Overview of the Development and Use of Akt Inhibitors in Prostate Cancer

Deregulation of the PI3K-Akt-mTOR pathway plays a critical role in the development and progression of many cancers. In prostate cancer, evidence suggests that it is mainly driven by PTEN loss of function. For many years, the development of selective Akt inhibitors has been challenging. In recent phase II and III clinical trials, Ipatasertib and Capivasertib associated with androgen deprivation therapies showed promising outcomes in patients with metastatic castration-resistant prostate cancer and PTEN-loss. Ongoing trials are currently assessing several Akt inhibitors in prostate cancer with different combinations, at different stages of the disease.

Decapitation and Dynamite: The Mutilated Mountainside Monument of Gaius Julius Aquila on the Coast of Bithynia et Pontus

The Roman monument locally known as Kuşkayası Yol Anıtı (literally bird rock road monument) in Turkish is an arresting site carved in relief on a mountainside. Its decapitated figures have hewn limbs, and dynamite has blasted out large chunks of the monument. Though scholars have tangentially touched upon Kuşkayası, there is little analysis of its visual symbolism and the mutilated human figure’s identity and destruction have been mysteries. This paper will analyse the monument and explicate its noteworthy blend of Roman Imperial and local iconography, a syncretistic design which participates in the Romanization of Bithynia et Pontus and legitimizes the monument’s builder Gaius Julius Aquila. Next, this paper will argue that the mysterious beheaded figure likely represents Aquila rather than Emperor Claudius. Finally, this paper will forward that Kuşkayası was the victim of Christian mutilation in Late Antiquity during its initial phase of destruction, and treasure hunters in its most recent phase. Kuşkayası represents an innovative symbolic composition and speaks both to the syncretistic public art tradition and the history of the destruction of antiquities on the Black Sea coast.

Current Understanding of Molecular Phase Separation in Chromosomes

Biomolecular phase separation denotes the demixing of a specific set of intracellular components without membrane encapsulation. Recent studies have found that biomolecular phase separation is involved in a wide range of cellular processes. In particular, phase separation is involved in the formation and regulation of chromosome structures at various levels. Here, we review the current understanding of biomolecular phase separation related to chromosomes. First, we discuss the fundamental principles of phase separation and introduce several examples of nuclear/chromosomal biomolecular assemblies formed by phase separation. We also briefly explain the experimental and computational methods used to study phase separation in chromosomes. Finally, we discuss a recent phase separation model, termed bridging-induced phase separation (BIPS), which can explain the formation of local chromosome structures.

CLRM-12. HYBRID DESIGNS FOR USING EXTERNAL CONTROLS IN PHASE 3 GLIOBLASTOMA TRIALS

While recent Phase 3 glioblastoma (GBM) trials have failed to establish novel therapies, they potentially provide a high-quality source of external control patients treated with temozolomide. We consider hybrid two-stage adaptive designs that leverage these external controls to safely accelerate Phase 3 GBM trials. The basic strategy is that first patients are randomized 1:1 between the control and experimental arms, then an interim check measures similarity between the trial's control patients and potential external controls, and finally if this interim similarity is high the randomization ratio is changed accordingly and the external controls are used in the final analysis. An extensive simulation study is conducted to assess operating characteristics and we discuss when these hybrid designs can accelerate GBM therapy development while maintaining strict error control.

Novel Antiretroviral Therapeutic Strategies for HIV

When the first cases of HIV infection appeared in the 1980s, AIDS was a deadly disease without any therapeutic alternatives. Currently, there is still no cure for most cases mainly due to the multiple tissues that act as a reservoir for this virus besides the high viral mutagenesis that leads to an antiretroviral drug resistance. Throughout the years, multiple drugs with specific mechanisms of action on distinct targets have been approved. In this review, the most recent phase III clinical studies and other research therapies as advanced antiretroviral nanodelivery systems will be here discussed. Although the combined antiretroviral therapy is effective in reducing viral loading to undetectable levels, it also presents some disadvantages, such as usual side effects, high frequency of administration, and the possibility of drug resistance. Therefore, several new drugs, delivery systems, and vaccines have been tested in pre-clinical and clinical trials. Regarding drug delivery, an attempt to change the route of administration of some conventional antiretrovirals has proven to be successful and surpassed some issues related to patient compliance. Nanotechnology has brought a new approach to overcoming certain obstacles of formulation design including drug solubility and biodistribution. Overall, the encapsulation of antiretroviral drugs into nanosystems has shown improved drug release and pharmacokinetic profile.

Eclecticism Style in Ceramic Art Practices of Ife Art School

Purpose: The study discusses Ife ceramic wares in tandem with the historical approach of the decorative patterns. It equally determines the origin of each style and how it moved and spread across the phases. The sequences of creative impulse and stylistic trends of ceramic practices in the art school from inception have not received scholarly attention in terms of the examination of the approaches towards the conceptions. The specific objective is to investigate the inception of eclecticism in the art school and circumstances behind the conceptions in order to reveal the contextual definitions of used designs and factors influence the innovation. Methodology: Descriptive and analytical approaches were used to trace decorative trends of each phase and the integration of the various motifs and styles of the previous phases in the new phases that sprung up. Samples of ceramic wares in the art school exhibition brochures, galleries and ceramic studios were collected for analysis and photographs were also taken for evidence. Findings: In concept, the praxis reveals traditional ideology at inception and desegregation of different themes, ideas, and styles in the recent phase of the practice. The practices are eclectic inclined as of late with reflection of traditional ideology, contemporary issues and customs of Western societies. Notwithstanding, the ceramic art tradition of the art school is aesthetically inclined both in principle and practice. Unique contribution to theory, policy and practice: No doubt, the sculptural creativeness of Ife wares has preserved cultural heritage for public awareness. This is largely evident in the proliferation of her ingenious adaptation of indigenous deco-stylistic techniques with Western influence that portrayed Nigerian traditional culture by themes, forms and styles in concepts and renditions.

Anisotropic Universe with Manimally Interacting Matter and Holographic Dark Energy

The holographic dark energy (HDE), a form of dark energy, has been a useful tool in explaining the recent phase transition of the universe. In this paper, we study the anisotropic and homogeneous Bianchi type-III model of the universe filled with minimally interacting matter and holographic dark energy under the framework of the Brans-Dicke (BD) scalar tensor theory of gravitation. Considering two physically plausible conditions such as, (i) the special law of variation for Hubble parameter and (ii) the scalar expansion proportional to the shear scalar, we propose two new models namely, exponential expansion model and power law expansion model. We also show the dynamics of these models fit with existing observational data and literature thereof. The transit behavior of the equation of state parameter for dark energy has been analyzed graphically. The jerk parameter is also studied for both of the models describing cosmological evolution. The Chittagong Univ. J. Sci. 42(1): 39-57, 2020

Lurbinectedin in Refractory Diffuse Malignant Peritoneal Mesothelioma: Report of Two Cases

Mesothelioma is a malignancy of serosal membranes. Parietal pleura is the most common site, with peritoneum being the second most frequent location. Malignant peritoneal mesothelioma (MPM) is a rare and aggressive disease. The prognosis is often very poor with median overall survival ranging from 6 to 18 months in patients who are not candidates for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) due to non-resectable disease or comorbid conditions. For patients with resectable disease, CRS and HIPEC have become the standard of care. However, for patients with unresectable malignant mesothelioma there is unfortunately no effective systemic treatment beyond the first line. Based on the results of a recent phase II trial, lurbinectedin has clinical activity and acceptable toxicity in the second- and third-line treatment of malignant pleural mesothelioma. However, until present, no data have been available for patients with MPM and for patients who become refractory after multiple treatment lines. We report on two patients with metastatic MPM who achieved durable disease control of 10+ and 8 months with lurbinectedin in the fourth and fifth treatment line, respectively.

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical trials for several of them. Multivalent bispecific IgG-modified formats predominate today, with a clear tendency for more target antigens and further increased valency in newer constructs. The strategies to augment anticancer efficacy are currently equally divided between disruption of multiple surface antigens, and additional redirection of cytotoxic T or NK lymphocytes against the tumor. Both effects complement other modern modalities, such as tyrosine kinase inhibitors and adoptive cell therapies, with which multispecifics are increasingly applied in combination or merged, for example, in the form of antibody producing CAR-T cells and oncolytics. While mainly focused on B-cell malignancies early on, the contemporary multispecific antibody sector accommodates twice as many trials against solid compared to hematologic cancers. An exciting emerging prospect is the targeting of intracellular neoantigens using T-cell receptor (TCR) fusion proteins or TCR-mimic antibody fragments. Considering the fact that introduction of PD-(L)1 inhibitors only a few years ago has already facilitated 5-year survival rates of 30–50% for per se highly lethal neoplasms, such as metastatic melanoma and non-small-cell lung carcinoma, the upcoming enforcement of current treatments with “next-generation” immunotherapeutics, offers a justified hope for the cure of some advanced cancers in the near future.

Contextualizing a single-arm trial of ceralasertib (cer) plus paclitaxel with real-world data (RWD) in patients (pts) with advanced melanoma previously treated with anti-PD-(L)1(PDx) therapies.

e21542 Background: Metastatic melanoma, especially in pts who do not respond to PDx therapy, is an area of high unmet need. Chemotherapy may be used but clinical efficacy is limited. A recent Phase I study (NCT02630199) showed that cer + paclitaxel had promising anti-tumor activity with durable responses in 34 melanoma pts after failing PDx therapy. Given the lack of published prospective clinical trial data in the post-PDx setting, RWD was used to contextualize the results of the trial. Methods: Adult pts (≥18 years) diagnosed with advanced melanoma between Jan2011-Jun2020, who received PDx therapy alone or in combination with anti-CTLA4, and also received chemotherapy immediately after the PDx line (chemo cohort) were selected from the nationwide US-based Flatiron Health EHR-derived de-identified database. A subgroup of pts who received taxane was also selected. Overall survival (OS) was assessed using Kaplan-Meier methods. Key covariates such as age, gender, LDH level, number of prior lines of therapy, presence of brain and liver metastases, and prior BRAF/MEK treatment, were adjusted using propensity score-based weighting approach. Cox regression models were used to obtain the effect estimates for OS comparing the trial arm against the RWD cohorts. Results: A cohort of 114 pts met the inclusion criteria, of which 69 received taxane. Compared with the trial arm, the RWD cohorts were older, contained more males, with higher proportions receiving prior BRAF/MEK inhibitors, with brain metastasis, and LDH≤ULN. Median OS was 7.4 months (mo) in the trial arm, compared to 5.6 (unadjusted) and 3.5 mo (adjusted) in the chemo cohort. Hazard ratio of 0.49 (95% CI: 0.29-0.83, trial vs. chemo) indicated significant benefits of the trial arm over the chemo cohort. Analyses using taxane subgroup showed similar findings. Conclusions: The RWD cohorts demonstrated poor outcomes for the pts receiving chemotherapy, in particular taxanes, confirming this is a population of unmet need. The results show the potential for improved outcomes using cer + paclitaxel in pts previously treated with PDx.[Table: see text]