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BackgroundBreast cancer (BC) affects racial and ethnic groups differently, leading to disparities in clinical presentation and outcomes. It is unclear how Hispanic ethnicity affects BC outcomes based on geographic location and proximity to the United States (U.S.)/Mexico border. We hypothesized that the impact of race/ethnicity on BC outcomes depends on geographic location and country of origin within each BC subtype.MethodsWe analyzed BC data from the Texas Cancer Registry by race/ethnicity/birthplace according to BC subtype (luminal A/luminal B/human epidermal growth factor receptor 2 [HER2]/triple-negative breast cancer[TNBC]). Other covariates included age, geographic location (U.S., Mexico), residency (border, non-border), treatments, and comorbidities. Crude and adjusted effects of race/ethnicity and birthplace on overall survival (OS) were analyzed using Cox regression methods.ResultsOur analysis of 76,310 patient records with specific BC subtypes revealed that Hispanic and non-Hispanic Black (NHB) patients were diagnosed at a younger age compared with non-Hispanic White (NHW) patients for all BC subtypes. For the 19,748 BC patients with complete data on race/ethnicity/birthplace/residency, Hispanic patients had a higher mortality risk in the Luminal A subtype, regardless of birthplace, whereas U.S.-born Hispanics had a higher risk of death in the TNBC subtype. In contrast, NHB patients had a higher mortality risk in the Luminal A and HER2 subtypes. Residence along the U.S./Mexico border had little impact on OS, with better outcomes in Luminal A patients and worse outcomes in Luminal B patients aged 60–74 years.ConclusionRace/ethnicity, geographic birth location, and residency were significant predictors of survival in BC. Migration, acculturation, and reduced healthcare access may contribute to outcome differences.

Abstract The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.

Abstract Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.

IntroductionThe ubiquitin-proteasome system (UPS) is an intracellular organelle responsible for targeted protein degradation, which represents a standard therapeutic target for many different human malignancies. Bortezomib, a reversible inhibitor of chymotrypsin-like proteasome activity, was first approved by the FDA in 2003 to treat multiple myeloma and is now used to treat a number of different cancers, including relapsed mantle cell lymphoma, diffuse large B-cell lymphoma, colorectal cancer, and thyroid carcinoma. Despite the success, bortezomib and other proteasome inhibitors are subject to severe side effects, and ultimately, drug resistance. We recently reported an oncogenic role for non-ATPase members of the 19S proteasome in chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and several different solid tumors. In the present study, we hypothesized that ATPase members of the 19S proteasome would also serve as biomarkers and putative therapeutic targets in AML and multiple other cancers.MethodsWe used data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) available at UALCAN and/or GEPIA2 to assess the expression and prognostic value of proteasome 26S subunit, ATPases 1-6 (PSMC1-6) of the 19S proteasome in cancer. UALCAN was also used to associate PSMC1-6 mRNA expression with distinct clinicopathological features. Finally, cBioPortal was employed to assess genomic alterations of PSMC genes across different cancer types.ResultsThe mRNA and protein expression of PSMC1-6 of the 19S proteasome were elevated in several cancers compared with normal controls, which often correlated with worse overall survival. In contrast, AML patients demonstrated reduced expression of these proteasome subunits compared with normal mononuclear cells. However, AML patients with high expression of PSMC2-5 had worse outcomes.DiscussionAltogether, our data suggest that components of the 19S proteasome could serve as prognostic biomarkers and novel therapeutic targets in AML and several other human malignancies.

Abstract Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have turned chronic myeloid leukaemia (CML) from a fatal disease into a manageable condition for most patients. Despite improved survival, targeting drug‐resistant leukaemia stem cells (LSCs) remains a challenge for curative CML therapy. Aberrant lipid metabolism can have a large impact on membrane dynamics, cell survival and therapeutic responses in cancer. While ceramide and sphingolipid levels were previously correlated with TKI response in CML, the role of lipid metabolism in TKI resistance is not well understood. We have identified downregulation of a critical regulator of lipid metabolism, G0/G1 switch gene 2 (G0S2), in multiple scenarios of TKI resistance, including (1) BCR::ABL1 kinase‐independent TKI resistance, (2) progression of CML from the chronic to the blast phase of the disease, and (3) in CML versus normal myeloid progenitors. Accordingly, CML patients with low G0S2 expression levels had a worse overall survival. G0S2 downregulation in CML was not a result of promoter hypermethylation or BCR::ABL1 kinase activity, but was rather due to transcriptional repression by MYC. Using CML cell lines, patient samples and G0s2 knockout (G0s2−/−) mice, we demonstrate a tumour suppressor role for G0S2 in CML and TKI resistance. Our data suggest that reduced G0S2 protein expression in CML disrupts glycerophospholipid metabolism, correlating with a block of differentiation that renders CML cells resistant to therapy. Altogether, our data unravel a new role for G0S2 in regulating myeloid differentiation and TKI response in CML, and suggest that restoring G0S2 may have clinical utility.

Plain English Summary A persistent myth is that restrictive eating disorders are outwardly recognizable due to severely low body weight or emaciation. Atypical anorexia nervosa (AAN) and anorexia nervosa (AN) are both characterized by restrictive eating behavior. Individuals with AAN do not have current low body weight, although some research suggests they have higher levels of impairment and eating disorder pathology than their peers with AN, and their physical health may be equally compromised. Despite this, individuals with AAN are more likely to have a longer duration of illness and less likely to receive inpatient care, suggesting their illness is not always recognized by others. Additionally, thinness is highly valued in today’s society and restrictive eating behavior or “dieting” is commonplace, which may promote trivialization, or even reinforcement, of initial weight loss by friends or family. With this in mind, our study aimed to explore the experiences of seven recovered individuals recovered from AN or AAN who were directly or indirectly told by peers, families, or healthcare professionals that they were “not sick enough” at some point during their course of illness. We explored the perceived effects on symptoms, motivation for treatment, mental health and well-being. Participants reported their symptoms were occasionally trivialized or dismissed, leading to shame, confusion, and self-doubt regarding the seriousness of their symptoms. For some, a deterioration in eating disorder symptoms ensued that led to additional weight loss, sometimes in a competitive or perfectionist pursuit to “succeed” at eating restrictively. Findings demonstrated the value of being seen and understood, as well as the potential damage of being considered as “not sick enough” by others when battling a restrictive eating disorder.

Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML.

FLT3-ITD+ acute myeloid leukemia (AML) accounts for ∼25% of all AML cases and is a subtype that carries a poor prognosis. microRNA-155 (miR-155) is specifically overexpressed in FLT3-ITD+ AML compared with FLT3 wild-type (FLT3-WT) AML and is critical for the growth of FLT3-ITD+ AML cells in vitro. However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear. In this study, we used a genetic mouse model to determine whether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease. Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, spleen, and peripheral blood. Mechanistically, miR-155 increases proliferation of the hematopoietic stem and progenitor cell compartments by reducing the growth-inhibitory effects of the interferon (IFN) response, and this involves targeting of Cebpb. Consistent with our observations in mice, primary FLT3-ITD+ AML clinical samples have significantly higher miR-155 levels and a lower IFN response compared with FLT3-WT AML samples. Further, inhibition of miR-155 in FLT3-ITD+ AML cell lines using CRISPR/Cas9, or primary FLT3-ITD+ AML samples using locked nucleic acid antisense inhibitors, results in an elevated IFN response and reduces colony formation. Altogether, our data reveal that miR-155 collaborates with FLT3-ITD to promote myeloid cell expansion in vivo and that this involves a multitarget mechanism that includes repression of IFN signaling.

Background: Breast cancer (BC) affects racial and ethnic groups differently, leading to disparities in clinical presentation and outcomes. It is unclear how Hispanic ethnicity affects BC outcomes based on geographic location and proximity to the United States (U.S.)/Mexico border. We hypothesized that the impact of race/ethnicity on BC outcomes depends on geographic location and country of origin within each BC subtype. Methods: We analyzed BC data from the Texas Cancer Registry by race/ ethnicity/birthplace according to BC subtype (luminal A/luminal B/human epidermal growth factor receptor 2 [HER2]/triple-negative breast cancer [TNBC]). Other covariates included age, geographic location (U.S., Mexico), residency (border, non-border), treatments, and comorbidities. Crude and adjusted effects of race/ethnicity and birthplace on overall survival (OS) were analyzed using Cox regression methods. Results: Our analysis of 76,310 patient records with specific BC subtypes revealed that Hispanic and non-Hispanic Black (NHB) patients were diagnosed at a younger age compared with non-Hispanic White (NHW) patients for all BC subtypes. For the 19,748 BC patients with complete data on race/ethnicity/ birthplace/residency, Hispanic patients had a higher mortality risk in the Luminal A subtype, regardless of birthplace, whereas U.S.-born Hispanics had a higher risk of death in the TNBC subtype. In contrast, NHB patients had a higher mortality risk in the Luminal A and HER2 subtypes. Residence along the U.S./Mexico border had little impact on OS, with better outcomes in Luminal A patients and worse outcomes in Luminal B patients aged 60–74 years. Conclusion: Race/ethnicity, geographic birth location, and residency were significant predictors of survival in BC. Migration, acculturation, and reduced healthcare access may contribute to outcome differences. [ABSTRACT FROM AUTHOR]

Prophylactic vaccination against infectious diseases is one of the most successful public health measures of our lifetime. More recently, therapeutic vaccination against established diseases such as cancer has proven to be more challenging. In the host, cancer cells evade immunologic regulation by multiple means, including altering the antigens expressed on their cell surface or recruiting inflammatory cells that repress immune surveillance. Nevertheless, recent clinical data suggest that two classes of antigens show efficacy for the development of anticancer vaccines: tumor-associated antigens and neoantigens. In addition, many different vaccines derived from antigens based on cellular, peptide/protein, and genomic components are in development to establish their efficacy in cancer therapy. Some vaccines have shown promising results, which may lead to favorable outcomes when combined with standard therapeutic approaches. This review provides an overview of the innate and adaptive immune systems, their interactions with cancer cells, and the development of various different vaccines for use in anticancer therapeutics.

Abstract Background Conducting systematic reviews is time-consuming but crucial to construct evidence-based patient decision aids, clinical practice guidelines and decision analyses. New methods might enable developers to produce a knowledge base more rapidly. However, trading off scientific rigour for speed when creating a knowledge base is controversial, and the consequences are insufficiently known. We developed and applied faster methods including systematic reviews and network meta-analyses, assessed their feasibility and compared them to a gold standard approach. We also assessed the feasibility of using decision analysis to perform this comparison. Methods Long-term treatment in bipolar disorder was our testing field. We developed two new methods: an empirically based, rapid network meta-analysis (NMA) and an expert NMA, and conducted a patient survey. We applied these methods to collect effect estimates for evidence-based treatments on outcomes important to patients. The relative importance of outcomes was obtained from patients using a stated preference method. We used multi-criteria decision analysis to compare a gold standard NMA with the rapid NMA in terms of the ability of the gold standard NMA to change the ranking and expected values of treatments for individual patients. Results Using rapid methods, it was feasible to identify evidence addressing outcomes important to patients. We found that replacing effect estimates from our rapid NMA with estimates from the gold standard NMA resulted in relatively small changes in the ranking and expected value of treatments. The rapid method sufficed to estimate the effects of nine out of ten options. To produce a ranking of treatments accurate for more than 95% of patients, it was necessary to supplement systematic with rapid methods and to use relative importance weights in the analysis. Integrating estimates of the outcome “treatment burden” had a larger impact on rankings than replacing rapid with gold standard methods. Using patients’ importance weights only modestly affected results. Conclusions The transfer of knowledge to practice could benefit from faster systematic reviewing methods. The results in this preliminary assessment suggest that an improved rapid NMA approach might replace gold standard NMAs. Decision analysis could be used to compare evidence summarisation methods.

Acute myeloid leukemia (AML) is a heterogeneous disease with a poor prognosis and remarkable resistance to chemotherapeutic agents. Understanding resistance mechanisms against currently available drugs helps to recognize the therapeutic obstacles. Various mechanisms of resistance to chemotherapy or targeted inhibitors have been described for AML cells, including a role for the bone marrow niche in both the initiation and persistence of the disease, and in drug resistance of the leukemic stem cell (LSC) population. The BM niche supports LSC survival through direct and indirect interactions among the stromal cells, hematopoietic stem/progenitor cells, and leukemic cells. Additionally, the BM niche mediates changes in metabolic and signal pathway activation due to the acquisition of new mutations or selection and expansion of a minor clone. This review briefly discusses the role of the BM microenvironment and metabolic pathways in resistance to therapy, as discovered through AML clinical studies or cell line and animal models.