Issue Information

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Fertility preservation for female cancer patients

Abstract

An improvement in the survival rates of cancer patients and recent advancements in assisted reproductive technologies have led to remarkable progress in oncofertility and fertility preservation treatments. Currently, for adults and postpubertal girls, oocyte or embryo cryopreservation is an established method. If their cancer treatment cannot be postponed for 2 weeks, ovarian tissue cryopreservation is offered as an experimental technique. For prepubertal girls, ovarian tissue cryopreservation is the only option. As for ovarian protection, there is insufficient evidence regarding the effectiveness of GnRH agonist in fertility preservation. In the past decade, the concept of fertility preservation for cancer patients has been rapidly spreading, but at present only a small part of young cancer patients receive fertility preservation services. It is partly because of the lack of adequate provision of information on fertility preservation and the lack of referral from oncology to the fertility clinic. In Japan, the clinical practice guidelines for fertility preservation in childhood, adolescent and young adult cancer patients was issued last year by the Japan Society of Clinical Oncology (JSCO). It would help Japanese health care providers, including oncologists and reproductive specialists, to increase their knowledge on fertility preservation for cancer patients and move forward the fertility preservation services. For further progress, it is also needed to establish a national registration system of fertility preservation for cancer patients to evaluate the safety and efficacy of the current management.

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Brain-resident memory CD8+ T cells induced by congenital CMV infection prevent brain pathology and virus reactivation

Abstract

Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with MCMV intraperitoneally is a well-established model of congenital HCMV infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here we used this model to investigate the role, dynamics and phenotype of CD8⁺ T cells in the brain following infection of newborn mice. We show that CD8⁺ T cells infiltrate the brain and form a pool of tissue-resident memory T cells (T_RM cells) that persist for lifetime. Adoptively transferred virus-specific CD8⁺ T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology and remain in the brain as T_RM cells. Brain CD8⁺ T_RM cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8⁺ T_RM cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain.

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On the response function and range dependence of manual estimation

Abstract

Manual estimates without vision of the hand are thought to constitute a form of cross-modal matching between stimulus size and finger opening. However, few investigations have systematically looked at how manual estimates relate a perceived size to the response across different ranges of stimuli. In two experiments (N = 18 and N = 14), we sought to map out the response properties for (1) manual estimates of visually presented stimuli as well as (2) visual estimates of proprioceptive stimuli, and to test whether these properties depend on the range of stimuli. We also looked at whether scalar variability is present in manual estimates, as predicted by Weber's Law for perceptual tasks. We found that manual estimates scale linearly and with a slope of close to 1 with object sizes up to 90 mm, before participants' hand size limited their responses. In contrast, we found a shallower response slope of about 0.7 when participants performed the inverse task, adjusting the size of a visual object to match a not actively chosen, induced finger opening. Our results were mixed with regards to scalar variability in large objects. We saw some indication of a plateau, but no evidence for an effect of mechanical constraints in the range studied (up to 90 mm). Participants also showed a clear tendency to overestimate small differences when a set of objects differed little in size, but not when stimulus differences were more pronounced.

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Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics

Abstract

Background

Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics.

Methods

Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case–control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER−), progesterone receptor (PR+/PR−), and HER2 (HER2+/HER2−). Analyses were conducted separately in pre- and postmenopausal women.

Results

Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11–27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2− breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05).

Conclusion

Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.

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Tumor-associated myeloid cells promote tumorigenesis of non-tumorigenic human and murine prostatic epithelial cell lines

Abstract

The etiology of prostate cancer is poorly understood, but it is a multi-step process that has been linked to environmental factors that induce inflammation within the gland. Glands of prostate cancer patients frequently contain multiple zones of disease at various stages of progression. The factors that drive disease progression from an indolent benign stage to aggressive disease are not well-defined. Prostate inflammation and carcinoma are associated with high levels of myeloid cell infiltration; these cells are linked to disease progression in other cancers, but their role in prostate cancer is unclear. To determine whether myeloid cells contribute to prostate cancer progression, the ability of prostate tumor-associated CD11b⁺ cells (TAMC) to drive prostate epithelial cell tumorigenesis was tested. Co-culture of CD11b⁺ TAMC with non-tumorigenic genetically primed prostate epithelial cells resulted in stable transformation and induction of tumorigenesis. RNA sequencing identified the IL-1α pathway as a potential molecular mechanism responsible for tumor promotion by TAMC. Inhibition of IL-1α delayed growth of TAMC-induced tumors. Further analysis showed that IL-1α inhibition led to decreased angiogenesis within tumors, suggesting that IL-1α promotes prostate tumor progression, potentially through augmentation of angiogenesis.

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Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity

Abstract

The accumulation of misfolded α-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the precise relationship between pathology and neurotoxicity and why these processes disproportionately affect certain neuron subpopulations are poorly understood. We show here that Math2-expressing neurons in the hippocampal Cornu ammonis (CA), a region significantly affected by aSyn pathology in advanced PD and DLB, are highly susceptible to pathological seeding with pre-formed fibrils (PFFs), in contrast to dentate gyrus neurons, which are relatively spared. Math2⁺ neurons also exhibited more rapid and severe cell loss in both in vitro and in vivo models of synucleinopathy. Toxicity resulting from PFF exposure was dependent on endogenous aSyn and could be attenuated by N-acetyl-cysteine through a glutathione-dependent process. Moreover, aSyn expression levels strongly correlate with relative vulnerability among hippocampal neuron subtypes of which Math2⁺ neurons contained the highest amount. Consistent with this, antisense oligonucleotide (ASO)-mediated knockdown of aSyn reduced the neuronal pathology in a time-dependent manner. However, significant neuroprotection was observed only with early ASO intervention and a substantial reduction of aSyn pathology, indicating toxicity occurs after a critical threshold of pathological burden is exceeded in vulnerable neurons. Together, our findings reveal considerable heterogeneity in endogenous aSyn levels among hippocampal neurons and suggest that this may contribute to the selective vulnerability observed in the context of synucleinopathies.

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