In high-risk adults aged 50 to 80 y, USPSTF recommends annual lung cancer screening with LDCT (moderate certainty).

SOURCE CITATION: US Preventive Services Task Force; Krist AH, Davidson KW, et al. Screening for lung cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325:962-70. 33687470.

In older adults without CVD, treating 100 persons with statins for 2.5 y prevents 1 MACE.

SOURCE CITATION: Yourman LC, Cenzer IS, Boscardin WJ, et al. Evaluation of time to benefit of statins for the primary prevention of cardiovascular events in adults aged 50 to 75 years: a meta-analysis. JAMA Intern Med. 2021;181:179-85. 33196766.

MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer.

How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC-driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacyl-tRNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC-driven tumors. We find that fewer glutamine-derived carbons are incorporated into GSH in tumor tissue relative to non-tumor tissue. Expression of GCLC, the rate-limiting enzyme of GSH synthesis, is attenuated by the MYC-induced microRNA miR-18a. Inhibition of miR-18a in vivo leads to increased GCLC protein expression and GSH abundance in tumor tissue. Finally, MYC-driven liver tumors exhibit increased sensitivity to acute oxidative stress. In summary, MYC-dependent attenuation of GCLC by miR-18a contributes to GSH depletion in vivo, and low GSH corresponds with increased sensitivity to oxidative stress in tumors. Our results identify new metabolic pathways deregulated in primary MYC tumors and implicate a role for MYC in regulating a major antioxidant pathway downstream of glutamine.

MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer.

UNLABELLED: Hepatocellular carcinoma (HCC) is associated with poor survival for patients and few effective treatment options, raising the need for novel therapeutic strategies. MicroRNAs (miRNAs) play important roles in tumor development and show deregulated patterns of expression in HCC. Because of the liver's unique affinity for small nucleic acids, miRNA-based therapy has been proposed in the treatment of liver disease. Thus, there is an urgent need to identify and characterize aberrantly expressed miRNAs in HCC. In our study, we profiled miRNA expression changes in de novo liver tumors driven by MYC and/or RAS, two canonical oncogenes activated in a majority of human HCCs. We identified an up-regulated miRNA megacluster comprised of 53 miRNAs on mouse chromosome 12qF1 (human homolog 14q32). This miRNA megacluster is up-regulated in all three transgenic liver models and in a subset of human HCCs. An unbiased functional analysis of all miRNAs within this cluster was performed. We found that miR-494 is overexpressed in human HCC and aids in transformation by regulating the G1 /S cell cycle transition through targeting of the Mutated in Colorectal Cancer tumor suppressor. miR-494 inhibition in human HCC cell lines decreases cellular transformation, and anti-miR-494 treatment of primary MYC-driven liver tumor formation significantly diminishes tumor size. CONCLUSION: Our findings identify a new therapeutic target (miR-494) for the treatment of HCC.

Pineapple translation factor SUI1 and ribosomal protein L36 promoters drive constitutive transgene expression patterns in Arabidopsis thaliana.

The availability of a variety of promoter sequences is necessary for the genetic engineering of plants, in basic research studies and for the development of transgenic crops. In this study, the promoter and 5' untranslated regions of the evolutionally conserved protein translation factor SUI1 gene and ribosomal protein L36 gene were isolated from pineapple and sequenced. Each promoter was translationally fused to the GUS reporter gene and transformed into the heterologous plant system Arabidopsis thaliana. Both the pineapple SUI1 and L36 promoters drove GUS expression in all tissues of Arabidopsis at levels comparable to the CaMV35S promoter. Transient assays determined that the pineapple SUI1 promoter also drove GUS expression in a variety of climacteric and non-climacteric fruit species. Thus the pineapple SUI1 and L36 promoters demonstrate the potential for using translation factor and ribosomal protein genes as a source of promoter sequences that can drive constitutive transgene expression patterns.

HER3 signalling is regulated through a multitude of redundant mechanisms in HER2-driven tumour cells.

HER2 (human epidermal growth factor receptor-2)-amplified tumours are characterized by constitutive signalling via the HER2-HER3 co-receptor complex. Although phosphorylation activity is driven entirely by the HER2 kinase, signal volume generated by the complex is under the control of HER3, and a large capacity to increase its signalling output accounts for the resiliency of the HER2-HER3 tumour driver and accounts for the limited efficacies of anti-cancer drugs designed to target it. In the present paper we describe deeper insights into the dynamic nature of HER3 signalling. Signalling output by HER3 is under several modes of regulation, including transcriptional, post-transcriptional, translational, post-translational and localizational control. These redundant mechanisms can each increase HER3 signalling output and are engaged in various degrees depending on how the HER3/PI3K (phosphoinositide 3-kinase)/Akt/mTOR (mammalian target of rapamycin) signalling network is disturbed. The highly dynamic nature of HER3 expression and signalling, and the plurality of downstream elements and redundant mechanisms that function to ensure HER3 signalling throughput identify HER3 as a major signalling hub in HER2-amplified cancers and a highly resourceful guardian of tumorigenic signalling in these tumours.

Impact of the evolution in RAS mutation analysis in Australian patients with metastatic colorectal cancer.

BACKGROUND: RAS mutation testing now routinely informs the optimal management of metastatic colorectal cancer (mCRC), specifically the finding of a RAS mutation defines patients who will not benefit from treatment with an epidermal growth factor receptor inhibitor. Over time more RAS genes have been tested and more sensitive techniques used. AIMS: To review routine care RAS testing and results over time. METHODS: A retrospective analysis of the molecular data collected prospectively in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry from 2009 to 2018 was undertaken. Patients with RAS data were further analyzed. In parallel, the RAS mutation status of patients enrolled in the Test Tailor Treat (TTT) program was examined for 2011-2018. RESULTS: Of 2908 patients in the TRACC registry, 1892 (65%) were tested, with 898 (47%) of tested patients found to be RAS mutant (RASmt). RAS data were available for 5935 TTT patients. Of the tested TRACC patients diagnosed in 2009 and 2010, 38% were RASmt. For each 2-year period from 2011/2012 through to 2017/2018, the prevalence of RASmt in TRACC and TTT was 42% and 40% (2011/2012), 52% and 40% (2013/2014), 47% and 49% (2015/2016), and 47% and 49% (2017/2018). CONCLUSIONS: Based on both TRACC and TTT data, the proportion of patients reported to have a RAS mutation increased from 2009 to 2015 but has remained relatively stable in recent years. The increased proportion of RASmt patients observed over time is likely largely driven by the uptake of extended RAS testing.

Loop diuretic use and increased rates of hip bone loss in older men: the Osteoporotic Fractures in Men Study.

BACKGROUND: Older adults commonly use loop diuretics, which can increase urinary calcium excretion, leading to potential bone loss. Studies examining the association between loop diuretics and bone mineral density (BMD) are lacking, particularly those involving men. METHODS: In this cohort study, we ascertained medication use (interviewer-administered questionnaire verified with inspection of medication containers) and measured the BMD of the total hip and 2 subregions (by dual-energy x-ray absorptiometry) at baseline and at a second visit an average of 4.6 years later among 3269 men aged 65 years and older. RESULTS: Eighty-four men were categorized as continuous users of loop diuretics, 181 as intermittent users of loop diuretics, and 3004 men as nonusers of loop diuretics. After adjustment for age, baseline BMD, body mass index, weight change from baseline, physical activity,clinic site, perceived health status, cigarette smoking status, diabetes mellitus, chronic obstructive pulmonary disease, congestive heart failure, hypertension, and statin use, the average annual rate of decline in total hip BMD steadily increased from -0.33% (95% confidence interval [CI], -0.36% to -0.31%) for nonusers,to -0.58% (95% CI, -0.69% to -0.47%) for intermittent users, and to -0.78% (95% CI, -0.96% to -0.60%)for continuous users. Findings were similar for change in BMD at the femoral neck and trochanter. CONCLUSIONS: We conclude that loop diuretic use in older men is associated with increased rates of hip bone loss. These results suggest that the potential for bone loss should be considered when loop diuretics are prescribed to older patients in clinical practice.

False recognition modality effects in short-term memory: Reversing the auditory advantage.

The auditory advantage in short-term false recognition - reduced false memories for auditory compared to visually presented words (Olszewska, Reuter-lorenz, Munier, & Bendler, 2015), has been attributed to greater item distinctiveness in auditory compared to visual memory traces. If so, varying auditory trace distinctiveness should influence false recognition rates. Phonologically and semantically related words were presented visually or aurally. The auditory advantage for semantic lists was replicated but a reversal was observed for phonological lists. Reducing modality-specific acoustic and phonological distinctiveness by increasing phonological similarity led to increased false memory. The findings are consistent with a framework positing the generation of input-dependent memory traces and the role of relative distinctiveness in influencing short-term memory.

Screening for prostate cancer in U.S. men ACPM position statement on preventive practice.

INTRODUCTION: Prostate cancer is the leading cancer in U.S. men, and the third leading cause of cancer deaths. Principal screening tests for detection of asymptomatic prostate cancer include digital rectal examination (DRE) and measurement of the serum tumor marker, prostate-specific antigen (PSA). There are risks and benefits associated with prostate cancer screening. Randomized controlled trials of screening by DRE and PSA are limited to two previously published studies. Two other large-scale randomized controlled trials are currently in progress. METHODS: This study reviewed the efficacy of DRE and PSA for prostate cancer screening found in the medical literature prior to July 2007. RESULTS: Applications of PSA screening tests used in clinical practice include (1) a PSA cutoff of 4 ng/ml, (2) age-specific PSA, (3) PSA velocity, (4) PSA density, and (5) percent free PSA. Prostate cancer screening can detect early disease and offers the potential to decrease morbidity and mortality. Prostate cancer screening benefits, however, remain unproven, pending results of ongoing trials. There is currently no convincing evidence that early screening, detection, and treatment improves mortality. Limitations of prostate cancer screening include potential adverse health effects associated with false-positive and negative results, and treatment side effects. CONCLUSIONS: The American College of Preventive Medicine concludes that there is insufficient evidence to recommend routine population screening with DRE or PSA. Clinicians caring for men, especially African-American men and those with positive family histories, should provide information about potential benefits and risks of prostate cancer screening, and the limitations of current evidence for screening, in order to maximize informed decision making.

Results of a real-world study on vortioxetine in patients with major depressive disorder in South East Asia (REVIDA).

OBJECTIVE: The REVIDA study aimed to assess the evolution of major depression symptoms in South East Asian (SEA) patients treated with vortioxetine for major depression in real-world clinical practice. METHODS: This non-interventional study was conducted from August 2016 to April 2017. A total of 138 patients (aged 18-65 years) with an active episode of major depression were recruited from Malaysia, Philippines, Singapore and Thailand. Vortioxetine was initiated on the first visit and patients were followed for 3 months. Depression severity was assessed using the PHQ-9 questionnaire (patient assessed) and CGI-S scale (physician assessed); cognitive function was assessed with the PDQ-D questionnaire; work productivity and activity impairment (WPAI) was assessed with the WPAI questionnaire. RESULTS: At baseline, 89.9% of patients were moderately to severely depressed (PHQ-9 score ≥10). During the 3 month treatment period, mean ± SD PHQ-9 score decreased from 18.7 ± 5.7 to 5.0 ± 5.3, mean ± SD CGI-S score decreased from 4.4 ± 0.7 to 2.2 ± 1.1 and mean ± SD PDQ-D score decreased from 42.1 ± 18.8 to 13.4 ± 13.0. By Month 3, response and remission rates reached 80.8% and 59.0%, respectively. Work productivity loss decreased from 73.6% to 30.5%, while activity impairment decreased from 71.5% to 24.6%. Positive correlations were observed between PHQ-9, PDQ-D, and WPAI work productivity loss and activity impairment. By Month 3, 82.0% of patients were either not depressed or only mildly depressed (PHQ-9 score ≤9). CONCLUSION: In real-world clinical settings, vortioxetine was effective in reducing depression severity and improving cognitive function and work productivity in SEA patients with major depression.

The impact of bevacizumab in metastatic colorectal cancer with an intact primary tumor: Results from a large prospective cohort study.

BACKGROUND: Debate continues regarding the benefits versus risks of initial resection of the primary tumor in metastatic colorectal cancer (mCRC) patients with an asymptomatic primary tumor. Although the benefit of the anti-vascular endothelial growth factor agent bevacizumab alongside first-line chemotherapy in mCRC is established, the impact of bevacizumab on the intact primary tumor (IPT) is less well understood. METHODS: Data from an Australian mCRC registry were used to assess the impact of bevacizumab-based regimens in the presence of an IPT, to see if this differs from effects in resected primary tumor (RPT) patients and to understand the safety profile of bevacizumab in patients with IPT. Progression-free survival (PFS), overall survival (OS) and safety endpoints were analyzed. RESULTS: Of 1204 mCRC patients, 826 (69%) were eligible for inclusion. Bevacizumab use was similar in both arms (IPT (64%) versus RPT (70%)); compared with chemotherapy alone, bevacizumab use was associated with significantly longer PFS (IPT: 8.5 months vs 4.7 months, P = 0.017; RPT: 10.8 months vs 5.8 months, P < 0.001) and OS (IPT: 20 months vs 14.8 months, P = 0.005; RPT: 24.4 months vs 17.3 months, P = 0.004)).1 Bevacizumab use in an IPT was associated with more GI perforations (4.5% vs 1.8%, P = 0.210) but less frequent bleeding (1.5% vs 5.3%, P = 0.050) and thrombosis (1.5% vs 2.7%, P = 0.470), versus chemotherapy alone. Median survival was equivalent between patients that did or did not experience bevacizumab-related adverse events - 20.0 months versus 19.9 months, hazard ratio = 0.98, P = 0.623.1 CONCLUSIONS: The addition of bevacizumab significantly improved survival outcomes in mCRC with an IPT. The occurrence of bevacizumab-related adverse events did not significantly impact survival outcomes.

Adjuvant therapy in gastric cancer.

Gastric cancer has a poor prognosis. The majority of patients will relapse after definitive surgery, and 5-year survival after surgery remains poor. The role of adjuvant therapy in gastric cancer has been controversial given the lack of significant survival benefit in many randomized studies so far. The results of a large North American study (Gastrointestinal Cancer Intergroup Trial INT 0116) reported that postoperative chemoradiotherapy conferred a survival advantage compared with surgery alone, which has led to the regimen being adopted as a new standard of care. However, controversies still remain regarding surgical technique, the place of more effective and less toxic chemotherapy regimens, and the use of more modern radiation planning techniques to improve treatment delivery and outcome in the adjuvant and neoadjuvant setting. This article reviews the current status of the adjuvant treatment for gastric cancer including discussion on the research directions aimed at optimizing treatment efficacy. Issues such as the identification of patients who are more likely to benefit from adjuvant therapy are also addressed. Further clinical trials are needed to move towards better consensus and standardization of care.

Teaching Pain Management in Interprofessional Medical Education: A Review of Three Portal of Geriatric Online Education Modules.

Chronic pain is an international healthcare crisis that affects an estimated 1.5 billion individuals worldwide, but pain management is not emphasized in the medical school curriculum, and thus supplemental education is essential. The Portal of Geriatric Online Education (POGOe) is a free repository of teaching modules for use by geriatric educators and learners. This article highlights three teaching modules available on this site: It's My Old Back Again: An Approach to Diagnosing and Managing Back Pain in the Older Adult (POGOe ID: 21670), Computer Based Learning Workbook, Third Edition module on Pain Management (POGOe ID: 21036), and Aging Q3 Curriculum on Pain Management of Older Adult Patients (POGOe ID: 21187). These modules were chosen based on their ability to address the major topics that the International Association for the Study of Pain proposes should be included in medical school curricula: mulitdimensional nature of pain, pain assessment and measurement, management of pain, and clinical conditions resulting in pain in older adults. They were also selected for their ability to be adapted for interprofessional education and how well they integrate basic science and clinical principles.