Enhancement of electroporation facilitated immunogene therapy via T-reg depletion

Regulatory T cells (T-regs) can negatively impact tumor antigen-specific immune responses after infiltration into tumor tissue. However, depletion of T-regs can facilitate enhanced anti-tumor responses, thus augmenting the potential for immunotherapies. Here we focus on treating a highly aggressive form of cancer using a murine melanoma model with a poor prognosis. We utilize a combination of T-reg depletion and immunotherapy plasmid DNA delivered into the B16F10 melanoma tumor model via electroporation. Plasmids encoding murine granulocyte macrophage colony-stimulating factor and human B71 were transfected with electroporation into the tumor and transient elimination of T-regs was achieved with CD25-depleting antibodies (PC61). The combinational treatment effectively depleted T-regs compared to the untreated tumor and significantly reduced lung metastases. The combination treatment was not effective in increasing the survival, but only effective in suppression of metastases. These results indicate the potential for combining T-reg depletion with immunotherapy-based gene electrotransfer to decrease systemic metastasis and potentially enhance survival

The GOGREEN survey: The environmental dependence of the star-forming galaxy main sequence at 1.0<z<1.51.0<z<1.5

We present results on the environmental dependence of the star-forming galaxy main sequence in 11 galaxy cluster fields at $1.0 < z < 1.5$ from the Gemini Observations of Galaxies in Rich Early Environments Survey (GOGREEN) survey. We use a homogeneously selected sample of field and cluster galaxies whose membership is derived from dynamical analysis. Using [OII]-derived star formation rates (SFRs), we find that cluster galaxies have suppressed SFRs at fixed stellar mass in comparison to their field counterparts by a factor of 1.4 $\pm$ 0.1 ($\sim3.3\sigma$) across the stellar mass range: $9.0 < \log(M_{*} /M_{\odot}) < 11.2$. We also find that this modest suppression in the cluster galaxy star-forming main sequence is mass and redshift dependent: the difference between cluster and field increases towards lower stellar masses and lower redshift. When comparing the distribution of cluster and field galaxy SFRs to the star-forming main sequence, we find an overall shift towards lower SFRs in the cluster population, and note the absence of a tail of high SFR galaxies as seen in the field. Given this observed suppression in the cluster galaxy star-forming main sequence, we explore the implications for several scenarios such as formation time differences between cluster and field galaxies, and environmentally-induced star formation quenching and associated timescales

The PALM Technique: histological findings of masked phototherapeutic keratectomy on rabbit corneas

BACKGROUND: To compare the corneal healing response between conventional and phototherapeutic keratectomy through a masking agent, in rabbit corneas. METHODS: 24 adult rabbits underwent phototherapeutic keratectomy. Animals were divided in two groups: 12 received photoablation through a masking agent (PALM gel) and the remaining 12 received conventional phototherapeutic keratectomy of equal depth and served as control. Light and transmission electron microscopy was performed in specimens of both groups obtained: immediately after, four hours, one week, one, three and six months after treatment. RESULTS: Reepitheliazation was complete within five days in all eyes. Light and transmission electron microscopy did not reveal any differences of the healing process in the experimental eyes compared to the controls. CONCLUSION: Photoablation through the PALM technique did not result any evident alterations of the reepithelisation and stromal healing process

The GOGREEN survey: Post-infall environmental quenching fails to predict the observed age difference between quiescent field and cluster galaxies at z>1

We study the star formation histories (SFHs) and mass-weighted ages of 331 UVJ-selected quiescent galaxies in 11 galaxy clusters and in the field at 11 has been driven by different physical processes than those at play at z=0

Completeness of reporting and risks of overstating impact in cluster randomised trials: a systematic review

Overstating the impact of interventions through incomplete or inaccurate reporting can lead to inappropriate scale-up of interventions with low impact. Accurate reporting of the impact of interventions is of great importance in global health research to protect scarce resources. In global health, the cluster randomised trial design is commonly used to evaluate complex, multicomponent interventions, and outcomes are often binary. Complete reporting of impact for binary outcomes means reporting both relative and absolute measures. We did a systematic review to assess reporting practices and potential to overstate impact in contemporary cluster randomised trials with binary primary outcome. We included all reports registered in the Cochrane Central Register of Controlled Trials of two-arm parallel cluster randomised trials with at least one binary primary outcome that were published in 2017. Of 73 cluster randomised trials, most (60 [82%]) showed incomplete reporting. Of 64 cluster randomised trials for which it was possible to evaluate, most (40 [63%]) reported results in such a way that impact could be overstated. Care is needed to report complete evidence of impact for the many interventions evaluated using the cluster randomised trial design worldwide

Proteostasis Dysregulation in Pancreatic Cancer

The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), has a dismal 5-year survival rate of less than 5%. Radical surgical resection, in combination with adjuvant chemotherapy, provides the best option for long-term patient survival. However, only approximately 20% of patients are resectable at the time of diagnosis, due to locally advanced or metastatic disease. There is an urgent need for the identification of new, specific, and more sensitive biomarkers for diagnosis, prognosis, and prediction to improve the treatment options for pancreatic cancer patients. Dysregulation of proteostasis is linked to many pathophysiological conditions, including various types of cancer. In this review, we report on findings relating to the main cellular protein degradation systems, the ubiquitin-proteasome system (UPS) and autophagy, in pancreatic cancer. The expression of several components of the proteolytic network, including E3 ubiquitinligases and deubiquitinating enzymes, are dysregulated in PDAC, which accounts for approximately 90% of all pancreatic malignancies. In the future, a deeper understanding of the emerging role of proteostasis in pancreatic cancer has the potential to provide clinically relevant biomarkers and new strategies for combinatorial therapeutic options to better help treat the patients.Peer reviewe

UCHL3 Regulates Topoisomerase-Induced Chromosomal Break Repair by Controlling TDP1 Proteostasis

Genomic damage can feature DNA-protein crosslinks whereby their acute accumulation is utilized to treat cancer and progressive accumulation causes neurodegeneration. This is typified by tyrosyl DNA phosphodiesterase 1 (TDP1), which repairs topoisomerase-mediated chromosomal breaks. Although TDP1 levels vary in multiple clinical settings, the mechanism underpinning this variation is unknown. We reveal that TDP1 is controlled by ubiquitylation and identify UCHL3 as the deubiquitylase that controls TDP1 proteostasis. Depletion of UCHL3 increases TDP1 ubiquitylation and turnover rate and sensitizes cells to TOP1 poisons. Overexpression of UCHL3, but not a catalytically inactive mutant, suppresses TDP1 ubiquitylation and turnover rate. TDP1 overexpression in the topoisomerase therapy-resistant rhabdomyosarcoma is driven by UCHL3 overexpression. In contrast, UCHL3 is downregulated in spinocerebellar ataxia with axonal neuropathy (SCAN1), causing elevated levels of TDP1 ubiquitylation and faster turnover rate. These data establish UCHL3 as a regulator of TDP1 proteostasis and, consequently, a fine-tuner of protein-linked DNA break repair

GOGREEN: a critical assessment of environmental trends in cosmological hydrodynamical simulations at z ~ 1

Recent observations have shown that the environmental quenching of galaxies at z ∼ 1 is qualitatively different to that in the local Universe. However, the physical origin of these differences has not yet been elucidated. In addition, while low-redshift comparisons between observed environmental trends and the predictions of cosmological hydrodynamical simulations are now routine, there have been relatively few comparisons at higher redshifts to date. Here we confront three state-of-the-art suites of simulations (BAHAMAS+MACSIS, EAGLE+Hydrangea, IllustrisTNG) with state-of-the-art observations of the field and cluster environments from the COSMOS/UltraVISTA and GOGREEN surveys, respectively, at z ∼ 1 to assess the realism of the simulations and gain insight into the evolution of environmental quenching. We show that while the simulations generally reproduce the stellar content and the stellar mass functions of quiescent and star-forming galaxies in the field, all the simulations struggle to capture the observed quenching of satellites in the cluster environment, in that they are overly efficient at quenching low-mass satellites. Furthermore, two of the suites do not sufficiently quench the highest mass galaxies in clusters, perhaps a result of insufficient feedback from AGN. The origin of the discrepancy at low stellar masses (⁠M∗≲1010 M⊙), which is present in all the simulations in spite of large differences in resolution, feedback implementations, and hydrodynamical solvers, is unclear. The next generation of simulations, which will push to significantly higher resolution and also include explicit modelling of the cold interstellar medium, may help us to shed light on the low-mass tension