method of postnatally assessing gestational age specifically for use by health workers in rural Africa is required.

Acutely ruptured intracranial saccular aneurysms treated with stent assisted coiling: complications and outcomes in 42 consecutive patients.

BACKGROUND: Antiplatelet agents are required to prevent thromboembolic complications from recently deployed intracranial stents, yet they carry a risk of bleeding complications that may be serious in patients with recent subarachnoid hemorrhage. METHOD: Consecutive patients at a single institution who had ruptured intracranial saccular aneurysms treated with stent assisted coiling were retrospectively reviewed. Our primary outcomes were ischemic stroke related to the stent and bleeding complications possibly related to antithrombotic therapy. Secondary outcomes included 3 month follow-up National Institute of Health Stroke Scale (NIHSS) scores and modified Rankin Scale (mRS) scores. RESULTS: 44 aneurysms in 42 patients were treated. Seven patients experienced ischemic strokes during their hospitalization. Five ischemic strokes were secondary to vasospasm; one was definitely related to thrombus formation within the stent and one was possibly related to the stent. Two patients had asymptomatic intracranial hemorrhages and one patient had a symptomatic intracranial hemorrhage. Patients with Hunt and Hess grades I-II (n=25) experienced no stent associated ischemic strokes or symptomatic intracranial hemorrhages. The two stent associated ischemic strokes and one symptomatic intracranial hemorrhage occurred in patients with Hunt and Hess grades III-V (n=17) and patients with external ventricular drains (EVDs) (n=17). Only one patient had disability at the 3 month follow-up that was possibly related to the stent (mRS score of 3 and NIHSS score of 2). CONCLUSION: These data suggest that higher grade hemorrhage patients, especially those with EVDs, are at greater risk for ischemic stroke and/or bleeding complications than lower grade patients. However, the complications had a small impact on mid-term disability outcomes in this cohort.

Prostate-regenerating capacity of cultured human adult prostate epithelial cells.

Experimentation with the progenitor/stem cells in adult prostate epithelium can be inconvenient due to a tight time line from tissue acquisition to cell isolation and to downstream experiments. To circumvent this inconvenience, we developed a simple technical procedure for culturing epithelial cells derived from human prostate tissue. In this study, benign prostate tissue was enzymatically digested and fractionated into epithelium and stroma, which were then cultured in the medium designed for prostate epithelial and stromal cells, respectively. The cultured cells were analyzed by immunocytochemical staining and flow cytometry. Prostate tissue-regenerating capacity of cultured cells in vitro was determined by co-culturing epithelial and stromal cells in dihydrotestosterone-containing RPMI. Cell lineages in formed acini-like structures were determined by immunohistochemistry. The culture of epithelial cells mainly consisted of basal cells. A minor population was negative for known lineage markers and positive for CD133. The culture also contained cells with high activity of aldehyde dehydrogenase. After co-culturing with stromal cells, the epithelial cells were able to form acini-like structures containing multiple cell lineages. Thus, the established culture of prostate epithelial cells provides an alternative source for studying progenitor/stem cells of prostate epithelium.

Isolation and activity of Xenorhabdus antimicrobial compounds against the plant pathogens Erwinia amylovora and Phytophthora nicotianae.

AIMS: Broad-spectrum antibiotics produced by symbiotic bacteria [entomopathogenic bacterium (EPB)] of entomopathogenic nematodes keep monoxenic conditions in insect cadavers in soil. This study evaluated antibiotics produced by EPB for their potential to control plant pathogenic bacteria and oomycetes. METHODS AND RESULTS: Entomopathogenic bacterium produce antibiotics effective against the fire blight bacterium Erwinia amylovora, including streptomycin resistant strains, and were as effective in phytotron experiments as kasugamycin or streptomycin. Xenorhabdus budapestensis and X. szentirmaii antibiotics inhibited colony formation and mycelial growth of Phytophthora nicotianae. From X. budapestensis, an arginine-rich fraction (bicornutin) was adsorbed by Amberlite((R)) XAD 1180, and eluted with methanol : 1 n HCI (99 : 1). Bicornutin inactivated zoospores, and inhibited germination and colony formation of cystospores at <<25 ppm. An UV-active molecule (bicornutin-A, MW = 826), separated by HPLC and thin-layer chromatography, was identified as a novel hexa-peptide : RLRRRX. CONCLUSIONS: Xenorhabdus budapestensis produces metabolites with strong antibacterial and cytotoxic activity. Individual compounds can be isolated, identified and patented, but their full antimicrobial potential may be multiplied by synergic interactions. SIGNIFICANCE AND IMPACT OF THE STUDY: Active compounds of two new Xenorhabdus species might control plant diseases caused by pathogens of great importance to agriculture such as Erw. amylovora and P. nicotianae.

Prostatic tumor stroma: a key player in cancer progression.

Although it is evident that prostatic epithelial stem cells are responsible for maintaining normal and malignant tissues, it is well recognized that epithelial cells do not exist independently, but act in concert with the stromal microenvironment. Prostatic stroma is pivotal for normal development and homeostasis. The genetic and morphological changes that occur in prostatic epithelial cells, as they progress from a normal to malignant phenotype, have been well described. However, it is evident that the surrounding microenvironment also plays a major role in cancer cell growth, survival, invasion and metastatic progression. Prostatic tumor stroma provides a niche environment for cancer stem cells and therefore contributes to self-renewal and differentiation. In order to target the tumor microenvironment and develop new therapeutics for prostate cancer, we must understand the role of the tumor stroma, specifically the events mediating the interactions between the cancer stem cell and its immediate microenvironment during cancer initiation and progression. This article presents the rationale and discusses the challenges to targeting prostatic tumor stroma in cancer therapies that will potentially treat prostate cancer.

Towards registered single quantum dot photonic devices.

We have registered the position and wavelength of a single InGaAs quantum dot using an innovative cryogenic laser lithography technique. This approach provides accurate marking of the location of self-organized dots and is particularly important for realizing any solid-state cavity quantum electrodynamics scheme where the overlap of the spectral and spatial characteristics of an emitter and a cavity is essential. We demonstrate progress in two key areas towards efficient single quantum dot photonic device implementation. Firstly, we show the registration and reacquisition of a single quantum dot with 50 and 150 nm accuracy, respectively. Secondly, we present data on the successful fabrication of a photonic crystal L3 cavity following the registration process.

Abnormal photoluminescence properties of GaN nanorods grown on Si(111) by molecular-beam epitaxy.

We have studied the photoluminescence properties of GaN nanorods grown on Si(111) substrates by radio-frequency plasma-assisted molecular-beam epitaxy. The hexagonal shaped nanorods with lateral average diameters from 30 to 150 nm are obtained by controlling the Ga flux with a fixed amount of nitrogen. As the diameters decrease, the main emission lines assigned as donor bound excitons are blueshifted, causing a spectral overlap of this emission line with that of the free exciton at 10 K due to the quantum size effect in the GaN nanorods. The temperature-dependent photoluminescence spectra show an abnormal behaviour with an 'S-like' shape for higher diameter nanorods. The activation energy of the free exciton for GaN nanorods with different diameters was also evaluated.