The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing

Prostate cancer is a leading cause of global cancer-related death but attempts to improve diagnoses and develop novel therapies have been confounded by significant patient heterogeneity. In recent years, the application of next-generation sequencing to hundreds of prostate tumours has defined novel molecular subtypes and characterized extensive genomic aberration underlying disease initiation and progression. It is now clear that the heterogeneity observed in the clinic is underpinned by a molecular landscape rife with complexity, where genomic rearrangements and rare mutations combine to amplify transcriptomic diversity. This review dissects our current understanding of prostate cancer ＇omics＇, including the sentinel role of copy number variation, the growing spectrum of oncogenic fusion genes, the potential influence of chromothripsis, and breakthroughs in defining mutation-associated subtypes. Increasing evidence suggests that genomic lesions frequently converge on specific cellular functions and signalling pathways, yet recurrent gene aberration appears rare. Therefore, it is critical that we continue to define individual tumour genomes, especially in the context of their expressed transcriptome. Only through improved characterisation of tumour to tumour variability can we advance to an age of precision therapy and personalized oncology.

<i>In Vitro</i>Anticancer Activity of Plant-Derived Cannabidiol on Prostate Cancer Cell Lines

Cannabinoids, the active components of Cannabis sativa Linnaeus, have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects and tumor regression, but their use in chemotherapy is limited by their psychotropic activity. To date, cannabinoids have been successfully used in the treatment of nausea and vomiting, two common side effects that accompany chemotherapy in cancer patients. Most non-THC plant cannabinoids e.g. cannabidiol and cannabigerol, seem to be devoid of psychotropic properties. However, the precise pathways through which these molecules produce an antitumor effect have not yet been fully characterized. We therefore investigated the antitumor and anti-inflammatory activities of cannabidiol (CBD) in human prostate cancer cell lines LNCaP, DU145, PC3, and assessed whether there is any advantage in using cannabis extracts enriched in cannabidiol and low in THC. Results obtained in a panel of prostate cancer cell lines clearly indicate that cannabidiol is a potent inhibitor of cancer cell growth, with significantly lower potency in non-cancer cells. The mRNA expression level of cannabinoid receptors CB1 and CB2, vascular endothelial growth factor (VEGF), PSA (prostate specific antigen) are significantly higher in human prostate cell lines. Treatment with Cannabis extract containing high CBD down regulates CB1, CB2, VEGF, PSA, pro-inflammatory cytokines/chemokine IL-6/IL-8. Our overall findings support the concept that cannabidiol, which lacks psychotropic activity, may possess anti-inflammatory property and down regulates both cannabinoid receptors, PSA, VEGF, IL-6 and IL-8. High CBD cannabis extracts are cytotoxic to androgen responsive LNCaP cells and may effectively inhibit spheroid formation in cancer stem cells. This activity may contribute to its anticancer and chemosensitizing effect against prostate cancer. Cannabidiol and other non-habit forming cannabinoids could be used as novel therapeutic agents for the treatment of prostate cancer.

Next generation patient-derived prostate cancer xenograft models

There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients＇ tumor tissue into nonobese diabetic/ severe combined immunodeficient （NOD/ SCID） mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer.

Prostate cancer metastasis-driving genes： hurdles and potential approaches in their identification

Metastatic prostate cancer is currently incurable. Metastasis is thoughtto result from changes in the expression of specific metastasis-driving genes in nonmetastatic prostate cancer tissue, leading to a cascade of activated downstream genes that set the metastatic process in motion. Such genes could potentially serve as effective therapeutic targets for improved management of the disease. They could be identified by comparative analysis of gene expression profiles of patient-derived metastatic and nonmetastatic prostate cancer tissues to pinpoint genes showing altered expression,

Mathematically modelling and controlling prostate cancer under intermittent hormone therapy

In this review, we summarize our recently developed mathematical models that predict the effects of intermittent androgen suppression therapy on prostate cancer （PCa）. Although hormone therapy for PCa shows remarkable results at the beginning of treatment, cancer cells frequently acquire the ability to grow without androgens during long-term therapy, resulting in an eventual relapse. To circumvent hormone resistance, intermittent androgen suppression was investigated as an alternative treatment option. However, at the present time, it is not possible to select an optimal schedule of on- and off-treatment cycles for any given patient. In addition, clinical trials have revealed that intermittent androgen suppression is effective for some patients but not for others. To resolve these two problems, we have developed mathematical models for PCa under intermittent androgen suppression. The mathematical models not only explain the mechanisms of intermittent androgen suppression but also provide an optimal treatment schedule for the on- and off-treatment periods.

A QSRR Study on the Chromatographic Retention Indices of Hydroxylated Polychlorinated Biphenyls

Hydroxylated Polychlorinated Biphenyls （HO-PCBs） are the metabolite of polychlorinated biphenyls and have drawn much attention because they have hazard on human health and ecosystems. Molecular connectivity index calculation has been performed for 19 HO-PCB compounds. A number of statistically based parameters have been extracted. Linear relationship between chromatographic retention index （RI） and the molecular connectivity index of 15 compounds in the training set has been established by multiple linear regression method. The other 4 HO-PCBs are used as the external test set. The result shows that the parameters can be well used to express the quantitative structure-retention relationship （QSRR） of HO-PCBs. Good stability and predictive ability have been demonstrated by leave-one-out cross-validation and the external test set.

Determining the mechanism behind yoga’s effects on preventing the symptoms of Alzheimer’s disease

Background on the relationship between meditation/yoga practice and its effect on Alzheimer's disease (AD): Dementia refers to a variety of conditions that affect the normal function of the brain, leading to symptoms like memory loss, issues with problem solving, difficulty in processing thoughts and disordered language (McKhann et al., 2011).

Chromoplexy： a new paradigm in genome remodeling and evolution

Early massively-parallel sequencing stu-dies have revealed the mutational land-scape of protein-coding genes in prostate cancer. However, most of these studies have not explored the extensive influence of geno- mic rearrangement in prostate cancer. In a recent Cell article, Baca and colleagues used whole-genome sequencing to tackle this issue, comprehensively surveying the abun-dance of genomic rearrangements present in a large cohort of 57 prostate cancers. They characterized a wide-spread phenomenon termed ＇chromoplexy＇, which may drive can-cer evolution through the phenomena of punctuated equilibrium by concurrently dys-regulating numerous cancer genes across multiple chromosomes. While the causes of this event still require elucidation, this defin-ing discovery undoubtedly offers an impor- tant glimpse into the evolutionary process of prostate cancer.

Apalutamide for metastatic castration-sensitive prostate cancer:final analysis of the Asian subpopulation in the TITAN trial

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial showed improvement in overall survival(OS)and other efficacy endpoints with apalutamide plus androgen deprivation therapy(ADT)versus ADT alone in patients with metastatic castration-sensitive prostate cancer(mCSPC).As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer,a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation.Event-driven endpoints were OS,and time from randomization to initiation of castration resistance,prostate-specific antigen(PSA)progression,and second progression-free survival(PFS2)on first subsequent therapy or death.Efficacy endpoints were assessed using the Kaplan–Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity.Participating Asian patients received once-daily apalutamide 240 mg(n=111)or placebo(n=110)plus ADT.After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide,apalutamide reduced the risk of death by 32%(hazard ratio[HR]:0.68;95%confidence interval[CI]:0.42–1.13),risk of castration resistance by 69%(HR:0.31;95%CI:0.21–0.46),PSA progression by 79%(HR:0.21;95%CI:0.13–0.35)and PFS2 by 24%(HR:0.76;95%CI:0.44–1.29)relative to placebo.The outcomes were comparable between subgroups with low-and high-volume disease at baseline.No new safety issues were identified.Apalutamide provides valuable clinical benefits to Asian patients with mCSPC,with an efficacy and safety profile consistent with that in the overall patient population.

Apalutamide for patients with metastatic castrationsensitive prostate cancer in East Asia:a subgroup analysis of the TITAN trial

Ethnicity might be associated with treatment outcomes in advanced prostate cancer.This study aimed to evaluate the efficacy and safety of androgen deprivation therapy(ADT)combined with apalutamide in East Asians with metastatic castration-sensitive prostate cancer(mCSPC).The original phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial was conducted at 260 sites in 23 countries.This subgroup analysis included patients enrolled in 62 participating centers in China,Japan,and Korea.Radiographic progression-free survival(PFS),time to prostate-specific antigen(PSA)progression,and PSA changes from baseline were compared between groups in the East Asian population.The intent-to-treat East Asian population included 111 and 110 participants in the apalutamide and placebo groups,respectively.The 24-month radiographic PFS rates were 76.1%and 52.3%in the apalutamide and placebo groups,respectively(apalutamide vs placebo:hazard ratio[HR]=0.506;95%confidence interval[CI],0.302–0.849;P=0.009).Median time to PSA progression was more favorable with apalutamide than placebo(HR=0.210;95%CI,0.124–0.357;P<0.001).Median maximum percentages of PSA decline from baseline were 99.0%and 73.9%in the apalutamide and placebo groups,respectively.The most common adverse event(AE)was rash in the apalutamide group,with a higher rate than that in the placebo group(37.3%vs 9.1%).The most common grade 3 or 4 AEs were rash(12[10.9%])and hypertension(12[10.9%])for apalutamide.The efficacy and safety of apalutamide in the East Asian subgroup of the TITAN trial are consistent with the global results.

Dynamic control of high-voltage actuator arrays by light-pattern projection on photoconductive switches

The ability to control high-voltage actuator arrays relies, to date, on expensive microelectronic processes or on individual wiring of each actuator to a single off-chip high-voltage switch. Here we present an alternative approach that uses on-chip photoconductive switches together with a light projection system to individually address high-voltage actuators. Each actuator is connected to one or more switches that are nominally OFF unless turned ON using direct light illumination. We selected hydrogenated amorphous silicon (a-Si:H) as our photoconductive material, and we provide a complete characterization of its light to dark conductance, breakdown field, and spectral response. The resulting switches are very robust, and we provide full details of their fabrication processes. We demonstrate that the switches can be integrated into different architectures to support both AC and DC-driven actuators and provide engineering guidelines for their functional design. To demonstrate the versatility of our approach, we demonstrate the use of the photoconductive switches in two distinctly different applications—control of µm-sized gate electrodes for patterning flow fields in a microfluidic chamber and control of cm-sized electrostatic actuators for creating mechanical deformations for haptic displays.

nfertility, impotence, and emasculation - psychosocia ：ontexts for abandoning reproduction

From a Darwinian perspective we live to reproduce, but in various situations genetic males elect not to reproduce by choosing medical treatments leading to infertility, impotence, and, in the extreme, emasculation. For many men, infertility can be psychologically distressing. However, for certain genetic males, being infertile may improve their quality of life. Examples include （1） men who seek vasectomy, （2） individuals with Gender Dysphoria （e.g., transwomen, and modern day voluntary eunuchs）, （3） most gay men, and （4） men treated for testicular and prostate cancer. Men who desire vasectomy typically have a Darwinian fitness W 〉1 at the time of their vasectomies; i.e., after they have their desired number of offspring or consider themselves past an age for parenting newborns. In contrast, prostate and testicular cancer patients, along with individuals with extreme Gender Dysphoria, do not necessarily seek to be sterile, but accept it as an unavoidable consequence of the treatment for their condition undertaken for survival （in case of cancer patients） or to achieve a better quality of life （for those with Gender Dysphoria）. Most gay men do not father children, but they may play an avuncular role, providing for their siblings＇ offspring＇s welfare, thus improving their inclusive fitness through kin selection. In a strictly Darwinian model, the primary motivation for all individuals is to reproduce, but there are many situations for men to remove themselves from the breeding populations because they have achieved a fitness W 〉1, or have stronger medical or psychological needs that preclude remaining fertile.

A personalized mRNA vaccine has exhibited potential in the treatment of pancreatic cancer

This commentary discusses a ground-breaking study on the use of personalized mRNA cancer vaccines for treating pancreatic ductal adenocarcinoma(PDAC),a highly malignant form of cancer.The study,which capitalizes on lipid nanoparticles for mRNA vaccine delivery,aims to induce an immune response against patient-specific neoantigens and offers a potential ray of hope for improving patient prognosis.Initial results from a Phase 1 clinical trial indicated a significant T cell response in half of the subjects,opening new avenues for PDAC treatment.However,despite the promising nature of these findings,the commentary emphasizes the challenges that remain.These include the complexity of identifying suitable antigens,the possibility of tumor immune escape,and the requirement for extensive large-scale trials to confirm long-term safety and efficacy.This commentary underscores the transformative potential of mRNA technology in oncology while highlighting the hurdles that need to be overcome for its widespread adoption.