p66ShcA promotes malignant breast cancer phenotypes by alleviating energetic and oxidative stress.

Significant efforts have focused on identifying targetable genetic drivers that support the growth of solid tumors and/or increase metastatic ability. During tumor development and progression to metastatic disease, physiological and pharmacological selective pressures influence parallel adaptive strategies within cancer cell sub-populations. Such adaptations allow cancer cells to withstand these stressful microenvironments. This Darwinian model of stress adaptation often prevents durable clinical responses and influences the emergence of aggressive cancers with increased metastatic fitness. However, the mechanisms contributing to such adaptive stress responses are poorly understood. We now demonstrate that the p66ShcA redox protein, itself a ROS inducer, is essential for survival in response to physiological stressors, including anchorage independence and nutrient deprivation, in the context of poor outcome breast cancers. Mechanistically, we show that p66ShcA promotes both glucose and glutamine metabolic reprogramming in breast cancer cells, to increase their capacity to engage catabolic metabolism and support glutathione synthesis. In doing so, chronic p66ShcA exposure contributes to adaptive stress responses, providing breast cancer cells with sufficient ATP and redox balance needed to withstand such transient stressed states. Our studies demonstrate that p66ShcA functionally contributes to the maintenance of aggressive phenotypes and the emergence of metastatic disease by forcing breast tumors to adapt to chronic and moderately elevated levels of oxidative stress.

Dung removal increases under higher dung beetle functional diversity regardless of grazing intensification.

Dung removal by macrofauna such as dung beetles is an important process for nutrient cycling in pasturelands. Intensification of farming practices generally reduces species and functional diversity of terrestrial invertebrates, which may negatively affect ecosystem services. Here, we investigate the effects of cattle-grazing intensification on dung removal by dung beetles in field experiments replicated in 38 pastures around the world. Within each study site, we measured dung removal in pastures managed with low- and high-intensity regimes to assess between-regime differences in dung beetle diversity and dung removal, whilst also considering climate and regional variations. The impacts of intensification were heterogeneous, either diminishing or increasing dung beetle species richness, functional diversity, and dung removal rates. The effects of beetle diversity on dung removal were more variable across sites than within sites. Dung removal increased with species richness across sites, while functional diversity consistently enhanced dung removal within sites, independently of cattle grazing intensity or climate. Our findings indicate that, despite intensified cattle stocking rates, ecosystem services related to decomposition and nutrient cycling can be maintained when a functionally diverse dung beetle community inhabits the human-modified landscape.

Exploiting the advantages of a wireless seed localization system that differentiates between the seeds: Breast cancer resection following neoadjuvant chemotherapy.

BACKGROUND: Most wireless localization methods utilize only one means of detection for the surgeon, sufficient to localize a single small breast lesion for excision. Complex cases requiring bracketing of a larger lesion or localization of two or more close lesions can superimpose the signal from separate "seeds" with such methods. The lack of discernment between the localization "seeds" can disorient the surgeon, risking a missed lesion on excision and longer operative times. with the use of neoadjuvant chemotherapy prior to breast surgery, the necessity of localizing both a breast lesion and an axillary lymph node previously biopsied is becoming frequent. CASE: A 44 year-old woman underwent neoadjuvant chmotherapy for a breast cancer the did not express estrogen receptor, progesterone receptor, or HER2 receptor. In establishing the extent of disease, a suspicious ipsilateral lymph node was biopsied and found to contain metastatic disease. She had an excellent response to the chemotherapy, with decreased size of the primary tumor and the previously biopsied lymph node. The patient desired breast conservation. The primary tumor and associated calcifications were bracketed using two different Smartclips™, with a third localizing the lymph node biopsied. CONCLUSION: This report illustrates how the use of three SmartClips™, within the EnVisioTM system, allowed for separate tracking of each "seed" throughout a complex surgery in a patient following neoadjuvant chemotherapy. This resulted in successful resection of both the tumor and the tagged lymph node.

Bremelanotide for Treatment of Female Hypoactive Sexual Desire.

Hypoactive sexual desire disorder (HSDD) is a persistent deficiency or absence of sexual fantasies and desire resulting in significant distress or interpersonal difficulty. Women with this disorder may display a lack of motivation for sexual activity, reduced responsiveness to erotic cues, a loss of interest during sexual activity, and avoidance of situations that could lead to sexual activity. The pathophysiology of HSDD is thought to be centered around inhibitory and excitatory hormones, neurotransmitters, and specific brain anatomy. Due to the multifactorial nature of HSDD, treatment can be complex and must attempt to target the biological and psychosocial aspects of the disorder. Bremelanotide is a melanocortin receptor agonist and has been recently approved by the FDA to treat HSDD. Bremelanotide is administered intranasally or as a subcutaneous injection. The recommended dosage of bremelanotide is 1.75 mg injected subcutaneously in the abdomen or thigh at least 45 min before sexual activity. Studies showed improvements in desire, arousal, and orgasm scores when 1.75 mg of bremelanotide was administered before sexual activity compared to a placebo. Bremelanotide is a promising way to treat HSDD.

Lamotrigine and Stevens-Johnson Syndrome Prevention.

Stevens-Johnson Syndrome (SJS) is a rare life-threatening condition characterized by severe mucocutaneous epidermal necrolysis and detachment of the epidermis. The condition centers around a delayed-type hypersensitivity reaction with a complex etiology stemming from a variety of causes. The number one cause is medication-related-common ones including sulfonamides, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory drugs. Genetics also play a role as several human leukocyte antigen (HLA) genotypes within certain ethnic groups have been implicated in adverse reactions to specific drugs. HLAB*15:02 has been identified in the Chinese and others of Southeast Asian origin to increase susceptibility to lamotrigine and carbamazepine-induced SJS. Furthermore, patients of Japanese origin with HLAB*31:01 and Koreans with HLA-B*44:03 are also at increased risk of SJS after receiving the same two drugs. Of the antiepileptics, one most commonly associated with SJS is lamotrigine, a pre-synaptic voltage-gated sodium channel inhibitor. Lamotrigine is an antiepileptic drug of the phenyltriazine class that is indicated for the prevention of focal and generalized seizures in epileptic patients as well as monotherapy or adjunctive maintenance treatment for Bipolar disorder. The occurrence of SJS is not a rigid contraindication to lamotrigine reintroduction in the same patient. To facilitate this, manufacturers have developed a strict re-challenge dosing regimen to facilitate successful reintroduction of lamotrigine. In order to prevent the recurrence of SJS during a re-challenge, timing of re-dose and initial rash severity must be considered. Therefore, to prevent SJS recurrence, prime lamotrigine re-challenge patients are those with mild initial rash that has not occurred within the previous 4 weeks. The Federal Food and Drug Administration recommends the testing HLA subtypes for those associated with SJS prior to starting lamotrigine.

STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer.

Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to limit oxidative stress. Intervention strategies that simultaneously induce energetic and oxidative stress therefore have therapeutic potential. Phenformin is a mitochondrial complex I inhibitor that induces bioenergetic stress. We now demonstrate that inflammatory mediators, including IFNγ and polyIC, potentiate the cytotoxicity of phenformin by inducing a parallel increase in oxidative stress through STAT1-dependent mechanisms. Indeed, STAT1 signaling downregulates NQO1, a key ROS scavenger, in many breast cancer models. Moreover, genetic ablation or pharmacological inhibition of NQO1 using ß-lapachone (an NQO1 bioactivatable drug) increases oxidative stress to selectively sensitize breast cancer models, including patient derived xenografts of HER2+ and triple negative disease, to the tumoricidal effects of phenformin. We provide evidence that therapies targeting ROS scavengers increase the anti-neoplastic efficacy of mitochondrial complex I inhibitors in breast cancer.

Characterization of common breast MRI abnormalities: comparison between abbreviated and full MRI protocols.

RATIONALE AND OBJECTIVES: To evaluate the diagnostic performance of abbreviated MRI (AB-MRI) in comparison to a full protocol MRI (FP-MRI) when evaluating common MRI abnormalities of a mass, non-mass enhancement and focus. MATERIALS AND METHODS: This retrospective reader study was Institutional Review Board approved and Health Insurance Portability and Accountability Act (HIPAA) compliant. AB-MRIs were reviewed from May 2018-December 2019 to identify women with an abnormal AB-MRI, FP-MRI within six months of the AB-MRI and an elevated risk for breast cancer. Six breast radiologists initially interpreted and recorded findings from the AB-MRI. Immediately after reviewing the AB-MRI, the same radiologists interpreted and recorded findings from the FP-MRI. Findings were recorded in an electronic data collection form. Cohen's Kappa test was used to calculate agreement. P < 0.05 was considered statistically significant. RESULTS: Of 119 patients who had an AB-MRI, our final study comprised of 32 patients who had 64 breast MRIs (32 AB-MRI and 32 FP-MRI). The amount of fibroglandular tissue for AB-MRI and FP-MRI showed excellent intra-reader agreement [Kappa: 0.89-1.00 (P < 0.0001)]. Substantial to excellent intra-reader agreement [Kappa: 0.74-0.93 (P < 0.0001)] was demonstrated for all 6 readers when identifying abnormalities seen on AB-MRI and FP-MRI. Moderate to excellent intra-reader agreement [Kappa: 0.41-0.87(P < 0.0001)] was demonstrated between the AB-MRI and FP-MRI for the final BI-RADS assessment. CONCLUSION: AB-MRI has acceptable intra-reader agreement with FP-MRI when characterizing common MRI abnormalities such as a mass, non-mass enhancement and focus suggesting that subsequent FP-MRI may not be needed.

Analysis of 612 Benign Papillomas Diagnosed at Core Biopsy: Rate of Upgrade to Malignancy, Factors Associated With Upgrade, and a Proposal for Selective Surgical Excision.

BACKGROUND. Despite numerous published studies, management of benign papillomas without atypia remains controversial. OBJECTIVE. The purpose of this study was to determine the malignancy upgrade rate of benign papillomas, identify risk factors for upgrade, and formulate criteria for selective surgery. METHODS. This retrospective study included benign papillomas without atypia diagnosed on percutaneous biopsy between December 1, 2000, and December 31, 2019. Papillomas that did not undergo surgical excision or at least 2 years of imaging and/or clinical follow-up were excluded. Clinical, imaging, and histopathologic features were extracted from the electronic medical record. Features associated with upgrade to malignancy were identified. Multivariable logistic regression was performed. RESULTS. The study included 612 benign papillomas in 543 women (mean age, 54.5 ± 12.1 [SD] years); 466 papillomas were excised, and 146 underwent imaging or clinical surveillance. The upgrade rate to malignancy was 2.3% (14/612). Upgrade rate was associated (p < .05) with radiology-pathology correlation (50.0% if discordant vs 2.1% if concordant), patient age (5.6% for 60 years and older vs 0.7% for younger than 60 years), presenting symptoms (6.7% if palpable mass or pathologic nipple discharge vs 1.3% if no symptoms), and lesion size (7.3% if ≥ 10 mm vs 0.6% if < 10 mm). Three of 14 upgraded papillomas were associated with four or more metachronous or concurrent peripheral papillomas. No incidental papilloma or papilloma reported as completely excised on core biopsy histopathologic analysis was upgraded. A predictive model combining radiology-pathology discordance, symptoms (palpable mass or nipple discharge), age 60 years old and older, size 10 mm or larger, and presence of four or more metachronous or concurrent peripheral papillomas achieved an AUC of 0.91, sensitivity of 79%, and spec-ificity of 89% for upgrade. Selective surgery based on presence of any of these five factors, although excluding from surgery incidental papillomas and papillomas reported as completely excised on histopathology, would have spared 294 of 612 lesions from routine excision and identified all 14 upgraded lesions. CONCLUSION. Benign nonatypical papillomas have a low malignancy upgrade rate; routine surgical excision may not be necessary. Selective excision is recommended for lesions satisfying any of the five criteria. Incidental papillomas or papillomas completely excised on histopathology may undergo imaging follow-up. CLINICAL IMPACT. The proposed criteria for selective surgery of benign papillomas on core biopsy would reduce surgeries without delaying diagnosis of malignancy.

Fetal liver hematopoiesis: from development to delivery.

Clinical transplants of hematopoietic stem cells (HSC) can provide a lifesaving therapy for many hematological diseases; however, therapeutic applications are hampered by donor availability. In vivo, HSC exist in a specified microenvironment called the niche. While most studies of the niche focus on those residing in the bone marrow (BM), a better understanding of the fetal liver niche during development is vital to design human pluripotent stem cell (PSC) culture and may provide valuable insights with regard to expanding HSCs ex vivo for transplantation. This review will discuss the importance of the fetal liver niche in HSC expansion, a feat that occurs during development and has great clinical potential. We will also discuss emerging approaches to generate expandable HSC in cell culture that attain more complexity in the form of cells or organoid models in combination with engineering and systems biology approaches. Overall, delivering HSC by charting developmental principles will help in the understanding of the molecular and biological interactions between HSCs and fetal liver cells for their controlled maturation and expansion.

High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell-Derived Organoids.

BACKGROUND & AIMS: Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for a predictive human system to study complicated DILI mechanism and susceptibility to individual drug. Here, we established a human liver organoid (HLO)-based screening model for analyzing DILI pathology at organoid resolution. METHODS: We first developed a reproducible method to generate HLO from storable foregut progenitors from pluripotent stem cell (PSC) lines with reproducible bile transport function. The qRT-PCR and single cell RNA-seq determined hepatocyte transcriptomic state in cells of HLO relative to primary hepatocytes. Histological and ultrastructural analyses were performed to evaluate micro-anatomical architecture. HLO based drug-induced liver injury assays were transformed into a 384 well based high-speed live imaging platform. RESULTS: HLO, generated from 10 different pluripotent stem cell lines, contain polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNA-seq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. The accumulation of fluorescent bile acid into organoid was impaired by CRISPR-Cas9-based gene editing and transporter inhibitor treatment with BSEP. Furthermore, we successfully developed an organoid based assay with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations (Sensitivity: 88.7%, Specificity: 88.9%). LoT positively predicts genomic predisposition (CYP2C9∗2) for Bosentan-induced cholestasis. CONCLUSIONS: Liver organoid-based Toxicity screen (LoT) is a potential assay system for liver toxicology studies, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.

Erythroid Lineage Cells in the Liver: Novel Immune Regulators and Beyond.

The lineage of the erythroid cell has been revisited in recent years. Instead of being classified as simply inert oxygen carriers, emerging evidence has shown that they are a tightly regulated in immune potent population with potential developmental plasticity for lineage crossing. Erythroid cells have been reported to exert immune regulatory function through secreted cytokines, or cell-cell contact, depending on the conditions of the microenvironment and disease models. In this review, we explain the natural history of erythroid cells in the liver through a developmental lens, as it offers perspectives into newly recognized roles of this lineage in liver biology. Here, we review the known immune roles of erythroid cells and discuss the mechanisms in the context of disease models and stages. Then, we explore the capability of erythroid lineage as a cell source for regenerative medicine. We propose that the versatile lineage of erythroid cells provides an underappreciated and potentially promising area for basic and translational research in the field of liver disease.

p66ShcA functions as a contextual promoter of breast cancer metastasis.

BACKGROUND: The p66ShcA redox protein is the longest isoform of the Shc1 gene and is variably expressed in breast cancers. In response to a variety of stress stimuli, p66ShcA becomes phosphorylated on serine 36, which allows it to translocate from the cytoplasm to the mitochondria where it stimulates the formation of reactive oxygen species (ROS). Conflicting studies suggest both pro- and anti-tumorigenic functions for p66ShcA, which prompted us to examine the contribution of tumor cell-intrinsic functions of p66ShcA during breast cancer metastasis. METHODS: We tested whether p66ShcA impacts the lung-metastatic ability of breast cancer cells. Breast cancer cells characteristic of the ErbB2+/luminal (NIC) or basal (4T1) subtypes were engineered to overexpress p66ShcA. In addition, lung-metastatic 4T1 variants (4T1-537) were engineered to lack endogenous p66ShcA via Crispr/Cas9 genomic editing. p66ShcA null cells were then reconstituted with wild-type p66ShcA or a mutant (S36A) that cannot translocate to the mitochondria, thereby lacking the ability to stimulate mitochondrial-dependent ROS production. These cells were tested for their ability to form spontaneous metastases from the primary site or seed and colonize the lung in experimental (tail vein) metastasis assays. These cells were further characterized with respect to their migration rates, focal adhesion dynamics, and resistance to anoikis in vitro. Finally, their ability to survive in circulation and seed the lungs of mice was assessed in vivo. RESULTS: We show that p66ShcA increases the lung-metastatic potential of breast cancer cells by augmenting their ability to navigate each stage of the metastatic cascade. A non-phosphorylatable p66ShcA-S36A mutant, which cannot translocate to the mitochondria, still potentiated breast cancer cell migration, lung colonization, and growth of secondary lung metastases. However, breast cancer cell survival in the circulation uniquely required an intact p66ShcA S36 phosphorylation site. CONCLUSION: This study provides the first evidence that both mitochondrial and non-mitochondrial p66ShcA pools collaborate in breast cancer cells to promote their maximal metastatic fitness.

Textural Characteristics of Biopsy-proven Metastatic Axillary Nodes on Preoperative Breast MRI in Breast Cancer Patients: A Feasibility Study.

OBJECTIVE: To determine the diagnostic accuracy of MRI textural analysis (TA) to differentiate malignant from benign axillary lymph nodes in patients with breast cancer. METHODS: This was an institutional review board-approved retrospective study of axillary lymph nodes in women with breast cancer that underwent ultrasound-guided biopsy and contrast-enhanced (CE) breast MRI from January 2015 to December 2018. TA of axillary lymph nodes was performed on 3D dynamic CE T1-weighted fat-suppressed, 3D delayed CE T1-weighted fat-suppressed, and T2-weighted fat-suppressed MRI sequences. Quantitative parameters used to measure TA were compared with pathologic diagnoses. Areas under the curve (AUC) were calculated using receiver operating characteristic curve analysis to distinguish between malignant and benign lymph nodes. RESULTS: Twenty-three biopsy-proven malignant lymph nodes and 24 benign lymph nodes were analyzed. The delayed CE T1-weighted fat-suppressed sequence had the greatest ability to differentiate malignant from benign outcome at all spatial scaling factors, with the highest AUC (0.84-0.93), sensitivity (0.78 [18/23] to 0.87 [20/23]), and specificity (0.76 [18/24] to 0.88 [21/24]). Kurtosis on the 3D delayed CE T1-weighted fat-suppressed sequence was the most prominent TA parameter differentiating malignant from benign lymph nodes (P < 0.0001). CONCLUSION: This study suggests that MRI TA could be helpful in distinguishing malignant from benign axillary lymph nodes. Kurtosis has the greatest potential on 3D delayed CE T1-weighted fat-suppressed sequences to distinguish malignant and benign lymph nodes.

Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids.

Human organoid systems recapitulate in vivo organ architecture yet fail to capture complex pathologies such as inflammation and fibrosis. Here, using 11 different healthy and diseased pluripotent stem cell lines, we developed a reproducible method to derive multi-cellular human liver organoids composed of hepatocyte-, stellate-, and Kupffer-like cells that exhibit transcriptomic resemblance to in vivo-derived tissues. Under free fatty acid treatment, organoids, but not reaggregated cocultured spheroids, recapitulated key features of steatohepatitis, including steatosis, inflammation, and fibrosis phenotypes in a successive manner. Interestingly, an organoid-level biophysical readout with atomic force microscopy demonstrated that organoid stiffening reflects the fibrosis severity. Furthermore, organoids from patients with genetic dysfunction of lysosomal acid lipase phenocopied severe steatohepatitis, rescued by FXR agonism-mediated reactive oxygen species suppression. The presented key methodology and preliminary results offer a new approach for studying a personalized basis for inflammation and fibrosis in humans, thus facilitating the discovery of effective treatments.

Changes in peripapillary blood vessel density in Graves' orbitopathy after orbital decompression surgery as measured by optical coherence tomography angiography.

The purpose is to evaluate the utility of optical coherence tomography (OCT) angiography in the evaluation of Graves' orbitopathy (GO) and response to orbital decompression in patients with and without dysthyroid optic neuropathy (DON). This was a single-center, prospective case series in a cohort of 12 patients (24 orbits) with GO and ±DON, (6 orbits) who underwent bilateral orbital decompression. All patients underwent pre- and postoperative OCT angiography of the peripapillary area. Vessel density indices were calculated in a 4.5 mm × 4.5 mm ellipsoid centered on the optic disk using split-spectrum amplitude decorrelation angiography algorithm, producing the vessel density measurements. Mean change in vessel density indices was compared between pre- and postoperative sessions and between patients with and without DON. Patient 1, a 34-year-old male with GO and unilateral DON OD, showed a significant reduction in blood vessel density indices oculus dexter (OD) (DON eye) after decompression while a more modest reduction was found oculus sinister (OS) with the greatest change noted intrapapillary. Patient 2, a 50-year-old male with DON OU, showed worsening neuropathy following decompression OD that was confirmed by angiographic density indices. Patient 3, a 55-year-female with DON, showed a reduction in blood vessel density OD and increased density OS. Patients without DON showed overall less impressive changes in indices as compared to those with DON. Using OCT angiography, response to surgical treatment in GO orbits, more so in orbits with DON, can be demonstrated and quantified using vessel density indices with reproducibility.

Transactive memory systems in context: A meta-analytic examination of contextual factors in transactive memory systems development and team performance.

Research on transactive memory systems (TMS) has been conducted in a variety of teams, a range of task types and increasingly, in settings around the world. Despite this proliferation, there has been relative inattention to contextual factors that produce TMS and explain heterogeneity in the TMS to team performance relationship. TMS studies are typically conducted in homogeneous settings (i.e., teams located in a single country) and often with sources of potential variation (i.e., environmental volatility, leadership, team human capital, and diversity) in TMS development controlled. Collating these individual studies, we use meta-analytic techniques to illuminate key contextual factors that may shape TMS and influence the TMS-performance association. Using 76 empirical studies representing 6,869 sampling units, we find that the strength of the TMS to performance relationship varies, depending on features of the national cultural context-the impact of TMS is stronger in cultural contexts where power distance and in-group collectivism are higher. Our results also suggest that environmental volatility, leadership effectiveness, and team human capital are positively associated with TMS, and informational and gender diversity are negatively associated with TMS development. Our findings also indicate fruitful areas for future research specifically aimed toward disentangling the effects of environmental, team, and national cultural context on TMS and team performance. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Gankyrin Promotes Tumor-Suppressor Protein Degradation to Drive Hepatocyte Proliferation.

Background & Aims: Uncontrolled liver proliferation is a key characteristic of liver cancer; however, the mechanisms by which this occurs are not well understood. Elucidation of these mechanisms is necessary for the development of better therapy. The oncogene Gankyrin (Gank) is overexpressed in both hepatocellular carcinoma and hepatoblastoma. The aim of this work was to determine the role of Gank in liver proliferation and elucidate the mechanism by which Gank promotes liver proliferation. Methods: We generated Gank liver-specific knock-out (GLKO) mice and examined liver biology and proliferation after surgical resection and liver injury. Results: Global profiling of gene expression in GLKO mice showed significant changes in pathways involved in liver cancer and proliferation. Investigations of liver proliferation after partial hepatectomy and CCl4 treatment showed that GLKO mice have dramatically inhibited proliferation of hepatocytes at early stages after surgery and injury. In control LoxP mice, liver proliferation was characterized by Gank-mediated reduction of tumor-suppressor proteins (TSPs). The failure of GLKO hepatocytes to proliferate is associated with a lack of down-regulation of these proteins. Surprisingly, we found that hepatic progenitor cells of GLKO mice start proliferation at later stages and restore the original size of the liver at 14 days after partial hepatectomy. To examine the proliferative activities of Gank in cancer cells, we used a small molecule, cjoc42, to inhibit interactions of Gank with the 26S proteasome. These studies showed that Gank triggers degradation of TSPs and that cjoc42-mediated inhibition of Gank increases levels of TSPs and inhibits proliferation of cancer cells. Conclusions: These studies show that Gank promotes hepatocyte proliferation by elimination of TSPs. This work provides background for the development of Gank-mediated therapy for the treatment of liver cancer. RNA sequencing data can be accessed in the NCBI Gene Expression Omnibus: GSE104395.