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Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy. Obesity and its associated metabolic changes, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Here, the authors show that restricting when mice eat, but not what or how much they eat, delays breast cancer initiation and reduces tumor growth in obese mice in addition to improving insulin sensitivity and restoring circadian rhythms.

The rising incidence of hepatocellular carcinoma (HCC) is partly driven by metabolic dysfunction-associated steatohepatitis (MASH). Recurrence after treatment is high, and advanced disease carries a poor prognosis. The immunosuppressive tumor microenvironment (TME) in HCC limits the efficacy of immunotherapy, necessitating innovative approaches. To evaluate the efficacy of a novel therapeutic strategy designed to stimulate an antitumor immune response by combining cryoablation (Cryo) to release tumor antigen with an intratumoral immunostimulant (CpG) to facilitate immune recognition and dual immune checkpoint inhibitors (CPI) to disinhibit T cells. RIL-175 cells were orthotopically injected into two liver lobes in mice on a MASH-inducing diet. One tumor in each mouse was treated with partial Cryo, systemic dual CPI (anti-PD-1 and anti-CTLA-4), intratumoral TLR9 agonist CpG, or combinations thereof, while the second tumor was untreated. Tumor growth was monitored prior to and after ablation. Immune cell profiles and cytokine levels in both treated and untreated tumors were analyzed postmortem. The combined treatment of Cryo with CpG and dual CPI achieved the strongest tumor control and survival benefit. Cryo alone increased growth of the untreated tumor but addition of CpG and CPI reversed this effect. Immunologically, CPI primarily drove CTL expansion and PD-1 modulation, whereas CpG suppressed Tregs. Cryo monotherapy leads to immunosuppression, characterized by elevated Tregs, MDSCs, and PD-1 expression. Combining Cryo with CpG and CPI counteracts the inherent limitations of each therapy and enhances systemic anti-tumor immune responses.

Recent evidence suggests that a rare population of self-renewing cancer stem cells (CSC) is responsible for cancer progression and therapeutic resistance. Chronic myeloid leukemia (CML) represents an important paradigm for understanding the genetic and epigenetic events involved in CSC production. CML progresses from a chronic phase (CP) in hematopoietic stem cells (HSC) that harbor the BCR-ABL translocation, to blast crisis (BC), characterized by aberrant activation of β-catenin within granulocyte-macrophage progenitors (GMP). A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving β-catenin activation. Here we show that BC CML myeloid progenitors, in particular GMP, serially transplant leukemia in immunocompromised mice and thus are enriched for leukemia stem cells (LSC). Notably, cDNA sequencing of Wnt/β-catenin pathway regulatory genes, including adenomatous polyposis coli, GSK3β, axin 1, β-catenin, lymphoid enhancer factor-1, cyclin D1, and c-myc, revealed a novel in-frame splice deletion of the GSK3β kinase domain in the GMP of BC samples that was not detectable by sequencing in blasts or normal progenitors. Moreover, BC CML progenitors with misspliced GSK3β have enhanced β-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3β reduces both in vitro replating and leukemic engraftment. We propose that CP CML is initiated by BCR-ABL expression in an HSC clone but that progression to BC may include missplicing of GSK3β in GMP LSC, enabling unphosphorylated β-catenin to participate in LSC self-renewal. Missplicing of GSK3β represents a unique mechanism for the emergence of BC CML LSC and might provide a novel diagnostic and therapeutic target.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has surpassed the hepatitis B virus and hepatitis C virus as the leading cause of chronic liver disease in most parts of the Western world. MASLD (formerly known as NAFLD) encompasses both simple steatosis and more aggressive metabolic dysfunction-associated steatohepatitis (MASH), which is accompanied by inflammation, fibrosis, and cirrhosis, and ultimately can lead to hepatocellular carcinoma (HCC). There are currently very few approved therapies for MASH. Weight loss strategies such as caloric restriction can ameliorate the harmful metabolic effect of MASH and inhibit HCC; however, it is difficult to implement and maintain in daily life, especially in individuals diagnosed with HCC. In this study, we tested a time-restricted feeding (TRF) nutritional intervention in mouse models of MASH and HCC. We show that TRF abrogated metabolic dysregulation induced by a Western diet without any calorie restriction or weight loss. TRF improved insulin sensitivity and reduced hyperinsulinemia, liver steatosis, inflammation, and fibrosis. Importantly, TRF inhibited liver tumors in two mouse models of obesity-driven HCC. Our data suggest that TRF is likely to be effective in abrogating MASH and HCC and warrant further studies of time-restricted eating in humans with MASH who are at higher risk of developing HCC.

Liver-directed therapy is a critical component of treatment strategies for hepatocellular carcinoma. These therapies included percutaneous image-guided ablation, transarterial chemoembolization, and transarterial radioembolization, and are administered by interventional radiologists. Depending on the stage of disease, a particular treatment modality, or a combination thereof, is expected to be most efficacious in achieving the goals of treatment for a particular patient. This article seeks to review the various liver-directed treatment modalities for treatment of hepatocellular carcinoma, with attention to their efficacy and patient selection criteria.

[...]radiologists are adept at identifying disease once it creates macroscopic structural changes, but they are less able to detect early or subtle changes or functional aberrations, as with pancreatic cancer, colon cancer and early diabetes.1 Without information regarding changes occurring at the cellular and molecular levels, the differential diagnoses of a given structural abnormality can be extensive. [...]a familiarity with the clinical trials of emerging targeted treatments, their imaging requirements, and the implications for surveillance and prognosis will help radiologists provide interpretations with greater clinical relevance. [...]the oncogene Myc and tumor suppressor gene p53 both act upon miRNAs.45-49 Studies linking them to hepatocellular carcinoma (HCC) have resulted in the development of a system of molecular classification of HCC based on miRNA.50,51 MicroRNAs have been shown to play a role in response to chemotherapy and in development of drug resistance.52-54 They may serve as a cancer biomarker and could represent a target for disease monitoring and therapy or for combined imaging and therapy, termed theranostics.55-60 Proteins can have a variety of functions, including serving as ligands or modulators of signal transduction, receptors, or enzymes. First-in-human ultrasound molecular imaging with a VEGFR2-specific ultrasound molecular contrast agent (BR55) in prostate cancer: A safety and feasibility pilot study.

Radiologists play a central role in the assessment of patient response to locoregional therapies for hepatocellular carcinoma (HCC). The identification of viable tumor following treatment guides further management and potentially affects transplantation eligibility. Liver Imaging Reporting and Data Systems (LI-RADS) first introduced the concept of LR-treated in 2014, and a new treatment response algorithm is included in the 2017 update to assist radiologists in image interpretation of HCC after locoregional therapy. In addition to offering imaging criteria for viable and nonviable HCC, new concepts of nonevaluable tumors as well as tumors with equivocal viability are introduced. Existing guidelines provided by response evaluation criteria in solid tumors (RECIST) and modified RECIST address patient-level assessments and are routinely used in clinical trials but do not address the variable appearances following different locoregional therapies. The new LI-RADS treatment response algorithm addresses this gap and offers a comprehensive approach to assess treatment response for individual lesions after a variety of locoregional therapies, using either contrast-enhanced CT or MRI.

Objective Being a healthcare professional can be a uniquely rewarding calling. However, the demands of training and practice can lead to chronic distress and serious psychological, interpersonal, and personal health burdens. Although higher burnout, depression, and suicide rates have been reported in healthcare professionals, only a minority receive treatment. Concerns regarding confidentiality, stigma, potential career implications, and cost and time constraints are cited as key barriers. Web-based and mobile applications have been shown to mitigate stress, burnout, depression, and suicidal ideation among several populations and may circumvent these barriers. Here, we reviewed published data on such resources and selected a small sample that readily can be used by healthcare providers. Methods We searched PubMed for articles evaluating stress, burnout, depression, and suicide prevention or intervention for healthcare students or providers and identified five categories of programs with significant effectiveness: Cognitive Behavioral Therapy (online), meditation, mindfulness, breathing, and relaxation techniques. Using these categories, we searched for Web-based (through Google and beacon.anu.edu.au —a wellness resource website) and mobile applications (Apple and mobile. va.gov/appstore ) for stress, burnout, depression, and suicide prevention and identified 36 resources to further evaluate based on relevance, applicability to healthcare providers (confidentiality, convenience, and cost), and the strength of findings supporting their effectiveness. Results We selected seven resources under five general categories designed to foster wellness and reduce burnout, depression, and suicide risk among healthcare workers: breathing (Breath2Relax), meditation (Headspace, guided meditation audios), Web-based Cognitive Behavioral Therapy (MoodGYM, Stress Gym), and suicide prevention apps (Stay Alive, Virtual Hope Box). Conclusions This list serves as a starting point to enhance coping with stressors as a healthcare student or professional in order to help mitigate burnout, depression, and suicidality. The next steps include adapting digital health strategies to specifically fit the needs of healthcare providers, with the ultimate goal of facilitating in-person care when warranted.

BackgroundDespite the positive impact of immunotherapy in improving outcomes in multiple other solid tumors, the five-year survival rate of pancreatic ductal adenocarcinoma (PDAC) remains at approximately 13%.1 PDAC tumors demonstrate high T-cell exclusion which contributes to its limited response to immunotherapies such as immune checkpoint blockade (ICB). For locally advanced PDAC not amenable to surgical resection, irreversible electroporation (IRE) is an ablative treatment option that effectively reduces local tumor burden.2 However, most patients will develop metastatic disease. The plant virus cowpea mosaic virus (CPMV) is a strong immune stimulant capable of inducing systemic antitumor immunity and immune infiltration into tumors upon intratumoral administration.3 To test the hypothesis that potent tumor localized immune stimulation will generate antitumor immunity to control primary tumor growth and subsequent metastasis, we combined IRE with CPMV and assessed its efficacy on survival and tumor infiltrating lymphocytes in a syngeneic, orthotopic PDAC tumor model.MethodsMice were inoculated with KPC46 PDAC cells into the pancreas tail during laparotomy. After three weeks and during a second laparotomy, tumors were treated with IRE, followed by PBS or CPMV intratumoral injection for the IRE and IRE+CPMV groups, respectively. For the sham and CPMV groups, tumors were injected with PBS or CPMV, respectively. Survival was monitored for 30 days. Tumors of similarly treated mice were harvested on days 3 and 10 after treatment to evaluate the efficacy of IRE+CPMV on primary tumor burden. Tumors were evaluated for immune infiltration by immunofluorescence. Lymph nodes were assessed for dendritic cells and T cells by flow cytometry. Data analysis was completed with one-way ANOVA.ResultsWe find that IRE+CPMV significantly increased survival at 30 days to 66.7% compared to sham (0%), CPMV (30%), and IRE (20%) groups (figure 1A). IRE+CPMV elicited higher CD8 T-cell infiltration into primary PDAC tumors compared to all other groups at day 10 after treatment (figure 1B). This was associated with increased dendritic cell activation with IRE+CPMV compared to all other groups (figure 1C). Analysis of day 10 lymph nodes also indicated IRE+CPMV group to elicit higher levels of CD8 effector memory T cells compared to sham (figure 1D).ConclusionsIRE+CPMV improved survival compared to all other groups. IRE+CPMV treatment was associated with enhanced CD8 T-cell infiltration in the tumor, with the analysis on dendritic cells suggesting effective T-cell priming. This indicates that IRE+CPMV is an effective strategy for early induction of immune activation and T-cell priming, which could potentially sensitize PDAC tumors to respond to ICB.AcknowledgementsThis work was supported by NIH/NCI R01 CA224605, NIH/NCI R01 CA274640, and NIH/NCI R01 CA254268, as well as the NIH/NCI T32 CA121938-18 and NIH/NIGMS K12 GM068524.ReferencesCommon Cancer Sites - Cancer Stat Facts. SEER. https://seer.cancer.gov/statfacts/html/common.htmlMartin RCGI, Kwon D, Chalikonda S, Sellers M, Kotz E, Scoggins C, et al. Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Annals of Surgery. 2015 Sep;262(3):486.Mao C, Beiss V, Ho GW, Fields J, Steinmetz NF, Fiering S. In situ vaccination with cowpea mosaic virus elicits systemic antitumor immunity and potentiates immune checkpoint blockade. J Immunother Cancer. 2022 Dec 2;10(12):e005834.Ethics ApprovalB6/129 F1 hybrid mice were obtained from The Jackson Laboratory. All animal experiments were conducted using protocols approved by the Institutional Animal Care and Use Committee (IACUC) of University of California San Diego.Abstract 879 Figure 1IRE+CPMV treatment elicits antitumor immunity. A) Survival at day 30 (n=9-10). B) CD8 T cells in day 10 tumors (n=4-5). C) CD69 expression in dendritic cells. (n=4-5) D) Percentage of CD8 effector memory T cells. (n=4-5). Bars=average +/- std.dev[Image Omitted. See PDF.]

Somatic cell fate is an outcome set by the activities of specific transcription factors and the chromatin landscape and is maintained by gene silencing of alternate cell fates through physical interactions with the nuclear scaffold. Here, we evaluate the role of the nuclear scaffold as a guardian of cell fate in human fibroblasts by comparing the effects of transient loss (knockdown) and mutation (progeria) of functional Lamin A/C, a core component of the nuclear scaffold. We observed that Lamin A/C deficiency or mutation disrupts nuclear morphology, and the mechanical properties of the nucleus when measured by a microfluidic cellular squeezing device. We also show that transient loss of Lamin A/C promotes opening of previously silenced heterochromatin domains and increases access to DNA in lamina-associated domains. These alterations in Lamin A/C resulted in acceleration of the kinetics of cellular reprogramming to pluripotency, while genetic mutation of Lamin A/C into progerin was found to induce a senescent phenotype that inhibits the induction of reprogramming genes. Our results highlight the physical role of the nuclear scaffold in safeguarding cellular fate.