PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression.

BACKGROUND: The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. METHODS: In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. RESULTS: PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. CONCLUSIONS: PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex-unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.

In Vivo Labeling and Detection of Circulating Tumor Cells in Mice Using OTL38.

PURPOSE: We recently developed an optical instrument to non-invasively detect fluorescently labeled circulating tumor cells (CTCs) in mice called 'Diffuse in vivo Flow Cytometry' (DiFC). OTL38 is a folate receptor (FR) targeted near-infrared (NIR) contrast agent that is FDA approved for use in fluorescence guided surgery of ovarian and lung cancer. In this work, we investigated the use OTL38 for in vivo labeling and detection of FR + CTCs with DiFC. PROCEDURES: We tested OTL38 labeling of FR + cancer cell lines (IGROV-1 and L1210A) as well as FR- MM.1S cells in suspensions of Human Peripheral Blood Mononuclear cells (PBMCs) in vitro. We also tested OTL38 labeling and NIR-DIFC detection of FR + L1210A cells in blood circulation in nude mice in vivo. RESULTS: 62% of IGROV-1 and 83% of L1210A were labeled above non-specific background levels in suspensions of PBMCs in vitro compared to only 2% of FR- MM.1S cells. L1210A cells could be labeled with OTL38 directly in circulation in vivo and externally detected using NIR-DiFC in mice with low false positive detection rates. CONCLUSIONS: This work shows the feasibility of labeling CTCs in vivo with OTL38 and detection with DiFC. Although further refinement of the DiFC instrument and signal processing algorithms and testing with other animal models is needed, this work may eventually pave the way for human use of DiFC.

Association between short-term exposure to ambient air pollutants and biomarkers indicative of inflammation and oxidative stress: a cross-sectional study using KoGES-HEXA data.

BACKGROUND: Air pollution-induced systemic inflammation and oxidative stress are hypothesized to be the major biological mechanisms underlying pathological outcomes. We examined the association between short-term exposure to ambient air pollutants and biomarkers of inflammation and oxidative stress in 2199 general middle-aged Korean population residing in metropolitan areas. METHODS: Serum levels of inflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor [TNF]-α) and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured. Daily concentrations of a series of air pollutants (particulate matter [PM]10, PM2.5, SO2, NO2, CO, and O3) were predicted using the Community Multiscale Air Quality modeling system, and participant-level pollutant exposure was determined using geocoded residential addresses. Short-term exposure was defined as the 1- to 7-day moving averages. RESULTS: The multivariable-adjusted linear models controlling for the sociodemographic, lifestyle, temporal, and meteorological factors identified positive associations of PM with IL-1ß, IL-8, IL-10, TNF-α, and 8-OHdG levels; SO2 with IL-10 levels, CO with IL-1ß, IL-10, and TNF-α levels; and O3 with IL-1ß, IL-8, and 8-OHdG levels. O3 levels were inversely associated with IL-10 levels. For each pollutant, the strongest associations were observed for the 7-day average PM and CO with IL-1ß (per 10-µg/m3 increase in PM10: 2.7%, 95% confidence interval [CI] = 0.6-4.8; per 10-µg/m3 increase in PM2.5: 6.4%, 95% CI = 2.4-10.5; per 0.1-ppm increase in CO: 3.3%, 95% CI = 0.3-6.5); the 2-day average SO2 with IL-10 levels (per 1-ppb increase in SO2: 1.1%, 95% CI = 0.1-2.1); and the 7-day average O3 with IL-8 levels (per 1-ppb increase in O3: 1.3%, 95% CI = 0.7-1.9). CONCLUSIONS: Short-term exposure to ambient air pollutants may induce oxidative damage and pro-inflammatory roles, together with counter-regulatory anti-inflammatory response.

Are Australian Cancer and Palliative Care Nurses Ready to Prescribe Medicines? A National Survey.

OBJECTIVES: Registered nurse prescribing has been put forth, for decades, as an innovative approach to meet growing healthcare needs, particularly in areas of care where medications are essential and highly controlled such as for patients requiring cancer and palliative care. However, the adoption of innovative health delivery models requires acceptance by key stakeholders. This study explores cancer and palliative care nurses' attitudes toward nurse prescribing and their perceptions about educational requirements for a nurse prescriber. DATA SOURCES: A cross-sectional survey was distributed to Australian nurses between March and July 2021. Data were collected using the Advancing Implementation of Nurse Prescribing in Australia online survey. Pearson χ2 tests were used to examine associations between nurses in cancer care, palliative care, and all other specialties on demographics, attitudes to nurse prescribing, and educational perspectives to become prescribers. Of the 4,424 nurses who participated in the survey, 161 nurses identified they worked in cancer care and 109 in palliative care settings. CONCLUSION: Although nurses have a common set of core capabilities, their work contexts and their professional experiences shape their attitudes toward practice. Nurses in cancer care were significantly less certain than nurses in palliative care [χ2(2) = 6.68, P = .04], and nurses from all other specialties [χ2(2) =13.87, P = <.01] of the benefits of nurse prescribing (ie, nurse prescribing would decrease health care system costs, reduce patient risk). Nurses in cancer care were more certain that successfully implementing nurse prescribing requires strong support from their medical and pharmacy colleagues. In addition, nurses working in cancer and palliative care agreed that improving patient care was their primary motivator for becoming a prescriber. IMPLICATIONS FOR NURSING PRACTICE: Open to expanding their role and responsibilities, nurses in cancer and palliative care settings reported that successfully adopting nurse prescribing must be supported by their other healthcare colleagues within the same environment, which demands strong interprofessional collaborative efforts.

Mapping the key characteristics of carcinogens for glyphosate and its formulations: A systematic review.

Glyphosate was classified as a probable human carcinogen (Group 2A) by the International Agency for Research on Cancer (IARC) partially due to strong mechanistic evidence in 2015. Since then, numerous studies of glyphosate and its formulations (GBF) have emerged. These studies can be evaluated for cancer hazard identification with the newly described ten key characteristics (KC) of carcinogens approach. Our objective was to assess all in vivo, ex vivo, and in vitro mechanistic studies of human and experimental animals (mammals) that compared exposure to glyphosate/GBF with low/no exposure counterparts for evidence of the ten KCs. A protocol with our methods adhering to PRISMA guidelines was registered a priori (INPLASY202180045). Two blinded reviewers screened all in vivo, ex vivo, and in vitro studies of glyphosate/GBF exposure in humans/mammals reporting any KC-related outcome available in PubMed before August 2021. Studies that met inclusion criteria underwent data extraction conducted in duplicate for each KC outcome reported along with key aspects of internal/external validity, results, and reference information. These data were used to construct a matrix that was subsequently analyzed in the program R to conduct strength of evidence and quality assessments. Of the 2537 articles screened, 175 articles met inclusion criteria, from which we extracted >50,000 data points related to KC outcomes. Data analysis revealed strong evidence for KC2, KC4, KC5, KC6, KC8, limited evidence for KC1 and KC3, and inadequate evidence for KC7, KC9, and KC10. Notably, our in-depth quality analyses of genotoxicity (KC2) and endocrine disruption (KC8) revealed strong and consistent positive findings. For KC2, we found: 1) studies conducted in humans and human cells provided stronger positive evidence than counterpart animal models; 2) GBF elicited a stronger effect in both human and animal systems when compared to glyphosate alone; and 3) the highest quality studies in humans and human cells consistently revealed strong evidence of genotoxicity. Our analysis of KC8 indicated that glyphosate's ability to modulate hormone levels and estrogen receptor activity is sensitive to both exposure concentration and formulation. The modulations observed provide clear evidence that glyphosate interacts with receptors, alters receptor activation, and modulates the levels and effects of endogenous ligands (including hormones). Our findings strengthen the mechanistic evidence that glyphosate is a probable human carcinogen and provide biological plausibility for previously reported cancer associations in humans, such as non-Hodgkin lymphoma. We identified potential molecular interactions and subsequent key events that were used to generate a probable pathway to lymphomagenesis.

Pernicious Anemia Presenting as a Mimicker of Thrombotic Thrombocytopenic Purpura.

A 52-year-old woman with no significant past medical history presented to the emergency room (ER) with nonspecific systemic symptoms, including fatigue, dyspnea on exertion, easy bruising, and palpitations. She was found to have significant pancytopenia. Hemolytic anemia, thrombocytopenia, and elevated PLASMIC score (6, High risk; PLASMIC = Platelet count; combined hemoLysis variable; absence of Active cancer; absence of Stem-cell or solid-organ transplant; MCV; INR; Creatinine) score at the time of presentation led to a concern for thrombotic thrombocytopenic purpura (TTP). Therapeutic plasma exchange (TPE) was deferred pending additional investigation. Workup revealed the true diagnosis of severe B12 deficiency, which would not have benefited from TPE and instead would have placed the patient at risk for harm, making the decision to defer treatment the correct and judicious approach. This is a case where anchoring on lab results may result in reaching the incorrect diagnosis. This case reminds clinicians of the importance of creating a broad differential and ensuring thorough history-taking is done for all patients.

Transverse Maxillary Deficiency Predicts Increased Upper Airway Collapsibility during Drug-Induced Sleep Endoscopy.

OBJECTIVE: To examine the relationship between craniofacial skeletal anatomy and objective measures of pharyngeal collapse obtained during drug-induced sleep endoscopy. We hypothesized that transverse maxillary deficiency and an increased pharyngeal length will be associated with higher levels of pharyngeal collapsibility. STUDY DESIGN: Cross-sectional analysis in a prospective cohort. SETTING: University Hospital. METHODS: A cross-sectional analysis was conducted in a cohort of consecutive patients from the positive airway pressure (PAP) alternatives clinic who underwent computed tomography (CT) analysis and drug-induced sleep endoscopy for characterization of upper airway collapsibility. PAP titration was used to determine pharyngeal critical pressure (PCRIT ) and pharyngeal opening pressure (PhOP). CT metrics included: Transverse maxillary dimensions (interpremolar and intermolar distances) and pharyngeal length (posterior nasal spine to hyoid distance). RESULTS: The cohort (n = 103) of severe obstructive sleep apnea (Apnea and Hipopnea Index 32.1 ± 21.3 events/h) was predominantly male (71.8%), Caucasian (81.6%), middle-aged (54.4 ± 14.3 years), and obese (body mass index [BMI] = 30.0 ± 4.9 kg/m2 ). Reduced transverse maxillary dimensions were associated with higher PCRIT (intermolar distance: ß [95% confidence interval, CI] = -.25 [-0.14, -0.36] cmH2 O/mm; p = .03) and PhOP (Interpremolar distance: ß = -.25 [-0.14, -0.36] cmH2 O/mm; p = .02). Longer pharyngeal length was also associated with higher PCRIT (ß = .11 [0.08, 0.14] cmH2 O/mm, p = .04) and PhOP (ß [95% CI] = .06 [0.03, 0.09] cmH2 O/mm, p = .04). These associations persisted after adjustments for sex, age, height, and BMI. CONCLUSION: Our results further the concept that skeletal restriction in the transverse dimension and hyoid descent are associated with elevations in pharyngeal collapsibility during sleep, suggesting a role of transverse deficiency in the pathogenesis of airway obstruction.

Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities.

Mis-sense mutations affecting TP53 promote carcinogenesis both by inactivating tumor suppression, and by conferring pro-carcinogenic activities. We report here that p53 DNA-binding domain (DBD) and transactivation domain (TAD) mis-sense mutants unexpectedly activate pro-carcinogenic epidermal growth factor receptor (EGFR) signaling via distinct, previously unrecognized molecular mechanisms. DBD- and TAD-specific TP53 mutants exhibited different cellular localization and induced distinct gene expression profiles. In multiple tissues, EGFR is stabilized by TAD and DBD mutants in the cytosolic and nuclear compartments respectively. TAD mutants promote EGFR-mediated signaling by enhancing EGFR interaction with AKT via DDX31 in the cytosol. Conversely, DBD mutants maintain EGFR activity in the nucleus, by blocking EGFR interaction with the phosphatase SHP1, triggering c-Myc and Cyclin D1 upregulation. Our findings suggest that p53 mutants carrying gain-of-function, mis-sense mutations affecting two different domains form new protein complexes that promote carcinogenesis by enhancing EGFR signaling via distinctive mechanisms, exposing clinically relevant therapeutic vulnerabilities.

Histone variant H3.3 promotes metastasis in alveolar rhabdomyosarcoma.

The relatively quiet mutational landscape of rhabdomyosarcoma (RMS) suggests that epigenetic deregulation could be central to oncogenesis and tumour aggressiveness. Histone variants have long been recognised as important epigenetic regulators of gene expression. However, the role of histone variants in RMS has not been studied hitherto. In this study, we show that histone variant H3.3 is overexpressed in alveolar RMS (ARMS), an aggressive subtype of RMS. Functionally, knockdown of H3F3A, which encodes for H3.3, significantly impairs the ability of ARMS cells to undertake migration and invasion and reduces Rho activation. In addition, a striking reduction in metastatic tumour burden and improved survival is apparent in vivo. Using RNA-sequencing and ChIP-sequencing analyses, we identified melanoma cell adhesion molecule (MCAM/CD146) as a direct downstream target of H3.3. Loss of H3.3 resulted in a reduction in the presence of active marks and an increase in the occupancy of H1 at the MCAM promoter. Cell migration and invasion were rescued in H3F3A-depleted cells through MCAM overexpression. Moreover, we identified G9a, a lysine methyltransferase encoded by EHMT2, as an upstream regulator of H3F3A. Therefore, this study identifies a novel H3.3 dependent axis involved in ARMS metastasis. These findings establish the potential of MCAM as a therapeutic target for high-risk ARMS patients. © 2022 The Pathological Society of Great Britain and Ireland.

Factors associated with early, late, and very late stent thrombosis among patients with acute coronary syndrome undergoing coronary stent placement: analysis from the ATLAS ACS 2-TIMI 51 trial.

Background: Stent thrombosis (ST) is an uncommon but serious complication of stent implantation. This study aimed to explore factors associated with early, late, and very late ST to help guide risk assessment and clinical decision-making on ST. Methods: The analysis included patients who received stent placement for the index acute coronary syndrome (ACS). Cumulative incidence of ST was assessed at 30 days (early ST), 31-360 days (late ST), 361-720 days (very late ST), and up to 720 days. Cox proportional hazards models were used to assess associations between ST and various factors, including patient characteristics [i.e., age, sex, ACS presentation, history of hypertension, smoking, diabetes, prior myocardial infarction (MI), heart failure, prior ischemic stroke, and cancer], laboratory tests [i.e., positive cardiac biomarker, hemoglobin, platelet count, white blood cell (WBC) count], and treatment [i.e., drug-eluting stent (DES) vs. bare-metal stent (BMS) and anticoagulant with rivaroxaban vs. placebo]. Results: Among the 8,741 stented patients, 155 ST events (2.25%) occurred by Day 720. The cumulative incidences of early, late, and very late ST were 0.80%, 0.81%, and 0.77%, respectively. After multivariable adjustment, age ≥ 75 [hazard ratio (HR) = 2.13 (95% confidence interval, CI: 1.26-3.60)], a history of prior MI [HR = 1.81 (95% CI: 1.22-2.68)], low hemoglobin level [HR = 2.34 (95% CI: 1.59-3.44)], and high WBC count [HR = 1.58 (95% CI: 1.02-2.46)] were associated with a greater risk of overall ST, whereas DES [HR = 0.56 (95% CI: 0.38-0.83)] and rivaroxaban therapy [HR = 0.63 (95% CI: 0.44-0.88)] were associated with a lower risk of overall ST up to 720 days. Low hemoglobin level and high WBC count were associated with early ST (low hemoglobin: HR = 2.35 [95% CI: 1.34-4.12]; high WBC count: HR = 2.11 [95% CI: 1.17-3.81]). Low hemoglobin level and prior MI were associated with a greater risk of late ST (low hemoglobin: HR = 2.32 [95% CI: 1.26-4.27]; prior MI: HR = 2.98 [95% CI: 1.67-5.31]), whereas DES was associated with a lower risk of late ST [HR = 0.33 (95% CI: 0.16-0.67)]. Age ≥75 years was associated with very late ST. Conclusion: The study identified positive and negative associations with early, late, and very late ST. These variables may be useful in constructing risk assessment models for ST. Clinical Trial Registration: http://www.clinicaltrials.gov, identifier NCT00809965.

Soy isoflavones decrease fibroglandular breast tissue measured by magnetic resonance imaging in premenopausal women: A 2-year randomized double-blind placebo controlled clinical trial.

BACKGROUND & AIMS: Populations consuming soy have reduced risk for breast cancer, but the mechanisms are unclear. We tested the hypothesis that soy isoflavones, which have ovarian hormone-like effects, can reduce fibroglandular breast tissue (FGBT, 'breast density'), a strong risk marker for breast cancer. METHODS: Premenopausal women (age 30-42 years) were randomized to consume isoflavones (136.6 mg as aglycone equivalents, n = 99) or placebo (n = 98) for 5 days per week up to 2 years, and changes in breast composition measured by magnetic resonance imaging at baseline and yearly intervals were compared after square root transformation using linear mixed effects regression models. RESULTS: By intention-to-treat analyses (n = 194), regression coefficients (ß estimates) of the interaction of time and isoflavone treatment were -0.238 (P = 0.06) and -0.258 (P < 0.05) before and after BMI adjustment, respectively for FGBT, 0.620 (P < 0.05) and 0.248 (P = 0.160), respectively for fatty breast tissue (FBT), and -0.155 (P < 0.05) and -0.107 (P < 0.05), respectively for FGBT as percent of total breast (FGBT%). ß Estimates for interaction of treatment with serum calcium were -2.705 for FBT, and 0.588 for FGBT% (P < 0.05, before but not after BMI adjustment). BMI (not transformed) was related to the interaction of treatment with time (ß = 0.298) or with calcium (ß = -1.248) (P < 0.05). Urinary excretion of isoflavones in adherent subjects (n = 135) significantly predicted these changes in breast composition. Based on the modeling results, after an average of 1.2, 2.2 and 3.3 years of supplementation, a mean decrease of FGBT by 5.3, 12.1, and 19.3 cc, respectively, and a mean decrease of FGBT% by 1.37, 2.43, and 3.50%, respectively, were estimated for isoflavone exposure compared to placebo treatment. Subjects with maximum isoflavone excretion were estimated to have 38 cc less FGBT (or ∼3.13% less FGBT%) than subjects without isoflavone excretion. Decrease in FGBT and FGBT% was more precise with daidzein than genistein. CONCLUSIONS: Soy isoflavones can induce a time- and concentration-dependent decrease in FGBT, a biomarker for breast cancer risk, in premenopausal women, and moderate effects of calcium on BMI and breast fat, suggesting a beneficial effect of soy consumption. TRIAL REGISTRATION: www. CLINICALTRIALS: gov identifier: NCT00204490. TRIAL REGISTRATION: www. CLINICALTRIALS: gov identifier: NCT00204490.

Effect of Short- to Long-Term Exposure to Ambient Particulate Matter on Cognitive Function in a Cohort of Middle-Aged and Older Adults: KoGES.

Exposure to ambient air pollution and its threat to human health is a global concern, especially in the elderly population. Therefore, more in-depth studies are required to understand the extent of the harmful effects of particulate matter (PM) based on duration and levels of exposure. An investigation was conducted to determine the association between short- (1-14 days), medium- (1, 3, and 6 months), and long-term (1, 2, and 3 years) exposure to air pollutants (PM2.5 and PM10) and cognitive function among Koreans (4175 participants, mean age 67.8 years, 55.2% women) aged over 50 years. Higher levels of PM2.5 exposure for short to long term and PM10 exposure for medium to long term were found to be associated with decreased cognitive function, as indicated by lower scores of the Mini-Mental State Examination adopted in Korean (K-MMSE). There were significant effect modifications by sex, age group, alcohol consumption, physical activity, and smoking status in the association between long-term PM2.5 and PM10 exposure and cognitive function. These findings, which underscore the importance of the efforts to reduce the exposure levels and durations of air pollutants, especially in the vulnerable elderly population, provide evidence for establishing more stringent policies for air pollution regulations.

Factors associated with recurrent spontaneous coronary artery dissection: a systematic review and meta-analysis.

BACKGROUND: The risk of recurrent spontaneous coronary artery dissection (SCAD) is a major concern to SCAD patients and clinicians. Identifying the high-risk subsets of recurrent SCAD remains an ongoing challenge. The meta-analysis aimed to assess the potential predictors for SCAD recurrence. METHODS: A literature search was performed in PubMed to collect studies that assessed potential factors associated with recurrence of SCAD among angiographically confirmed SCAD patients, including pregnancy, ventricular arrhythmia at presentation, history of hypertension, migraine, fibromuscular dysplasia (FMD), extracoronary vascular abnormalities (EVA), recent emotional or physical stress, and use of thienopyridine, beta-blocker, or statin. A meta-analytic approach was employed to estimate the relative risk (RR) with a 95% confidence interval (CI) by fitting random-effects models using the generic inverse variance weighted method. RESULTS: A total of 14 studies representing 4206 SCAD patients were included. Hypertension (RR, 1.49; 95% CI, 1.05-2.12; P = 0.0247) and FMD (RR, 2.02; 95% CI, 1.03-3.94; P = 0.0404) were associated with a greater risk of SCAD recurrence. The use of beta-blocker (RR, 0.51; 95% CI, 0.33-0.77; P = 0.0013) was associated with a lower risk of SCAD recurrence. Pregnancy, ventricular arrhythmia at presentation, migraine, EVA, recent emotional or physical stress, and use of thienopyridine or statin were not significantly associated with recurrent SCAD ( P > 0.05). CONCLUSION: SCAD patients with hypertension or FMD were at a higher risk of recurrence, whereas beta-blocker usage was related to a reduced risk. These findings may provide insights into risk prediction and management after the SCAD episode.

Prognostic value of hemoglobin-to-red cell distribution width ratio in cancer: a systematic review and meta-analysis.

Background: The hemoglobin-to-red cell distribution width ratio (HRR) has emerged as a novel integrative biomarker predictive of overall and disease-free survival in cancer patients. This study aimed to investigate the prognostic significance of HRR in the cancer population. Methods: A literature search was performed in PubMed/MEDLINE from inception to 1 July 2021, to collect studies assessing the prognostic value of HRR in cancer patients. The primary and secondary end points were all-cause mortality and occurrence of disease progression or relapse, respectively. A meta-analytic approach was employed to estimate the pooled hazard ratio with 95% CI by fitting random-effects models. Results: A total of 11 retrospective cohort studies representing 2985 cancer patients were included. Compared with patients with high HRR, patients with low HRR had a twofold risk of all-cause mortality (hazard ratio: 2.29; 95% CI: 1.76-2.98; p < 0.0001). There was substantial heterogeneity in the association of HRR with mortality across the studies (I2: 66.8%; 95% CI: 35.3-82.9%; p = 0.0014). Similarly, low HRR was associated with a twofold risk of disease progression or relapse (hazard ratio: 2.19; 95% CI: 1.74-2.76; p < 0.0001). No significant heterogeneity was observed (I2: 16.8%; 95% CI: 0.0-60.7%; p = 0.30). Conclusion: Low HRR was associated with mortality and disease progression or relapse in patients with cancer. Further studies are required to standardize the HRR cutoff value and investigate whether HRR can be incorporated into risk assessment models for predicting adverse prognosis in cancer patients.

Hemoglobin and red cell distribution width are both widely available and routinely measured in blood tests. The hemoglobin-to-red cell distribution width ratio has recently been introduced as a new potential marker for predicting the clinical course and outcome in patients with various types of cancer. In the present meta-analysis of 11 studies representing 2985 cancer patients, the authors showed that cancer patients with a lower hemoglobin-to-red cell distribution width ratio were more likely to experience disease progression or relapse and had a greater mortality risk.

Racial/Ethnic Bullying Subtypes and Alcohol, Tobacco, and Marijuana Use Among US Adolescents.

BACKGROUND: The study examines the rate of alcohol, tobacco, and marijuana use among White, African American, and Latino adolescents and whether racial/ethnic bullying subtypes (victim-only, bullies-only, and bully/victim) are related to alcohol, tobacco, and marijuana use. METHODS: We used data from the 2009-2010 Health Behaviour in School-aged Children study (n = 9863) to examine differences in alcohol, tobacco, and marijuana use among White, African American, and Latino adolescents in the USA, and assessed whether racial/ethnic bullying involvement was associated with alcohol, tobacco, and marijuana use among these adolescents. Adolescents were categorized into four groups based on whether they had experienced racial bullying perpetration, victimization, both perpetration, and victimization, or neither perpetration nor victimization. Descriptive statistics were conducted to examine the distributions of the study variables and describe the samples. Spearman's rank-order correlation analyses were used to examine the relationships among the variables. Multinomial logistic regression was conducted to examine alcohol, tobacco, and marijuana use among the racial bully victimization, perpetration, and victimization-perpetration groups compared to the non-involved group by race/ethnicity. RESULTS: The White victim-only group was more likely to use alcohol but less likely to use tobacco. The African American victim-only group was more likely to use alcohol, and the bully/victim group was more likely to use marijuana. The Latino victim-only group was more likely to use alcohol, whereas the bully/victim group was more likely to use tobacco. CONCLUSION: Our findings have implications for the development and implementation of prevention and intervention programs across different racial/ethnic adolescent groups.

The development and clinical use of oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes: dawn of the total oral therapy era.

INTRODUCTION: Intravenous and subcutaneous hypomethylating agents have held a key role in myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia treatment. Following the approval of the cedazuridine/decitabine combination, ASTX727, as well as development of an oral formulation of azacitidine, CC-486, in the USA in 2020, these agents could gradually replace their injectable counterparts. AREAS COVERED: ASTX727 is approved for the treatment of adult patients with intermediate 1 or high-risk MDS as well as those with chronic myelomonocytic leukemia based on the findings from the ASTX727-01-B and ASCERTAIN trials. Oral azacitidine (CC-486) is approved for maintenance treatment of acute myeloid leukemia after induction chemotherapy for patients unfit for allogeneic hematopoietic cell transplant based on the findings from the QUAZAR AML-001 trial. EXPERT OPINION: Oral hypomethylating agent formulations have the potential to offer a convenient alternative to injectable hypomethylating agent. However, their current FDA-approved indications are narrow and efficacy needs to be shown in clinical trials before considering use beyond the approved indications. Areas of special interest include: identification of predictive biomarkers for clinical benefit, post-transplant maintenance therapy, and potential combination therapies with other oral agents such as venetoclax, IDH and FLT3 inhibitors.

The impact of marijuana use on liver transplant recipients: A 900 patient single center experience.

INTRODUCTION: Increased societal prevalence of marijuana continues to challenge liver transplant (LT) programs. This study aimed to examine the potential effects of marijuana use on outcomes. METHODS: This retrospective study included recipients who underwent LT between 1/2012 and 6/2018. According to pre-LT marijuana use, patients were classified into recent (≤6 months of LT), former (chronic use but not ≤6 months), or non-users. Additionally, the impact of post-LT marijuana use on survival was assessed. RESULTS: Of 926 eligible patients, 184 were pre-LT marijuana users (42 recent; 142 former) (median follow-up: 30.3 months). Pre-users were more likely to be male, White, and have histories of tobacco, alcohol, and illicit drug use. Additionally, recent users were of higher acuity, with higher MELD and requiring ICU admission. Patient survival at 1-year was 89% in non-users, 94% (HR: 0.494, 95% CI: 0.239-1.022 vs. non-users) in former users, and 83% (HR: 1.516, 95% CI: 0.701-3.282) in recent users. Post-operative complications in pre-LT users and the survival analysis for post-LT marijuana users vs. non-users did not show significance. CONCLUSIONS: Our results demonstrated that marijuana use did not have an adverse impact on post-LT outcomes; however, further studies utilizing larger cohorts are warranted.

Malignant Phyllodes Tumor: Imaging Features With Histopathologic Correlation.

Phyllodes tumors (PT) are rare fibroepithelial lesions of the breast that commonly present as rapidly enlarging, palpable masses. Phyllodes tumors may be classified as benign, borderline, or malignant on the basis of histopathologic analysis. Although malignant PT cannot be distinguished from benign PT on the basis of imaging findings alone, studies suggest that malignant PT tend to be larger and irregular in shape, and they are less likely to have circumscribed margins. If biopsy results are indeterminate, excisional biopsy should be performed. Malignant PT can be difficult to distinguish histologically from sarcomas and spindle cell metaplastic breast carcinoma; the distinction is important for prognosis and treatment. Malignant PT are treated surgically with wide local excision, without a clear role for adjuvant radiation or chemotherapy in most cases. Nearly one-third of malignant PT recur locally, usually within a few years after initial diagnosis. Distant metastatic disease is rare, and the five-year overall survival rate of malignant PT is close to 80%. The purpose of this article is to review the clinical presentation, imaging appearance, histopathology, and management of malignant PT.