Is Low Polydispersity Always Beneficial? Exploring the Impact of Size Polydispersity on the Microstructure and Rheological Properties of Graphene Oxide.

Graphene oxide (GO) is a promising material widely utilized in advanced materials engineering, such as in the development of soft robotics, sensors, and flexible devices. Considering that GOs are often processed using solution-based methods, a comprehensive understanding of the fundamental characteristics of GO in dispersion states becomes crucial given their significant influence on the ultimate properties of the device. GOs inherently exhibit polydispersity in solution, which plays a critical role in determining the mechanical behavior and flowability. However, research in the domain of 2D colloids concerning the effects of GO's polydispersity on its rheological properties and microstructure is relatively scant. Consequently, gaining a comprehensive understanding of how GO's polydispersity affects these critical aspects remains a pressing concern. In this study, we aim to investigate the dispersions and structure of GOs and clarify the effect of polydispersity on the rheological properties and yielding behavior. Using a rheometer, polarized optical microscopy, and small-angle X-ray scattering, we found that higher polydispersity in the same average size leads to overall improved rheological properties and higher flowability during yielding. Thus, our study can be beneficial in the employment of polydispersity in the processing of GO such as 3D printing and fiber spinning.

Additive-Free Gelation of Graphene Oxide Dispersions via Mild Thermal Annealing: Implications for 3D Printing and Supercapacitor Applications.

Herein, a mild thermal annealing (MTA) process is presented for additive-free gelation of graphene oxide (GO) dispersions. This process transitions the GO from a nematic liquid crystal phase to a random network structure, significantly enhancing its rheological properties by order of magnitude. This transition is facilitated by the diffusion of functional groups on the GO surface, which induces hydrophobic attractions, leading to a stable network structure. Employing rheo-SAXS experiments, detailed insights are provided into the microstructural changes of GO gel under shear stress, establishing a direct correlation between its rheological behavior and microstructure. The distinctive properties of MTA-processed inks are illustrated, seamlessly integrating with 3D printing, to yield a highly porous lattice structure that demonstrates promising potential as a supercapacitor electrode. The MTA process, an additive-free approach to gelation, maintains the inherent dispersion properties of GO while offering scalability. Thus, this method brings significant economic and environmental advantages compared to conventional gelation techniques. The findings not only advance the fundamental understanding of 2D colloidal network gels but also increase the potential of GO for a wide range of applications, from gas and liquid absorbers to electrodes for energy storage and conversion, and biomedical fields.

Functional Thermoplastic Polyurethane Elastomers with α, ω-Hydroxyl End-Functionalized Polyacrylates.

Thermoplastic polyurethane (TPU) is an essential class of materials for demanding applications, from soft robotics and electronics to medical devices and batteries. However, traditional TPU development is primarily relied on specific soft segments, such as polyether, polyester, and polycarbonate polyols. Here, a novel method is introduced for developing TPU elastomers with enhanced performance and superior functionalities compared to conventional TPUs, achieved through the use of α,ω-hydroxyl end-functionalized polyacrylates. This approach involves a defect-free synthesis of α,ω-hydroxyl end-functionalized polyacrylates through visible-light-driven photoiniferter polymerization. By strategically blending these functionalized polyacrylates with conventional polyols, TPUs that exhibit exceptional toughness and notable self-healing capabilities, traits rarely found in existing TPUs are engineered. Furthermore, incorporating photo-crosslinkable acrylic monomers has enabled the creation of the first TPU with superior elastomeric properties and photopatterning capabilities. This approach paves the way for a new direction in polyurethane engineering, introducing a novel class of soft segments and unlocking the potential for a wide range of advanced applications.

Molecular Mechanisms Determining Mammalian Oocyte Quality with the Treatment of Cancer Therapy.

Cancer is a global public health issue and remains one of the leading causes of death in the United States (Siegel et al. CA Cancer J Clin. 72:7-33, 2022). It is estimated in the US in 2022, about 935,000 new cases of cancer will be diagnosed in women, and the probability of developing invasive cancer is 5.8% for females younger than 50 years old (Siegel et al. CA Cancer J Clin. 72:7-33, 2022). However, advances in screening programs, diagnostic methods, and therapeutic options have greatly increased the five-year survival rate in reproductive-age women with a variety of cancers. Given the clinical consequences of gonadotoxic cancer therapies, young, female cancer survivors may face compromised fertility, premature ovarian insufficiency, early-onset menopause, and endocrine dysregulation (Bedoschi et al. Future Oncol. 12:2333-44, 2016). Gonadotoxic side effects may include decreased oocyte quality within surviving follicles, loss of ovarian follicles, and impaired ovarian function. In reproductive-age women, oocyte quality is an important element for successful clinical pregnancies and healthy offspring as poor-quality oocytes may be a cause of infertility (McClam et al. Biol Reprod. 106:328-37, 2022; Marteil et al. Reprod Biol. 9:203-24, 2009; Krisher. J Anim Sci. 82: E14-E23, 2004). Thus, it is critical to determine the quantity and quality of surviving follicles in the ovary after cancer treatment and to assess oocyte quality within those surviving follicles as these are markers for determining the capacity for ovarian function restoration and future fertility, especially for young cancer survivors (Xu et al. Nat Med. 17:1562-3, 2011). The long-term effects of cancer therapeutics on oocyte quality are influenced by factors including, but not limited to, individual patient characteristics (e.g. age, health history, comorbidities, etc.), disease type, or treatment regimen (Marci et al. Reprod Biol Endocrinol. 16:1-112, 2018). These effects may translate clinically into an impaired production of viable oocytes and compromised fertility (Garutti et al. ESMO Open. 6:100276, 2021).

KIT in oocytes: a key factor for oocyte survival and reproductive lifespan.

BACKGROUND: The KITL-KIT interaction is known as an important initiator in oocyte activation through the downstream pathway of PI3K-AKT-FOXO3 signalling. Previous studies utilising germ cell-specific Kit mutant knockin and kinase domain knockout models with Vasa-Cre suggested the crucial role of KIT in oocyte activation at the primordial follicle stage. METHODS: We utilised mice with complete postnatal deletion of KIT expression in oocytes via Gdf9-iCre and conducted analyses on ovarian follicle development, specific markers, hormone assays, and fertility outcomes. FINDINGS: Our findings reveal contrasting phenotypes compared to previous mouse models with prenatal deletion of Kit. Specifically, postnatal deletion of Kit exhibit no defects in germ cell nest breakdown, follicle activation, and folliculogenesis during development. Remarkably, upon reaching full maturity, mice with postnatal deletion of Kit experience a complete loss of ovarian reserve, growing follicles, and ovarian function. Furthermore, mice display smaller ovarian size and weight, delayed folliculogenesis, and phenotypes indicative of primary ovarian insufficiency (POI), including elevated serum levels of FSH, reduced AMH, and absence of ovarian follicles, ultimately resulting in infertility. Additionally, the ovaries exhibit randomly distributed expression of granulosa and theca cell markers such as Inhibin α, ACVR2B, and LHR. Notably, there is the uncontrolled expression of p-SMAD3 and Ki67 throughout the ovarian sections, along with the widespread presence of luteinised stroma cells and cleaved Caspase-3-positive dying cells. INTERPRETATION: These genetic studies underscore the indispensable role of KIT in oocytes for maintaining the survival of ovarian follicles and ensuring the reproductive lifespan. FUNDING: This work was supported by National Institutes of Health grant R01HD096042 and startup funds from UNMC (S.Y.K.).

The Role of Scientific Research in Human Papillomavirus Vaccine Discussions on Twitter: Social Network Analysis.

BACKGROUND: Attitudes toward the human papillomavirus (HPV) vaccine and accuracy of information shared about this topic in web-based settings vary widely. As real-time, global exposure to web-based discourse about HPV immunization shapes the attitudes of people toward vaccination, the spread of misinformation and misrepresentation of scientific knowledge contribute to vaccine hesitancy. OBJECTIVE: In this study, we aimed to better understand the type and quality of scientific research shared on Twitter (recently rebranded as X) by vaccine-hesitant and vaccine-confident communities. METHODS: To analyze the use of scientific research on social media, we collected tweets and retweets using a list of keywords associated with HPV and HPV vaccines using the Academic Research Product Track application programming interface from January 2019 to May 2021. From this data set, we identified tweets referring to or sharing scientific literature through a Boolean search for any tweets with embedded links, hashtags, or keywords associated with scientific papers. First, we used social network analysis to build a retweet or reply network to identify the clusters of users belonging to either the vaccine-confident or vaccine-hesitant communities. Second, we thematically assessed all shared papers based on typology of evidence. Finally, we compared the quality of research evidence and bibliometrics between the shared papers in the vaccine-confident and vaccine-hesitant communities. RESULTS: We extracted 250 unique scientific papers (including peer-reviewed papers, preprints, and gray literature) from approximately 1 million English-language tweets. Social network maps were generated for the vaccine-confident and vaccine-hesitant communities sharing scientific research on Twitter. Vaccine-hesitant communities share fewer scientific papers; yet, these are more broadly disseminated despite being published in less prestigious journals compared to those shared by the vaccine-confident community. CONCLUSIONS: Vaccine-hesitant communities have adopted communication tools traditionally wielded by health promotion communities. Vaccine-confident communities would benefit from a more cohesive communication strategy to communicate their messages more widely and effectively.

Constructing a Comprehensive Nanopattern Library through Morphological Transitions of Block Copolymer Surface Micelles via Direct Solvent Immersion.

This study establishes a comprehensive library of nanopatterns achievable by a single block copolymer (BCP), ranging from spheres to complex structures like split micelles, flower-like clusters, toroids, disordered micelle arrays, and unspecified unique shapes. The ordinary nanostructures of polystyrene-b-poly(2-vinylpyridine) (PS-b-P2VP) surface micelles deposited on a SiOx surface undergo a unique morphology transformation when immersed directly in solvents. Investigating parameters such as immersion solvents, BCP molecular weight, substrate interactions, and temperature, this work reveals the influence of these parameters on the thermodynamics and kinetics governing the morphology transformation. Additionally, the practical application of BCP nanopattern templates for fabricating metal nanostructures through direct solvent immersion of surface micelles is demonstrated. This approach offers an efficient and effective method for producing diverse nanostructures, with the potential to be employed in nanolithography, catalysts, electronics, membranes, plasmonics, and photonics.

Structural Homogeneity of Macromolecular Networks by End-to-End Click Chemistry between Discrete Tetrahedral Star Macromolecules.

Cross-linking via the end-to-end click chemistry of multiarm star polymers creates polymer networks with minimal inhomogeneities. Although it has been suggested that the mechanical and swelling properties of such networks depend on the absence of defects, the structural details of homogeneous networks created by this method have not yet been studied at the molecular level. Here, we report the synthesis of discrete tetrahedral star macromolecules (dTSMs) composed of polylactide (PLA) arms with discrete molecular weight and sequence. Polymer networks prepared by 4 × 4 cross-linking by Cu-free strain-promoted cyclooctyne-azide click chemistry (SPAAC) reaction exhibited a high degree of swelling (>40 fold by weight) in solvents without sacrificing mechanical robustness (elastic modulus >4 kPa). The structural details of the networks were investigated by network disassembly spectrometry (NDS) using MALDI-TOF mass spectrometry. By implementing a cleavable repeating unit in the discrete PLA arms of dTSM in a sequence-specific manner, the networks could be disassembled into fragments having discrete molecular weights precisely representing their connectivity in the network. This NDS analysis confirmed that end-to-end click reactions of dTSM networks resulted in the formation of a homogeneous network above the critical concentration (∼10 w/v%) of building blocks in the solution.

Sodium thiosulfate does not protect ovarian reserve from cisplatin-induced gonadotoxicity†.

Cisplatin, a platinum-containing alkylating agent, is used in the treatment of various tumors owing to its potent antitumor activity. However, it causes permanent and adverse effects, particularly hearing loss and depletion of ovarian reserve. Until recently, there were no clinically available protective agents to mitigate the adverse side effects of cisplatin-induced cytotoxicity. In 2022, sodium thiosulfate (STS) was approved by the Food and Drug Administration for mitigating hearing loss in children and adolescents undergoing cisplatin treatment. Consequently, our investigation aimed to determine if STS could protect ovarian reserve against cisplatin-induced gonadotoxicity. In an ex vivo culture, the cisplatin-only group exhibited a loss of primordial follicles, while post-STS administration after cisplatin exposure effectively protected primordial follicles. However, when post-STS was administrated either 6 or 4 h after cisplatin exposure, it did not confer protection against cisplatin-induced gonadotoxicity in postnatal day 7 or adolescent mouse models. Immunofluorescence assays using γH2AX and cPARP revealed that oocytes within primordial follicles exhibited DNA damage after cisplatin exposure, irrespective of post-STS administration. This underscores the rapid and heightened sensitivity of oocytes to gonadotoxicity. In addition, oocytes demonstrated an increased expression of pCHK2 rather than pERK, suggesting that the pathway leading to oocyte death differs from the pathway observed in the inner ear cell death following cisplatin exposure. These results imply that while the administration of STS after cisplatin is highly beneficial in preventing hearing loss, it does not confer a protective effect on the ovaries in mouse models.

Metabolic characteristics of granulosa cell tumor: role of PPARγ signaling†.

Granulosa cell tumors are relatively rare, posing challenges for comprehension and therapeutic development due to limited cases and preclinical models. Metabolic reprogramming, a hallmark of cancer, manifests in granulosa cell tumors with notable lipid accumulation and increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), a key lipid metabolism regulator. The roles of these features, however, remain unclear. In our previous work, we established a granulosa cell tumor model in mice by introducing a constitutively active Pik3ca mutant in oocytes, enabling the study of predictable tumor patterns from postnatal day 50. In this study, we characterized metabolic alterations during tumorigenesis (postnatal day 8 to day 50) and tumor growth (day 50 to day 65) in this model and explored the impact of PPARγ antagonism on human granulosa cell tumor proliferation. The tumor exhibited significant lipid accumulation, with PPARγ and the proliferation marker Ki67 co-localizing at postnatal day 65. Transcriptome analysis demonstrates that pathways for lipid metabolism and mitochondrial oxidation are promoted during tumorigenesis and tumor growth, respectively. Overlappingly upregulated genes during tumorigenesis and tumor growth are associated with lipid metabolism pathways. Correspondingly, mouse granulosa cell tumor shows overexpression of peroxisome proliferator-activated receptor gamma and DGAT2 proteins at postnatal day 65. Furthermore, GW9662 reduces the proliferation of KGN human granulosa cell tumor cells and decreases the phosphorylation of AKT and SMAD3. Our findings identify metabolic abnormalities in ooPIK3CA* granulosa cell tumor model and suggest peroxisome proliferator-activated receptor gamma as a potential driver for primary granulosa cell tumor growth.

Enhanced stability, formulations, and rheological properties of nanoemulsions produced with microfludization for eco-friendly process.

HYPOTHESIS: Eco-friendly processes that are emerging around the world require mass production of low-energy, low-cost nanoemulsions. The process involving the high-concentrated nanoemulsions and diluting them with a large amount of solvent can certainly save the cost; however, not much detailed research has been conducted on the stability mechanism and rheological characteristics of high-concentrated nanoemulsions. EXPERIMENTS: In this study, we produced nanoemulsions via the microfluidization (MF) process, comparing their dispersion stability and rheological characteristics with macroemulsions across various oil and surfactant concentrations. Droplet mobility and dispersion stability depended on these concentrations, with Asakura-Osawa-type attractive depletion considering interparticle interaction's role in stability changes. We investigated nanoemulsions' long-term stability based on turbidity and droplet size changes over four weeks, proposing a stability diagram showing four different states depending on emulsification conditions. FINDINGS: We explored the microstructure of emulsions under varying mixing conditions, observing their effects on droplet mobility and rheological properties. We monitored changes in rheology, turbidity, and droplet size over 4 weeks, establishing stability diagrams for macro- and nanoemulsions. The stability diagrams revealed that the stability of emulsions are sensitively dependent on the droplet size, concentrations, surfactant cocentrations and the strcture of coexistent phases in case of macroscopic segregation are significantly different depending on the droplet sizes. We identified their respective stability mechanisms and discovered the relationship between stability and rheological properties for highly concentrated nanoemulsion.

Key takeaways for knowledge expansion of early-career scientists conducting Transdisciplinary Research in Energetics and Cancer (TREC): a report from the TREC Training Workshop 2022.

The overall goal of the annual Transdisciplinary Research in Energetics and Cancer (TREC) Training Workshop is to provide transdisciplinary training for scientists in energetics and cancer and clinical care. The 2022 Workshop included 27 early-to-mid career investigators (trainees) pursuing diverse TREC research areas in basic, clinical, and population sciences. The 2022 trainees participated in a gallery walk, an interactive qualitative program evaluation method, to summarize key takeaways related to program objectives. Writing groups were formed and collaborated on this summary of the 5 key takeaways from the TREC Workshop. The 2022 TREC Workshop provided a targeted and unique networking opportunity that facilitated meaningful collaborative work addressing research and clinical needs in energetics and cancer. This report summarizes the 2022 TREC Workshop's key takeaways and future directions for innovative transdisciplinary energetics and cancer research.

Uncovering Tumor-Promoting Roles of Activin A in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with high incidence rates of metastasis and cachexia. High circulating activin A, a homodimer of inhibin ßA subunits that are encoded by INHBA gene, predicts poor survival among PDAC patients. However, it still raises the question of whether activin A suppression renders favorable PDAC outcomes. Here, the authors demonstrate that activin A is abundantly detected in tumor and stromal cells on PDAC tissue microarray and mouse PDAC sections. In orthotopic male mice, activin A suppression, which is acquired by tumor-targeted Inhba siRNA using cholesterol-modified polymeric nanoparticles, retards tumor growth/metastasis and cachexia and improves survival when compared to scramble siRNA-treated group. Histologically, activin A suppression coincides with decreased expression of proliferation marker Ki67 but increased accumulation of α-SMAhigh fibroblasts and cytotoxic T cells in the tumors. In vitro data demonstrate that activin A promotes KPC cell proliferation and induces the downregulation of α-SMA and upregulation of IL-6 in pancreatic stellate cells (PSC) in the SMAD3-dependent mechanism. Moreover, conditioned media from activin A-stimulated PSC promoted KPC cell growth. Collectively, our data provide a mechanistic basis for tumor-promoting roles of activin A and support therapeutic potentials of tumor activin A suppression for PDAC.

HPV vaccine narratives on Twitter during the COVID-19 pandemic: a social network, thematic, and sentiment analysis.

INTRODUCTION: The COVID-19 pandemic has increased online interactions and the spread of misinformation. Some researchers anticipate benefits stemming from improved public awareness of the value of vaccines while others worry concerns around vaccine development and public health mandates may have damaged public trust. There is a need to understand whether the COVID-19 pandemic, vaccine development, and vaccine mandates have influenced HPV vaccine attitudes and sentiments to inform health communication strategies. METHODS: We collected 596,987 global English-language tweets from January 2019-May 2021 using Twitter's Academic Research Product track. We determined vaccine confident and hesitant networks discussing HPV immunization using social network analysis. Then, we used a neural network approach to natural language processing to measure narratives and sentiment pertaining to HPV immunization. RESULTS: Most of the tweets in the vaccine hesitant network were negative in tone (54.9%) and focused on safety concerns surrounding the HPV vaccine while most of the tweets in the vaccine confident network were neutral (51.6%) and emphasized the health benefits of vaccination. Growth in negative sentiment among the vaccine hesitant network corresponded with legislative efforts in the State of New York to mandate HPV vaccination for public school students in 2019 and the WHO declaration of COVID-19 as a Global Health Emergency in 2020. In the vaccine confident network, the number of tweets concerning the HPV vaccine decreased during the COVID-19 pandemic but in both vaccine hesitant and confident networks, the sentiments, and themes of tweets about HPV vaccine were unchanged. CONCLUSIONS: Although we did not observe a difference in narratives or sentiments surrounding the HPV vaccine during the COVID-19 pandemic, we observed a decreased focus on the HPV vaccine among vaccine confident groups. As routine vaccine catch-up programs restart, there is a need to invest in health communication online to raise awareness about the benefits and safety of the HPV vaccine.

Thyroid hormone triiodothyronine does not protect ovarian reserve from DNA damage induced by X-ray and cisplatin.

PURPOSE: Cancer therapy can induce premature ovarian insufficiency, necessitating methods for preserving fertility in female cancer patients. However, the only accepted clinical practice for doing so is cryopreservation of embryos, unfertilized ova, and ovarian tissue, despite potential options such as in vitro maturation of follicles. Therefore, considerable interest has arisen in fertoprotective agents, with research on rat ovarian granulosa cells suggesting that triiodothyronine (T3) regulates an anti-apoptosis mechanism that protects the ovarian reserve from paclitaxel-induced DNA damage. In this study, we used postnatal day 5 mouse ovary to confirm the existence of T3 thyroid hormone receptor (THR), as well as to investigate the potential protective effects of T3 against cisplatin- and X-ray-induced apoptosis. We also tested the potential anti-apoptotic effect of T3 in the breast cancer cell line MDA-MB-231. METHODS: We treated cultured mouse ovaries with varying concentration of T3 and 4 µM cisplatin and 0.2 Gy X-ray. Real-time PCR, histological analysis, immunoblot analysis, and immunofluorescence were performed to assess the potential anti-apoptotic effects of T3. RESULTS: We confirmed that THR alpha and beta are expressed in the mouse ovary. T3 (0.1, 1, 10, 100 nM, and 1 µM) does not protect ovarian reserve from cisplatin- or X-ray-induced apoptosis or DNA damage. Similarly, it does not protect mouse granulosa cells and MDA-MB-231 cells from cisplatin- or X-ray-induced apoptosis. CONCLUSION: Our findings suggest that T3 is ineffective as a fertoprotective agent, and its candidacy as a potential agent to preserve fertility should be reconsidered.

Intensified Nonequilibrium Effect of Polymer Nanocomposites with Decreasing Nanoparticle Size.

What are the most important and decisive parameters that determine the structure and the property of polymer nanocomposites (PNCs)? Previous studies answered that controlling the nanoparticle interface is critical, which can be achieved with a choice of a compatible nanoparticle, a proper surface modification, and a change in the polymer chain length. In addition to these parameters, the processing condition of PNCs has recently emerged as an influential parameter for controlling PNC properties, suggesting the existence of the nonequilibrium effect of PNCs. In this regard, we chose the solvent as a main change in the processing condition and investigated the initial solvent-driven nonequilibrium effect of PNCs with varied nanoparticle (NP) sizes. We found that the type of the initial solvent is indeed crucial in determining the ultimate properties of the PNCs, and this becomes more influential as the size of NPs decreases. The decreasing size of NPs causes a conformational change in the adsorbed polymers from tightly packed layers to loosely dangling chains. This results in much greater differences in NP microstructures and rheological properties of PNCs, indicating a stronger nonequilibrium effect with smaller NPs.

Expression and T cell regulatory action of the PD-1 immune checkpoint in the ovary and fallopian tube.

PROBLEM: Immune cell trafficking and surveillance within the ovary and fallopian tube are thought to impact fertility and also tumorigenesis in those organs. However, little is known of how native cells of the ovary and fallopian tube interact with resident immune cells. Interaction of the Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint with PD-L1 is associated with downregulated immune response. We have begun to address the question of whether PD-1 ligand or its receptors (PD-L1/-L2) can regulate immune cell function in these tissues of the female reproductive tract. METHOD OF STUDY: PD-1 and ligand protein expression was evaluated in human ovary and fallopian tube specimens, the latter of which included stages of tubal cell transformation and early tumorigenesis. Ovarian expression analysis included the determination of the proteins in human follicular fluid (HFF) specimens collected during in vitro fertilization procedures. Finally, checkpoint bioactivity of HFF was determined by treatment of separately-isolated human T cells and the measurement of interferon gamma (IFNγ). RESULTS: We show that membrane bound and soluble variants of PD-1 and ligands are expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were present in HFF at bioactive levels that control T cell PD-1 activation and IFNγ production; full-length checkpoint proteins were found to be highly enriched in HFF exosome fractions. CONCLUSION: The detection of PD-1 checkpoint proteins in the human ovary and fallopian tube suggests that the pathway is involved in immunomodulation during folliculogenesis, the window of ovulation, and subsequent egg and embryo immune-privilege. Immunomodulatory action of receptor and ligands in HFF exosomes is suggestive of an acute checkpoint role during ovulation. This is the first study in the role of PD-1 checkpoint proteins in human tubo-ovarian specimens and the first examination of its potential regulatory action in the contexts of normal and assisted reproduction.

TAp63 determines the fate of oocytes against DNA damage.

Cyclophosphamide and doxorubicin lead to premature ovarian insufficiency as an off-target effect. However, their oocyte death pathway has been debated. Here, we clarified the precise mechanism of ovarian depletion induced by cyclophosphamide and doxorubicin. Dormant oocytes instead of activated oocytes with high PI3K activity were more sensitive to cyclophosphamide. Checkpoint kinase 2 (CHK2) inhibitor rather than GNF2 protected oocytes from cyclophosphamide and doxorubicin, as cyclophosphamide up-regulated p-CHK2 and depleted primordial follicles in Abl1 knockout mice. Contrary to previous reports, TAp63 is pivotal in cyclophosphamide and doxorubicin-induced oocyte death. Oocyte-specific Trp63 knockout mice prevented primordial follicle loss and maintained reproductive function from cyclophosphamide and doxorubicin, indicated by undetectable levels of BAX and cPARP. Here, we demonstrated that TAp63 is fundamental in determining the signaling of oocyte death against DNA damage. This study establishes the role of TAp63 as a target molecule of adjuvant therapies to protect the ovarian reserve from different classes of chemotherapy.

Adipose Tissue Wasting as a Determinant of Pancreatic Cancer-Related Cachexia.

Pancreatic cancer (PC) is the third leading cause of cancer-related death in the US, and its 5-year survival rate is approximately 10%. The low survival rates largely stem from diagnostic delay and the presence of significant adipose tissue and muscle wasting, commonly referred to as cachexia. Cachexia is present in nearly 80% of PC patients and is a key cause of poor response to treatment and about 20% of death in PC patients. However, there are few clinical interventions proven to be effective against PC-related cachexia. Different cancer types feature distinct secretome profiles and functional characteristics which would lead to cachexia development differently. Therefore, here we discuss affected tissues and potential mechanisms leading to cachexia in PC. We postulate that the most affected tissue during the development of PC-related cachexia is adipose tissue, historically and still thought to be just an inert repository for excess energy in relation to cancer-related cachexia. Adipose tissue loss is considerably greater than muscle loss in quantity and shows a correlation with poor survival in PC patients. Moreover, we suggest that PC mediates adipose atrophy by accelerating adipocyte lipid turnover and fibroblast infiltration.