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Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance, in multiple TNBC models. Analysis of publicly available datasets reveals elevated IMPDH2 expression to associate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, both genetic depletion and pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemo-resistant lesions., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Recurrent ovarian cancer patients, especially those resistant to platinum, lack effective curative treatments. To address this, we conducted a phase 2 clinical trial (NCT02853318) combining pembrolizumab with bevacizumab, to increase T cell infiltration into the tumor, and oral cyclophosphamide, to reduce the number of regulatory T cells. The trial accrued 40 heavily pretreated recurrent ovarian cancer patients. The primary endpoint, progression free survival, was extended to a median of 10.2 months. The secondary endpoints demonstrated an objective response rate of 47.5%, and disease control in 30% of patients for over a year while maintaining a good quality of life. We performed comprehensive molecular, immune, microbiome, and metabolic profiling on samples of trial patients. Here, we show increased T and B cell clusters and distinct microbial patterns with amino acid and lipid metabolism are linked to exceptional clinical responses. This study suggests the immune milieu and host-microbiome can be leveraged to improve antitumor response in future immunotherapy trials., Competing Interests: Competing interests: The authors declare no competing interests. This study was approved by the Roswell Park Institutional Review Board (IRB), and all patients provided written informed consent before initiating any study procedures. Participants did not receive financial compensation. This study followed the Consolidated Standards of Reporting Trials ( CONSORT ) reporting guideline. While all work was completed at the Roswell Park Comprehensive Cancer Center by author Shanmuga Chilakapata, this author has relocated to Northeastern University., (© 2024. The Author(s).)

Bone metastases occur in the majority of advanced breast cancer patients, and the most common complications are osteolytic bone metastases. However, due to the limitations of models and methodologies for bone metastasis studies, the intricacies of bone metastasis have not been fully acknowledged and revealed in prior work. Our earlier study indicated that certain breast cancer cells undergo a pre-osteolytic stage before the establishment of overt metastatic lesions. Here, we further identify a differential bone morphology between ER (estrogen receptor) + and ER - breast cancer. Specifically, we observe a more pronounced osteolytic phenotype in the bone metastatic lesions of ER - cells investigated, linked to elevated hypoxia signaling that stimulates the secretion of osteolytic inducers from cancer cells. In the in vivo mouse model, the application of the hypoxia-inducible factor (HIF) inhibitor 2-methoxyestradiol demonstrates a promising efficacy in suppressing tumor growth and osteoclast differentiation in the bone lesions established by bone-tropic subpopulation of ER - MDA-MB-231 cell. Overall, our findings explore the complexity of phenotype and morphology in bone metastatic lesions of ER + and ER - breast cancer, which offers a compelling rationale for leveraging HIF inhibitors to the treatment targeting skeletal complications of breast cancer bone metastases, especially for ER - tumors., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: All co-authors of this publication have met the criteria for authorship required by Nature Portfolio journals as reported in the contributions section and as agreed among collaborators beforehand. This research did not include medical research involving human participants or local partners. This research was not severely restricted or prohibited in the setting of the researchers and does not result in stigmatization, incrimination, discrimination, or personal risk to participants. Informed consent: All participants provided written informed consent at enrollment., (© 2024. The Author(s).)

An aged immune system undergoes substantial changes where myelopoiesis dominates within the bone marrow. Monocytic-MDSCs (M-MDSCs) have been found to play an important role in osteoclastogenesis and bone resorption. In this study, we sought to provide a more comprehensive understanding of the osteoclastogenic potential of bone marrow M-MDSCs during normal aging through transcriptomic and metabolic changes. Using young mature and aged mice, detailed immunophenotypic analyses of myeloid cells revealed that the M-MDSCs were not increased in bone marrow, however M-MDSCS were significantly expanded in peripheral tissues. Although aged mice exhibited a similar number of M-MDSCs in bone marrow, these M-MDSCs had significantly higher osteoclastogenic potential and greater demineralization activity. Intriguingly, osteoclast progenitors from aged bone marrow M-MDSCs exhibited greater mitochondrial respiration rate and glucose metabolism. Further, transcriptomic analyses revealed the upregulation of mitochondrial oxidative phosphorylation and glucose metabolism genes. Interestingly, there was 8-fold increase in Cd38 mRNA gene expression, consistent with the Mouse Aging Cell Atlas transcriptomic database, and confirmed by qRT-PCR. CD38 regulates NAD + availability, and 78c, a small molecule inhibitor of CD38, reduced the mitochondrial oxygen consumption rate and glucose metabolism and inhibited the osteoclastogenic potential of aged mice bone marrow-derived M-MDSCs. These results indicate that the age-related increase in Cd38 expression in M-MDSCs bias the transcriptome of M-MDSCs towards osteoclastogenesis. This enhanced understanding of the mechanistic underpinnings of M-MDSCs and their osteoclastogenesis during aging could lead to new therapeutic approaches for age-related bone loss and promote healthy aging., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Immuno-oncology has transformed the treatment of cancer, with several immunotherapies becoming the standard treatment across histologies. Despite these advancements, the majority of patients do not experience durable clinical benefits, highlighting the imperative for ongoing advancement in immuno-oncology. Computational immuno-oncology emerges as a forefront discipline that draws on biomedical data science and intersects with oncology, immunology, and clinical research, with the overarching goal to accelerate the development of effective and safe immuno-oncology treatments from the laboratory to the clinic. In this review, we outline 10 critical challenges and opportunities in computational immuno-oncology, emphasizing the importance of robust computational strategies and interdisciplinary collaborations amid the constantly evolving interplay between clinical needs and technological innovation., Competing Interests: Competing interests: RB declares PCT/US15/612657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof), PCT/US63/055227 (Methods and Compositions for Treating Autoimmune and Allergic Disorders). AM is an equity holder in Picture Health, Elucid Bioimaging, and Inspirata. Currently, he serves on the advisory board of Picture Health, and SimBioSys. He currently consults for Takeda; He also has sponsored research agreements with AstraZeneca and Bristol Myers-Squibb; his technology has been licensed to Picture Health and Elucid Bioimaging; he is also involved in two different R01 grants with Inspirata; he also serves as a member for the Frederick National Laboratory Advisory Committee.VDJ has performed consulting for VincerX Pharmaceuticals, Providence St. John, Los Angeles; she is a founder of Bioinformatica. JSB-S, EK, DM are full time, paid employees of NCI/NIH. EJF is on the Scientific Advisory Board of Resistance Bio, a consultant for Mestag and Merck, and receives research funding from AbbVie. SG reports current and past research funding from Regeneron Pharmaceuticals, Boehringer Ingelheim, BMS (Celgene), Genentech, EMD Serono, Pfizer, and Takeda. ER is a co-founder of MedAware, Metabomed and Pangea Biomed (divested), and an unpaid member of Pangea Biomed’s and GSK Oncology scientific advisory boards. DVV is a co-founder and chief scientist of Barrier Biosciences and holds equity in the company. NV is on the Consulting/Advisory Boards of Sanofi/Genzyme (2022), Oncocyte (2021), Eli Lilly (2021), Regeneron (2022), Amgen (2023), Xencor (2023), AstraZeneca (2023), Tempus (2023), Pfizer (2024), Summit Therapeutics (2024), OncoHost (2024); she reports travel reimbursement from Regeneron; research grants from Oncocyte (2022–), Circulogene and Mirati, funding from Circulogene, and honoraria from Nebraska Oncology Society, Scienomics Group, Grace, OncLive and OMNI-Oncology. EMVA reports personal fees from Tango Therapeutics, Genome Medical, Genomic Life, Monte Rosa Therapeutics, Manifold Bio, Enara Bio, Riva Therapeutics, Foaley & Hoag, and Serinus Bio, grants and personal fees from Novartis Institute for Biomedical Research, and grants from BMS, Janssen, and Sanofi outside the submitted work; in addition, EMVA has a patent for institutional patents filed on chromatin mutations and immunotherapy response and methods for clinical interpretation pending., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The thymus is the central organ involved with T-cell development and the production of naïve T cells. During normal aging, the thymus undergoes marked involution, reducing naïve T-cell output and resulting in a predominance of long-lived memory T cells in the periphery. Outside of aging, systemic stress responses that induce corticosteroids (CS), or other insults such as radiation exposure, induce thymocyte apoptosis, resulting in a transient acute thymic involution with subsequent recovery occurring after cessation of the stimulus. Despite the increasing utilization of immunostimulatory regimens in cancer, effects on the thymus and naïve T cell output have not been well characterized. Using both mouse and human systems, the thymic effects of systemic immunostimulatory regimens, such as high dose IL-2 (HD IL-2) with or without agonistic anti-CD40 mAbs and acute primary viral infection, were investigated. These regimens produced a marked acute thymic involution in mice, which correlated with elevated serum glucocorticoid levels and a diminishment of naïve T cells in the periphery. This effect was transient and followed with a rapid thymic "rebound" effect, in which an even greater quantity of thymocytes was observed compared to controls. Similar results were observed in humans, as patients receiving HD IL-2 treatment for cancer demonstrated significantly increased cortisol levels, accompanied by decreased peripheral blood naïve T cells and reduced T-cell receptor excision circles (TRECs), a marker indicative of recent thymic emigrants. Mice adrenalectomized prior to receiving immunotherapy or viral infection demonstrated protection from this glucocorticoid-mediated thymic involution, despite experiencing a substantially higher inflammatory cytokine response and increased immunopathology. Investigation into the effects of immunostimulation on middle aged (7-12 months) and advance aged (22-24 months) mice, which had already undergone significant thymic involution and had a diminished naïve T cell population in the periphery at baseline, revealed that even further involution was incurred. Thymic rebound hyperplasia, however, only occurred in young and middle-aged recipients, while advance aged not only lacked this rebound hyperplasia, but were entirely absent of any indication of thymic restoration. This coincided with prolonged deficits in naïve T cell numbers in advanced aged recipients, further skewing the already memory dominant T cell pool. These results demonstrate that, in both mice and humans, systemic immunostimulatory cancer therapies, as well as immune challenges like subacute viral infections, have the potential to induce profound, but transient, glucocorticoid-mediated thymic involution and substantially reduced thymic output, resulting in the reduction of peripheral naive T cells. This can then be followed by a marked rebound effect with naïve T cell restoration, events that were shown not to occur in advanced-aged mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Collins, Khuat, Sckisel, Vick, Minnar, Dunai, Le, Curti, Crittenden, Merleev, Sheng, Chao, Maverakis, Rosario, Monjazeb, Blazar, Longo, Canter and Murphy.)

In adult patients affected by degenerative disc disease with lumbar instability and chronic low back pain, spine surgery with lumbar fixation aims to reduce segmental instability and pain. Different techniques have been developed, but the optimal surgical technique remains controversial. No studies have compared the clinical and radiological outcomes between stand-alone pedicle screw fixation (SAPF) and minimally invasive transforaminal lumbar interbody fusion (MI-TLIF). This was a retrospective study. All patients who underwent surgery for single-level L4-L5 or L5-S1 lumbar stenosis, associated with minor lumbar instability and treated with SAPF or MI-TLIF techniques were included in the study. Data were collected preoperatively and at 24 monts follow-up. Clinical primary outcomes were Oswestry Disability Index (ODI) and Numerical Rating Scale (NRS). Secondary outcomes were patient satisfaction, walking ability and self reported back and leg pain. In addition, perioperative data and complications were recorded. Segmental lordosis (L4-L5 and L5-S1) and overall lumbar lordosis (L1-S1) were measured on lumbar X-Rays preoperatively and at least 24 months postoperatively. 277 patients were firstly identified. Baseline data and a minimum of two-year follow-up were available for 62 patients. After the propensity score matching, 44 patients (22 patients in the SAPF group and 22 patients in the MI-TLIF group) were matched. At 24 months follow-up, no difference between the two groups of patients in NRS (p = 0.11) and ODI scores (p = 0.21) were observed. Patients' satisfaction at follow-up was also not significantly different between the two groups. In both groups, a significant improvement in the walked distance was observed after surgery (p = 0.05) while no difference was observed regarding the type of surgery performed (p = 1.00). No differences were found in the pre- and post-operative median lumbar lordosis (p = 0.91 and p = 0.67) and the same findings were observed for lumbar segmental lordosis (p = 0.65 and p = 0.41 respectively). Significant improvements in ODI and NRS-scores were recorded after 24 months follow-up with both SAPF and MI-TLIF. No significant differences in postoperative PROMs and patients' satisfaction were observed between the groups. The results of our study indicate no superiority of either surgical technique concerning pain and functional outcomes after 24 months., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tumors typically lack canonical danger signals required to activate adaptive immunity and also frequently employ substantial immunomodulatory mechanisms that downregulate adaptive responses and contribute to escape from immune surveillance. Given the variety of mechanisms involved in shielding tumors from immune recognition, it is not surprising that single-agent immunomodulatory approaches have been largely unsuccessful in generating durable antitumor responses. Here we report a unique combination of immunomodulatory and cytostatic agents that recondition the tumor microenvironment and eliminate complex and/or poor-prognosis tumor types including the non-immunogenic 4T-1 model of TNBC, the aggressive MOC-2 model of HNSCC, and the high-risk MYCN-amplified model of neuroblastoma. A course of therapy optimized for TNBC cured a majority of tumors in both ectopic and orthotopic settings and eliminated metastatic spread in all animals tested at the highest doses. Immune responses were transferable between therapeutic donor and naïve recipient through adoptive transfer, and a sizeable abscopal effect on distant, untreated lesions could be demonstrated experimentally. Similar results were observed in HNSCC and neuroblastoma models, with characteristic remodeling of the tumor microenvironment documented in all model systems. scRNA-seq analysis implicated upregulation of innate immune responses and antigen presentation in tumor cells and the myeloid cell compartment as critical early events. This analysis also highlighted the potential importance of the autonomic nervous system in the governance of inflammatory processes. The data indicate that the targeting of multiple pathways and mechanisms of action can result in substantial synergistic antitumor effects and suggest follow-up in the neoadjuvant setting may be warranted., (© 2024 Federation of American Societies for Experimental Biology.)

The canonical mechanism behind tamoxifen's therapeutic effect on estrogen receptor α/ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to tamoxifen (Tam) therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remains unclear. In a window-of-opportunity trial on patients with newly diagnosed stage I-III ESR1+/HER2/wild-type p53 breast cancer who were randomized to arms with or without Tam prior to surgery, we reveal that the ESR1-p53 interaction in tumors was inhibited by Tam. This resulted in functional reactivation of p53 leading to transcriptional reprogramming that favors tumor-suppressive signaling, as well as downregulation of oncogenic pathways. These findings illustrating the convergence of ESR1 and p53 signaling during Tam therapy enrich mechanistic understanding of the impact of p53 on the response to Tam therapy., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

This paper describes a novel architecture that aims to create a template for the implementation of an IT platform, supporting the deployment and integration of the different digital twin subsystems that compose a complex urban intelligence system. In more detail, the proposed Smart City IT architecture has the following main purposes: (i) facilitating the deployment of the subsystems in a cloud environment; (ii) effectively storing, integrating, managing, and sharing the huge amount of heterogeneous data acquired and produced by each subsystem, using a data lake; (iii) supporting data exchange and sharing; (iv) managing and executing workflows, to automatically coordinate and run processes; and (v) to provide and visualize the required information. A prototype of the proposed IT solution was implemented leveraging open-source frameworks and technologies, to test its functionalities and performance. The results of the tests performed in real-world settings confirmed that the proposed architecture could efficiently and easily support the deployment and integration of heterogeneous subsystems, allowing them to share and integrate their data and to select, extract, and visualize the information required by a user, as well as promoting the integration with other external systems, and defining and executing workflows to orchestrate the various subsystems involved in complex analyses and processes.

Background: Prostate cancer is a significant health concern, particularly among African American (AA) men who exhibit higher incidence and mortality compared to European American (EA) men. Understanding the molecular mechanisms underlying these disparities is imperative for enhancing clinical management and achieving better outcomes., Methods: Employing a multi-omics approach, we analyzed prostate cancer in both AA and EA men. Using Illumina methylation arrays and RNA sequencing, we investigated DNA methylation and gene expression in tumor and non-tumor prostate tissues. Additionally, Boolean analysis was utilized to unravel complex networks contributing to racial disparities in prostate cancer., Results: When comparing tumor and adjacent non-tumor prostate tissues, we found that DNA hypermethylated regions are enriched for PRC2/H3K27me3 pathways and EZH2/SUZ12 cofactors. Olfactory/ribosomal pathways and distinct cofactors, including CTCF and KMT2A, were enriched in DNA hypomethylated regions in prostate tumors from AA men. We identified race-specific inverse associations of DNA methylation with expression of several androgen receptor (AR) associated genes, including the GATA family of transcription factors and TRIM63. This suggests that race-specific dysregulation of the AR signaling pathway exists in prostate cancer. To investigate the effect of AR inhibition on race-specific gene expression changes, we generated in-silico patient-specific prostate cancer Boolean networks. Our simulations revealed prolonged AR inhibition causes significant dysregulation of TGF-β, IDH1, and cell cycle pathways specifically in AA prostate cancer. We further quantified global gene expression changes, which revealed differential expression of genes related to microtubules, immune function, and TMPRSS2-fusion pathways, specifically in prostate tumors of AA men. Enrichment of these pathways significantly correlated with an altered risk of disease progression in a race-specific manner., Conclusions: Our study reveals unique signaling networks underlying prostate cancer biology in AA and EA men, offering potential insights for clinical management strategies tailored to specific racial groups. Targeting AR and associated pathways could be particularly beneficial in addressing the disparities observed in prostate cancer outcomes in the context of AA and EA men. Further investigation into these identified pathways may lead to the development of personalized therapeutic approaches to improve outcomes for prostate cancer patients across different racial backgrounds., (© 2024. The Author(s).)

Purpose: Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters., Experimental Design: Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key "nodes" responsible for EMT induction., Results: Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect., Conclusions: This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification., (©2024 American Association for Cancer Research.)

Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer. Despite decades of intense investigation, treatment options remain limited, and rapid recurrence with distant metastases remains a significant challenge. Cancer cell-intrinsic production of cytokines such as type I interferons (IFN-I) is a known potent modulator of response to therapy in many cancers, including TNBC, and can influence therapeutic outcome. Here, we report that, in TNBC systems, the aryl hydrocarbon receptor (AhR) suppresses IFN-I expression via inhibition of STImulator of Interferon Genes (STING), a key mediator of interferon production. Intratumoral STING activity is essential in mediating the efficacy of PARP inhibitors (PARPi) which are used in the treatment of cancers harboring BRCA1 deficiency. We find that, in TNBC cells, PARPi treatment activates AhR in a BRCA1 deficiency-dependent manner, thus suggesting the presence of a negative feedback loop aimed at modulating PARPi efficacy. Importantly, our results indicate that the combined inhibition of PARP and AhR is superior in elevating IFN-I expression as compared to PARPi-alone. Thus, AhR inhibition may allow for enhanced IFN-I production upon PARPi in BRCA1-deficient breast cancers, most of which are of TNBC origin, and may represent a therapeutically viable strategy to enhance PARPi efficacy., (© 2024. The Author(s).)

As professional secretory cells, β-cells require adaptable mRNA translation to facilitate a rapid synthesis of proteins, including insulin, in response to changing metabolic cues. Specialized mRNA translation programs are essential drivers of cellular development and differentiation. However, in the pancreatic β-cell, the majority of factors identified to promote growth and development function primarily at the level of transcription. Therefore, despite its importance, the regulatory role of mRNA translation in the formation and maintenance of functional β-cells is not well defined. In this study, we have identified a translational regulatory mechanism mediated by the specialized mRNA translation factor eukaryotic initiation factor 5A (eIF5A), which facilitates the maintenance of β-cell identity and function. The mRNA translation function of eIF5A is only active when it is posttranslationally modified ("hypusinated") by the enzyme deoxyhypusine synthase (DHPS). We have discovered that the absence of β-cell DHPS in mice reduces the synthesis of proteins critical to β-cell identity and function at the stage of β-cell maturation, leading to a rapid and reproducible onset of diabetes. Therefore, our work has revealed a gatekeeper of specialized mRNA translation that permits the β-cell, a metabolically responsive secretory cell, to maintain the integrity of protein synthesis necessary during times of induced or increased demand., (© 2024 by the American Diabetes Association.)

Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a CD68 hi IRF8 lo G-CSF hi gene signature suggests poorer prognosis in triple-negative breast cancer (TNBC), a G-CSF-expressing subtype. Our data highlight the underappreciated, pro-metastatic roles of AMs in response to G-CSF and identify the contribution of IRF8-deficient AMs to metastatic burden. AMs are an attractive target of local neoadjuvant G-CSF blockade to recover anti-metastatic activity., Competing Interests: M.O. has received research support from Alphageneron, AIM Therapeutics, Eli Lilly, and Pfizer. The other authors declare no competing interests., (© 2024 Roswell Park Comprehensive Cancer Center.)

The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m 2 , has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

Background: Cancer immunotherapies can produce complete therapeutic responses, however, outcomes in ovarian cancer (OC) are modest. While adoptive T-cell transfer (ACT) has been evaluated in OC, durable effects are rare. Poor therapeutic efficacy is likely multifactorial, stemming from limited antigen recognition, insufficient tumor targeting due to a suppressive tumor microenvironment (TME), and limited intratumoral accumulation/persistence of infused T cells. Importantly, host T cells infiltrate tumors, and ACT approaches that leverage endogenous tumor-infiltrating T cells for antitumor immunity could effectively magnify therapeutic responses., Methods: Using retroviral transduction, we have generated T cells that secrete a folate receptor alpha (FRα)-directed bispecific T-cell engager (FR-B T cells), a tumor antigen commonly overexpressed in OC and other tumor types. The antitumor activity and therapeutic efficacy of FR-B T cells was assessed using FRα+ cancer cell lines, OC patient samples, and preclinical tumor models with accompanying mechanistic studies. Different cytokine stimulation of T cells (interleukin (IL)-2+IL-7 vs IL-2+IL-15) during FR-B T cell production and the resulting impact on therapeutic outcome following ACT was also assessed., Results: FR-B T cells efficiently lysed FRα+ cell lines, targeted FRα+ OC patient tumor cells, and were found to engage and activate patient T cells present in the TME through secretion of T cell engagers. Additionally, FR-B T cell therapy was effective in an immunocompetent in vivo OC model, with response duration dependent on both endogenous T cells and FR-B T cell persistence. IL-2/IL-15 preconditioning prior to ACT produced less differentiated FR-B T cells and enhanced therapeutic efficacy, with mechanistic studies revealing preferential accumulation of TCF-1+CD39-CD69- stem-like CD8+ FR B T cells in the peritoneal cavity over solid tumors., Conclusions: These findings highlight the therapeutic potential of FR-B T cells in OC and suggest FR-B T cells can persist in extratumoral spaces while actively directing antitumor immunity. As the therapeutic activity of infused T cell therapies in solid tumor indications is often limited by poor intratumoral accumulation of transferred T cells, engager-secreting T cells that can effectively leverage endogenous immunity may have distinct mechanistic advantages for enhancing therapeutic responses rates., Competing Interests: Competing interests: AJRM, TT, and KO are inventors on provisional patents pertaining to the development and use of BiTE-secreting T cells in cancer. KO is a co-founder of Tactiva Therapeutics. All other authors have no financial conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant LOS on the tumor microenvironment., Experimental Design: We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733), or surgery upfront, without any neoadjuvant therapy. We also conducted a longitudinal analysis of multiple biomarkers in the plasma of treated patients., Results: In comparison with FFX+CRT, LOS+FFX+CRT downregulated immunosuppression and pro-invasion genes. Overall survival (OS) was associated with dendritic cell (DC) and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel-related genes for those treated with LOS+FFX+CRT. Furthermore, LOS induced specific changes in circulating levels of IL-8, sTie2, and TGF-β. IF revealed significantly less residual disease in lesions treated with LOS+FFX+CRT. Finally, patients with a complete/near complete pathologic response in the LOS+FFX+CRT-treated group had reduced CD4+FOXP3+ regulatory T cells (Tregs), fewer immunosuppressive FOXP3+ cancer cells (C-FOXP3), and increased CD8+ T cells in pancreatic ductal adenocarcinoma lesions., Conclusions: Adding LOS to FFX+CRT reduced pro-invasion and immunosuppression-related genes, which were associated with improved OS in patients with LAPC. Lesions from responders in the LOS+FFX+CRT-treated group had reduced Tregs, decreased C-FOXP3 and increased CD8+ T cells. These findings suggest that LOS may potentiate the benefit of FFX+CRT by reducing immunosuppression., (©2023 American Association for Cancer Research.)

Mutations found in skin are acquired in specific patterns, clustering around mutation-prone genomic locations. The most mutation-prone genomic areas, mutation hotspots, first induce the growth of small cell clones in healthy skin. Mutations accumulate over time, and clones with driver mutations may give rise to skin cancer. Early mutation accumulation is a crucial first step in photocarcinogenesis. Therefore, a sufficient understanding of the process may help predict disease onset and identify avenues for skin cancer prevention. Early epidermal mutation profiles are typically established using high-depth targeted next-generation sequencing. However, there is currently a lack of tools for designing custom panels to capture mutation-enriched genomic regions efficiently. To address this issue, we created a computational algorithm that implements a pseudo-exhaustive approach to identify the best genomic areas to target. We benchmarked the current algorithm in three independent mutation datasets of human epidermal samples. Compared to the sequencing panel designs originally used in these publications, the mutation capture efficacy (number of mutations/base pairs sequenced) of our designed panel improved 9.6-12.1-fold. Mutation burden in the chronically sun-exposed and intermittently sun-exposed normal epidermis was measured within genomic regions identified by hotSPOT based on cutaneous squamous cell carcinoma (cSCC) mutation patterns. We found a significant increase in mutation capture efficacy and mutation burden in cSCC hotspots in chronically sun-exposed vs. intermittently sun-exposed epidermis ( p < 0.0001). Our results show that our hotSPOT web application provides a publicly available resource for researchers to design custom panels, enabling efficient detection of somatic mutations in clinically normal tissues and other similar targeted sequencing studies. Moreover, hotSPOT also enables the comparison of mutation burden between normal tissues and cancer.

Identifying and leveraging unique points of metabolic dysregulation in different disease settings is vital for safe and effective incorporation of metabolism-targeted therapies in the clinic. In addition, it has been shown identification of master metabolic transcriptional regulators (MMTR) of individual metabolic pathways, and how they relate to the disease in question, may offer the key to understanding therapeutic response. In prostate cancer, we have previously demonstrated polyamine biosynthesis and the methionine cycle were targetable metabolic vulnerabilities. However, the MMTRs of these pathways, and how they affect treatment, have yet to be explored. We sought to characterize differential sensitivity of prostate cancer to polyamine- and methionine-targeted therapies by identifying novel MMTRs. We began by developing a gene signature from patient samples, which can predict response to metabolic therapy, and further uncovered a MMTR, JAZF1. We characterized the effects of JAZF1 overexpression on prostate cancer cells, basally and in the context of treatment, by assessing mRNA levels, proliferation, colony formation capability, and key metabolic processes. Lastly, we confirmed the relevance of our findings in large publicly available cohorts of prostate cancer patient samples. We demonstrated differential sensitivity to polyamine and methionine therapies and identified JAZF1 as a MMTR of this response., Implications: We have shown JAZF1 can alter sensitivity of cells and its expression can segregate patient populations into those that do, or do not highly express polyamine genes, leading to better prediction of response to a polyamine targeting therapy., (©2022 The Authors; Published by the American Association for Cancer Research.)

Cancer cells encounter a hostile tumor microenvironment (TME), and their adaptations to metabolic stresses determine metastatic competence. Here, we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) is induced in hypoxic tumors acquiring metabolic plasticity and invasive phenotype. In mouse models of breast cancer, genetic ablation of PFKFB4 significantly delays distant organ metastasis, reducing local lymph node invasion by suppressing expression of invasive gene signature including integrin β3. Photoacoustic imaging followed by metabolomics analyses of hypoxic tumors show that PFKFB4 drives metabolic flexibility, enabling rapid detoxification of reactive oxygen species favoring survival under selective pressure. Mechanistically, hypoxic induction triggers nuclear translocation of PFKFB4 accentuating non-canonical transcriptional activation of HIF-1α, and breast cancer patients with increased nuclear PFKFB4 in their tumors are found to be significantly associated with poor prognosis. Our findings imply that PFKFB4 induction is crucial for tumor cell adaptation in the hypoxic TME that determines metastatic competence., Competing Interests: Declaration of interests S.L. serves on the Scientific Advisory Board of 20n Bio, and S.D. holds equity in Coactigon Inc., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Contrary to the "obesity paradox," which arises from retrospective studies relying on body mass index to define obesity, epidemiologic evidence suggests central or visceral obesity is associated with a higher risk for the development of lung cancer. About 60% of individuals at high risk for developing lung cancer or those already with early-stage disease are either overweight or obese. Findings from resected patient tumors and mouse lung tumor models show obesity dampens immune activity in the tumor microenvironment (TME) encouraging disease progression. In line with this, we have observed a marked, obesity-specific enhancement in the presence and phenotype of immunosuppressive regulatory T (Treg) cells in murine tumors as well as the airways of both humans and mice. Leveraging direct metabolomic measurements and robust inferred analyses from RNA-sequencing data, we here demonstrate for the first time that visceral adiposity alters the lung microenvironment via dysregulated acetyl-CoA metabolism in a direction that facilitates immune suppression and lung carcinogenesis., (© 2022. The Author(s).)

Like BRCA2, MAGEC3 is an ovarian cancer predisposition gene that has been shown to have prognostic significance in ovarian cancer patients. Despite the clinical significance of each gene, no studies have been conducted to assess the clinical significance of their combined expression. We therefore sought to determine the relationship between MAGEC3 and BRCA2 expression in ovarian cancer and their association with patient characteristics and outcomes. Immunohistochemical staining was quantitated on tumor microarrays of human tumor samples obtained from 357 patients with epithelial ovarian cancer to ascertain BRCA2 expression levels. In conjunction with our previously published MAGEC3 expression data, we observed a weak inverse correlation of MAGEC3 with BRCA2 expression (r = −0.15; p < 0.05) in cases with full-length BRCA2. Patients with optimal cytoreduction, loss of MAGEC3, and detectable BRCA2 expression had better overall (median OS: 127.9 vs. 65.3 months, p = 0.035) and progression-free (median PFS: 85.3 vs. 18.8 months, p = 0.002) survival compared to patients that were BRCA2 expressors with MAGEC3 normal levels. Our results suggest that combined expression of MAGEC3 and BRCA2 serves as a better predictor of prognosis than each marker alone.

This study addresses the roles of nuclear receptor corepressor 2 (NCOR2) in prostate cancer (PC) progression in response to androgen deprivation therapy (ADT). Reduced NCOR2 expression significantly associates with shorter disease-free survival in patients with PC receiving adjuvant ADT. Utilizing the CWR22 xenograft model, we demonstrate that stably reduced NCOR2 expression accelerates disease recurrence following ADT, associates with gene expression patterns that include neuroendocrine features, and induces DNA hypermethylation. Stably reduced NCOR2 expression in isogenic LNCaP (androgen-sensitive) and LNCaP-C4-2 (androgen-independent) cells revealed that NCOR2 reduction phenocopies the impact of androgen treatment and induces global DNA hypermethylation patterns. NCOR2 genomic binding is greatest in LNCaP-C4-2 cells and most clearly associates with forkhead box (FOX) transcription factor FOXA1 binding. NCOR2 binding significantly associates with transcriptional regulation most when in active enhancer regions. These studies reveal robust roles for NCOR2 in regulating the PC transcriptome and epigenome and underscore recent mutational studies linking NCOR2 loss of function to PC disease progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The simplistic approaches to language circuits are continuously challenged by new findings in brain structure and connectivity. The posterior middle frontal gyrus and area 55b (pFMG/area55b), in particular, has gained a renewed interest in the overall language network. Methods: This is a retrospective single-center cohort study of patients who have undergone awake craniotomy for tumor resection. Navigated transcranial magnetic simulation (nTMS), tractography, and intraoperative findings were correlated with language outcomes. Results: Sixty-five awake craniotomies were performed between 2012 and 2020, and 24 patients were included. nTMS elicited 42 positive responses, 76.2% in the inferior frontal gyrus (IFG), and hesitation was the most common error (71.4%). In the pMFG/area55b, there were seven positive errors (five hesitations and two phonemic errors). This area had the highest positive predictive value (43.0%), negative predictive value (98.3%), sensitivity (50.0%), and specificity (99.0%) among all the frontal gyri. Intraoperatively, there were 33 cortical positive responses-two (6.0%) in the superior frontal gyrus (SFG), 15 (45.5%) in the MFG, and 16 (48.5%) in the IFG. A total of 29 subcortical positive responses were elicited-21 in the deep IFG-MFG gyri and eight in the deep SFG-MFG gyri. The most common errors identified were speech arrest at the cortical level (20 responses-13 in the IFG and seven in the MFG) and anomia at the subcortical level (nine patients-eight in the deep IFG-MFG and one in the deep MFG-SFG). Moreover, 83.3% of patients had a transitory deterioration of language after surgery, mainly in the expressive component ( p = 0.03). An increased number of gyri with intraoperative positive responses were related with better preoperative ( p = 0.037) and worse postoperative ( p = 0.029) outcomes. The involvement of the SFG-MFG subcortical area was related with worse language outcomes ( p = 0.037). Positive nTMS mapping in the IFG was associated with a better preoperative language outcome ( p = 0.017), relating to a better performance in the expressive component, while positive mapping in the MFG was related to a worse preoperative receptive component of language ( p = 0.031). Conclusion: This case series suggests that the posterior middle frontal gyrus, including area 55b, is an important integration cortical hub for both dorsal and ventral streams of language., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hazem, Awan, Lavrador, Patel, Wren, Lucena, Semedo, Irzan, Melbourne, Ourselin, Shapey, Kailaya-Vasan, Gullan, Ashkan, Bhangoo and Vergani.)

Hepatic Fasciola is a frequent disease in the Peruvian highlands. We present a case of hepatic Fasciola from the Andean zone of La Libertad, with symptoms of several months of evolution with pain in the right hypochondrium, jaundice and coluria. An abdominal CT scan was performed, demonstrating a liver mass probable neoplasm, and was referred to the Institute of Neoplastic Diseases. Laboratory tests were completed finding eosinophilia and variable increases in liver function tests. Fascioliasis was presented as a differential diagnosis and a Western Bloot examination was performed confirming its diagnosis. Treatment with 2 cycles of Triclabendazole was started, with a favorable clinical evolution.

This paper deals with the design of a decentralized guidance and control strategy for a swarm of unmanned aerial vehicles (UAVs), with the objective of maintaining a given connection topology with assigned mutual distances while flying to a target area. In the absence of obstacles, the assigned topology, based on an extended Delaunay triangulation concept, implements regular and connected formation shapes. In the presence of obstacles, this technique is combined with a model predictive control (MPC) that allows forming independent sub-swarms optimizing the formation spreading to avoid obstacles and collisions between neighboring vehicles. A custom numerical simulator was developed in a Matlab/Simulink environment to prove the effectiveness of the proposed guidance and control scheme in several 2D operational scenarios with obstacles of different sizes and increasing number of aircraft.

The retinoblastoma tumor suppressor gene (RB1) plays a critical role in coordinating multiple pathways that impact cancer initiation, disease progression, and therapeutic responses. Here we probed molecular features associated with the RB-pathway across 31 tumor-types. While the RB-pathway has been purported to exhibit multiple mutually exclusive genetic events, only RB1 alteration is mutually exclusive with deregulation of CDK4/6 activity. An ER+ breast cancer model with targeted RB1 deletion was used to identify signatures of CDK4/6 activity and RB-dependency (CDK4/6-RB integrated signature). This signature was prognostic in tumor-types with gene expression features indicative of slower growth. Single copy loss on chromosome 13q encompassing the RB1 locus is prevalent in many cancers, yielding reduced expression of multiple genes in cis, and is inversely related to the CDK4/6-RB integrated signature supporting a cause-effect relationship. Genes that are positively and inversely correlated with the CDK4/6-RB integrated signature define new tumor-specific pathways associated with RB-pathway activity.

Prostatic luminal epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen, sensitizing them to perturbations of connected metabolic pathways. Enhanced flux is driven by spermidine/spermine N1-acetyltransferase (SSAT) activity, which acetylates polyamines leading to their secretion and drives biosynthetic demand. The methionine salvage pathway recycles one-carbon units lost to polyamine biosynthesis to the methionine cycle to overcome stress. Prostate cancer (CaP) relies on methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme, to relieve strain. Here, we show that inhibition of MTAP alongside SSAT upregulation is synergistic in androgen sensitive and castration recurrent CaP models in vitro and in vivo. The combination treatment increases apoptosis in radical prostatectomy ex vivo explant samples. This unique high metabolic flux through polyamine biosynthesis and connected one carbon metabolism in CaP creates a metabolic dependency. Enhancing this flux while simultaneously targeting this dependency in prostate cancer results in an effective therapeutic approach potentially translatable to the clinic.

Salt consumption in many countries of the world exceeds the level recommended by WHO (5 g/day), which is associated with negative effects on health. Public health strategies to achieve the WHO's objectives include salt content monitoring, improved nutritional labelling and product reformulation. This study aimed to determine the sodium content in street food (SF), fast foods (FF) and artisanal foods (AF) of the Northwest of Argentina, which is not regulated. Moisture, ash and sodium were determined according to the Official Methods of Analysis (AOAC) in 189 samples from each of the three categories. The average and range values were: SF 520 (R: 74-932); FF 599 (R: 371-1093) and AF 575 (R: 152-1373) mg Na/100 g. Thus, general sodium content is high, which means that the consumption of a serving from most of the studied foods leads to an individual exceeding the recommended daily intake values. This study contributes to the knowledge of sodium content in evaluated foods and its contribution to the population intake. This reinforces the importance of implementing new public policies and regulations, advising consumers to check food nutritional labels andselect foods lower in salt content, raising food manufacturers' awarenessabout the importance of reducing sodium content in foods they produce and in public health.

Introduction: Influenza epidemics are of higher risk at the extremes of life and in people with comorbidities. Effective -vaccination prevents the occurrence of serious cases and decreases mortality., Objective: To describe deaths from influenza with a history of timely vaccination, from the 2010 to the 2018 season in Mexico., Method: Cross-sectional, descriptive study where the Influenza Epidemiological Surveillance System database was used., Results: From 2010 to 2018, 65 vaccinated individuals died from influenza, from which 55% of cases (n = 36) were due to type A (H1N1), 51% (n = 33) were females, median age was 57 years, 21 % (n = 14) did not meet the operational definition of influenza-like illness or severe acute respiratory infection, 83% (n = 54) had at least one comorbidity, with the most common being diabetes mellitus and hypertension (32% each); 55% (n = 36) of deaths received antiviral treatment and only 8% (n = 5) had no comorbidities and received treatment with oseltamivir., Conclusions: Deaths from influenza with timely vaccination represent a very low percentage of the totality. Vaccination against influenza has been a specific prevention strategy that decreases disease burden., (Copyright: © 2019 Permanyer.)

Introduction: Influenza epidemics are of higher risk at the extremes of life and in people with comorbidities. Effective vaccination prevents the occurrence of serious cases and decreases mortality., Objective: To describe deaths from influenza with a history of timely vaccination, from the 2010 to the 2018 season in Mexico., Method: Cross-sectional, descriptive study where the Influenza Epidemiological Surveillance System database was used., Results: From 2010 to 2018, 65 vaccinated individuals died from influenza, from which 55% of cases (n = 36) were due to type A (H1N1), 51% (n = 33) were females, median age was 57 years, 21 % (n = 14) did not meet the operational definition of influenza-like illness or severe acute respiratory infection, 83% (n = 54) had at least one comorbidity, with the most common being diabetes mellitus and hypertension (32% each); 55% (n = 36) of deaths received antiviral treatment and only 8% (n = 5) had no comorbidities and received treatment with oseltamivir., Conclusions: Deaths from influenza with timely vaccination represent a very low percentage of the totality. Vaccination against influenza has been a specific prevention strategy that decreases disease burden., (Copyright: © 2019 Permanyer.)

Understanding metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics in the clinic. Here, using transcriptomic data for 10,704 tumor and normal samples from The Cancer Genome Atlas, across 26 disease sites, we present a novel bioinformatics pipeline that distinguishes tumor from normal tissues, based on differential gene expression for 114 metabolic pathways. We confirm pathway dysregulation in separate patient populations, demonstrating the robustness of our approach. Bootstrapping simulations were then applied to assess the biological significance of these alterations. We provide distinct examples of the types of analysis that can be accomplished with this tool to understand cancer specific metabolic dysregulation, highlighting novel pathways of interest, and patterns of metabolic flux, in both common and rare disease sites. Further, we show that Master Metabolic Transcriptional Regulators explain why metabolic differences exist, can segregate patient populations, and predict responders to different metabolism-targeted therapeutics.

Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.

Andean potatoes (Solanum tuberosum andigenum) are a staple food for Andean population; there is great biodiversity but only few varieties are cultivated nowadays. In order to contribute to biodiversity conservation of Andean potatoes, information about their morphological, nutritional and functional characteristics was generated. In gene bank (INTA-Balcarce), varieties collected from regional producers were preserved. Forty-four genotypes were multiplied and characterized. Morphological characteristics; proximate composition and functional compounds were analyzed. Cluster analysis separated them into 3 groups according to distinguishing characteristics, which define industrial or nutritional applications. Group 2 was characterized by higher content of macronutrients and Group 3 with the highest antioxidant activity, both would be advisable for direct consumption. Genotype CS 1418 had big size and oval form so it could be destined to potato chips industry. Knowledge on nutritional and functional properties of genotypes contributes to promoting the cultivation depending on properties and also to preserve biodiversity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Folate impacts the genome and epigenome by feeding into one-carbon metabolism to produce critical metabolites, deoxythymidine monophosphate and s-adenosylmethionine. The impact of folate exposure and intervention timing on cancer progression remains controversial. Due to polyamine metabolism's extraordinary biosynthetic flux in prostate cancer (CaP) we demonstrated androgen stimulated CaP is susceptible to dietary folate deficiency. We hypothesized dietary folate levels may also affect castration recurrent CaP. We used the CWR22 human xenograft model which recurs following androgen withdrawal. Engrafted mice were fed a folate depleted or supplemented diet beginning at androgen withdrawal, or prior to xenograft implantation. Both folate depletion and supplementation at the time of withdrawal significantly decreased recurrence incidence. Folate supplementation prior to xenograft implantation increased time to recurrence, suggesting a protective role. By contrast, folate depleted recurrent tumors exhibited transcriptional adaptive responses that maintained high polyamine levels at the expense of increased DNA damage and DNA methylation alterations. Mining of publically available data demonstrated folate related pathways are exceptionally dysregulated in human CaP, which correlated with decreased time to biochemical recurrence. These findings highlight the potential for novel therapeutic interventions that target these metabolic pathways in CaP and provide a rationale to apply such strategies alongside androgen withdrawal., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

To assess the acceptability and use of the female condom and diaphragm among female sex workers in the Dominican Republic, 243 participants were followed for 5 months. Participants received female and male condoms and a diaphragm along with proper counseling at monthly visits. Seventy-six percent reported used of female condom at least once during the final month of the study, compared with 50% that used the diaphragm with male condoms and 9% that used the diaphragm alone. The proportion of women reporting every sex act protected with some barrier method increased from 66% at first month to 77% at final month (p < 0.05). Participants reported higher acceptability and use of the female condom than the diaphragm. The introduction of female-controlled barrier methods resulted in the use of a wide range of prevention methods and a significant reduction in unprotected sex.

We have analyzed the gene modulation induced by zoledronic acid (ZOL) in androgen-resistant prostate cancer PC3 cells with cDNA microarray platform to identify new molecular targets of ZOL in prostate cancer. The gene coding for cysteine-rich, angiogenic inducer, 61 (CYR61) resulted highly downregulated with a fold change of 5.58. Therefore, we have studied the effects of ZOL on CYR61 protein product, and we have found that CYR61 protein expression was decreased significantly after exposure to ZOL. The effect of ZOL on CYR61 expression was dose and time dependent was due to a reduced transcriptional activity of CYR61 promoter. Moreover, the effects induced by ZOL were paralleled by decreased activation of Ras-Raf-1- and Akt-dependent pathways that was dependent from isoprenylation inhibition, since it was antagonized by the addition of geranylgeraniol. Finally, we have investigated the role of CYR61 in the regulation of growth inhibition and invasion/motility of PC3 cells using a shRNA for CYR61 to downregulate the expression of CYR61 protein. The enhanced inhibition of proliferation and motility/invasion induced by ZOL by S-phase accumulation. In the same experimental conditions, CYR61 protein downregulation potentiated the inactivation of the Ras-dependent proliferation pathway and cell cycle inhibitors p21 and p27 expression., ((c) 2009 UICC.)