Immune-related adverse events are associated with efficacy of immune checkpoint inhibitors (ICIs). We hypothesize that immune-mediated thrombocytopenia could be a biomarker for response to ICIs.
This ...retrospective study included 215 patients with metastatic malignancies treated with ICIs. Patients were stratified by nadir platelet count. Outcomes of interest were progression-free survival and overall survival.
On multivariate analysis, grade 1 thrombocytopenia was positively associated with overall survival compared with patients who did not develop thrombocytopenia (hazard ratio HR= 0.28 95% CI: 0.13–0.60; p = 0.001), while grade 2–4 thrombocytopenia was not (HR= 0.36 95% CI: 0.13–1.04; p = 0.060). There was no association between degree of thrombocytopenia and progression-free survival.
Follow-up studies are warranted to substantiate the predictive significance of thrombocytopenia in patients receiving ICIs.
Immune checkpoint inhibitors (ICIs) are a class of drug that are increasingly being used in different cancers. The extent of response to treatment with ICIs differs among individuals. There is a lack of biomarkers, which would help clinicians predict response to ICIs. In our study, we aimed to explore the development of low platelets as a potential biomarker. Our findings suggest that cancer patients receiving ICIs who develop a mild decrease in platelet count tend to live longer than those who do not. However, this was not true for those who developed a severe decrease in platelet count. The mechanism of how ICIs affect platelets may be related to the interaction between the immune system and platelets. More studies are needed to validate our results and better understand the role of platelets in cancer biology.
Both the risk and the rate of development of atherosclerosis are increased in diabetics, but the mechanisms involved are unknown. Here we report a glucose-mediated increase in CD36 mRNA translation ...efficiency that results in increased expression of the macrophage scavenger receptor CD36. Expression of CD36 was increased in endarterectomy lesions from patients with a history of hyperglycemia. Macrophages that were differentiated from human peripheral blood monocytes in the presence of high glucose concentrations showed increased expression of cell-surface CD36 secondary to an increase in translational efficiency of CD36 mRNA. We obtained similar data from primary cells isolated from human vascular lesions, and we found that glucose sensitivity is a function of ribosomal reinitiation following translation of an upstream open reading frame (uORF). Increased translation of macrophage CD36 transcript under high glucose conditions provides a mechanism for accelerated atherosclerosis in diabetics.
The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2), is expressed mainly in brain and prostate. Expression of TMEFF2 is deregulated in prostate cancer, ...suggesting a role in this disease, but the molecular mechanism(s) involved in this effect are not clear. Although androgens promote tmeff2 transcription, androgen delivery to castrated animals carrying CWR22 xenografts increases TMEFF2 protein levels in the absence of mRNA changes, suggesting that TMEFF2 may also be post-transcriptionally regulated. Here we show that translation of TMEFF2 is regulated by androgens. Addition of physiological concentrations of dihydrotestosterone (DHT) to prostate cancer cell lines increases translation of endogenous TMEFF2 or transfected TMEFF2-Luciferase fusions, and this effect requires the presence of upstream open reading frames (uORFs) in the 5'-untranslated region (5'-UTR) of TMEFF2. Using chemical and siRNA inhibition of the androgen receptor (AR), we show that the androgen effect on TMEFF2 translation is mediated by the AR. Importantly, DHT also promotes phosphorylation of the α subunit of the translation initiation factor 2 (eIF2α) in an AR-dependent manner, paralleling the effect on TMEFF2 translation. Moreover, endoplasmic reticulum (ER) stress conditions, which promote eIF2α phosphorylation, also stimulate TMEFF2 translation. These results indicate that androgen signaling promotes eIF2α phosphorylation and subsequent translation of TMEFF2 via a mechanism that requires uORFs in the 5'-UTR of TMEFF2.
Recent observational studies suggest that bisphosphonates (BP) and antidiabetic drugs are associated with colorectal cancer risk reduction. Hence, we evaluated the colorectal cancer preventive ...effects of BPs (zometa and fosamax), individually and when combined with metformin, in azoxymethane-induced rat colon cancer model. Rat (30/group) were randomized and treated subcutaneously with azoxymethane to induce colorectal cancer. Dietary intervention with zometa or fosamax (0, 20, or 100 ppm) or metformin (1,000 ppm) or the combinations (zometa/fosamax 20 ppm plus metformin 1,000 ppm) began 4 weeks after azoxymethane treatment, at premalignant lesions stage. Rats were killed 40 weeks post drug intervention to assess colorectal cancer preventive efficacy. Dietary zometa (20 ppm) inhibited noninvasive adenocarcinomas multiplicity by 37% (
< 0.03) when compared with control diet fed group. Fosamax at 20 ppm and 100 ppm significantly reduced adenocarcinoma incidence (
< 0.005) and inhibited the noninvasive adenocarcinoma multiplicities by 43.8% (
< 0.009) and 60.8% (
< 0.004), respectively, compared with the group fed control diet. At 1,000 ppm dose, metformin failed to suppress colon adenocarcinoma formation. However, the lower dose combinations of zometa or fosamax with metformin resulted in significant inhibition of noninvasive adenocarcinoma by 48% (
< 0.006) and 64% (
< 0.0002), and invasive adenocarcinoma by 49% (
< 0.0005) and 38% (
< 0.006), respectively. Biomarker analysis of combination drug-treated tumors showed a decrease in cell proliferation with increased apoptosis when compared with untreated tumors. Overall, our results suggest that the combination of low doses of zometa or fosamax with metformin showed synergistic effect and significantly inhibited colon adenocarcinoma incidence and multiplicity.
The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is a γ-2
herpesvirus that is implicated in the pathogenesis
of Kaposi's sarcoma, and of primary effusion
B-cell lymphomas (PELs). KSHV infects ...malignant and progenitor
cells of Kaposi's sarcoma and PEL,,, it encodes putative oncogenes,, and genes that may cause Kaposi's sarcoma pathogenesis by stimulating
angiogenesis,,,.
The G-protein-coupled receptor encoded by an open reading frame (ORF 74) of
KSHV is expressed in Kaposi's sarcoma lesions and in PEL, and stimulates signalling pathways linked to cell
proliferation in a constitutive (agonist-independent) way. Here we show that signalling by this KSHV G-protein-coupled receptor
leads to cell transformation and tumorigenicity, and induces a switch to an
angiogenic phenotype mediated by vascular endothelial growth
factor, an angiogenesis, and
Kaposi's-spindle-cell growth factor. We find that
this receptor can activate two protein kinases, JNK/SAPK and p38MAPK, by triggering
signalling cascades like those induced by inflammatory cytokines
that are angiogenesis activators and mitogens for Kaposi's
sarcoma cells and B cells. We conclude that the KSHV G-protein-coupled
receptor is a viral oncogene that can exploit cell signalling pathways to
induce transformation and angiogenesis in KSHV-mediated oncogenesis.
Background
Clinical trials are key elements of the processes that account for many of the recent advances in cancer care. Unfortunately, they are becoming more challenging to conduct. Furthermore, a ...large number of clinical trials in oncology close early due to poor accrual. To identify opportunities for continued improvement in clinical trial enrollment, we sought to identify the obstacles encountered by our clinical trial research staff in these activities.
Methods
This is a prospective qualitative study, using Grounded Theory Methodology that was concluded at Stephenson Cancer Center (SCC). SCC has been the lead accruer to National Cancer Institute-Lead Academic Participating Sites (NCI-LAPS) trials over the past three years, and in addition, fields investigator-initiated and industry-sponsored trials.
We conducted a survey of our research staff including all research nurses and disease site coordinators who participate in recruitment, screening, consenting, data collection, and compliance for interventional clinical trials. We then performed a follow-up meeting with our research coordinators to clarify responses. The study objectives were to highlight common barriers to recruiting adult cancer patients, encountered by research coordinators from all disease sites and to propose effective solutions to identified barriers.
Results
We are reporting our results of investigating barriers to clinical trials enrollment from a new perspective. The most commonly reported obstacles for clinical trials enrollment from our research staff's perspective were categorized into five themes: clinical trials protocol, communication barriers and cultural beliefs, financial barriers, patients' comorbidities and performance status, and physicians’ commitment.
Conclusions
Although assessing barriers encountered by clinical research staff is an infrequently used metric for improving clinical trial enrollment, it provides an important perspective in the field. Implementing interventions to improve clinical trial feasibility and accrual is critical to improving cancer care.
Autoantibodies against factor VIII (FVIII) are rare but can cause life-threatening bleeding requiring costly factor replacement and prolonged immunosuppression. We report 4 consecutively treated ...patients whose acquired FVIII inhibitors responded rapidly to immunosuppressive regimens that included rituximab, a monoclonal antibody against CD20+ B cells. Three patients had spontaneously occurring inhibitors. The fourth, a patient with mild hemophilia A, developed both an autoantibody and an alloantibody following recombinant FVIII treatment. Pretreatment FVIII activities ranged from less than 1% to 4% and inhibitor titers from 5 to 60 Bethesda units (BU). One patient with polymyalgia rheumatica who developed the inhibitor while receiving prednisone responded to single agent rituximab. The hemophilia patient had rapid resolution of the autoantibody, whereas the alloantibody persisted for months. Responses continue off treatment from more than 7 to more than 12 months. This report adds to the growing evidence that rituximab has efficacy in immune disorders resulting from autoantibody formation.
The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It ...also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.
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