Genomic and Immunologic Correlates in Prostate Cancer with High Expression of KLK2.

The identification of surfaceome proteins is a main goal in cancer research to design antibody-based therapeutic strategies. T cell engagers based on KLK2, a kallikrein specifically expressed in prostate cancer (PRAD), are currently in early clinical development. Using genomic information from different sources, we evaluated the immune microenvironment and genomic profile of prostate tumors with high expression of KLK2. KLK2 was specifically expressed in PRAD but it was not significant associated with Gleason score. Additionally, KLK2 expression did not associate with the presence of any immune cell population and T cell activating markers. A mild correlation between the high expression of KLK2 and the deletion of TMPRSS2 was identified. KLK2 expression associated with high levels of surface proteins linked with a detrimental response to immune checkpoint inhibitors (ICIs) including CHRNA2, FAM174B, OR51E2, TSPAN1, PTPRN2, and the non-surface protein TRPM4. However, no association of these genes with an outcome in PRAD was observed. Finally, the expression of these genes in PRAD did not associate with an outcome in PRAD and any immune populations. We describe the immunologic microenvironment on PRAD tumors with a high expression of KLK2, including a gene signature linked with an inert immune microenvironment, that predicts the response to ICIs in other tumor types. Strategies targeting KLK2 with T cell engagers or antibody-drug conjugates will define whether T cell mobilization or antigen release and stimulation of immune cell death are sufficient effects to induce clinical activity.

A snapshot of COVID-19 infection in patients with solid tumors.

Coronavirus disease 2019 (COVID-19) pandemic is affecting a high percentage of the population at an unprecedented rate. Cancer patients comprise a subgroup especially vulnerable to this infection. Herein, we present a prospective analysis of epidemiological, clinical, radiological and laboratory data of consecutive adult cancer patients seen in the Clínico San Carlos University Hospital (Madrid, Spain), and admitted to hospital and tested for COVID-19 between 21 February 2020 and 8 May 2020 due to clinical suspicion of infection. Data from 73 patients with confirmed COVID-19 and active solid tumors or diagnosed within the previous 5 years were analyzed. The most frequent malignancy was lung cancer (19%) and 54 patients (74%) were on active cancer treatment. Most common findings on presentation included cough (55%), fever (52%) and dyspnea (45%), and 32 (44%) patients showed oxygen saturation levels below 95%. Radiologically, 54 (73%) patients presented an abnormal pattern, the most frequent being infiltrates (64%). 18 (24.7%) patients died in hospital and 55 (75.3%) were discharged with clinical resolution of the event. Multivariable logistic regression adjusted for age and tumor stage showed higher odds of in-hospital death associated with a history of cardiovascular disease, hospitalization in the previous 30 days, and several features on admission including dyspnea, higher qSOFA score, higher C-reactive protein levels and an abnormal neutrophil count. We present prospective, real-world evidence that can help articulate cancer care protocols for patients infected with SARS-CoV-2, with special focus on features on admission that can stratify patients with a higher risk of death from COVID-19.

Prognostic value of human leukocyte antigen G expression in solid tumors: a systematic review and meta-analysis.

Introduction: Identification of modulators of the immune response with inhibitory properties that could be susceptible for therapeutic intervention is a key goal in cancer research. An example is the human leukocyte antigen G (HLA-G), a nonclassical major histocompatibility complex (MHC) class I molecule, involved in cancer progression. Methods: In this article we performed a systematic review and meta-analysis on the association between HLA-G expression and outcome in solid tumors. This study was performed in accordance with PRISMA guidelines and registered in PROSPERO. Results: A total of 25 studies met the inclusion criteria. These studies comprised data from 4871 patients reporting overall survival (OS), and 961 patients, reporting disease free survival (DFS). HLA-G expression was associated with worse OS (HR 2.09, 95% CI = 1.67 to 2.63; P < .001), that was higher in gastric (HR = 3.40; 95% CI = 1.64 to 7.03), pancreatic (HR = 1.72; 95% CI = 0.79 to 3.74) and colorectal (HR = 1.55; 95% CI = 1.16 to 2.07) cancer. No significant differences were observed between the most commonly utilized antibody (4H84) and other methods of detection. HLA-G expression was associated with DFS which approached but did not meet statistical significance. Discussion: In summary, we describe the first meta-analysis associating HLA-G expression and worse survival in a variety of solid tumors. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022311973.

PKC alpha mediates maternal touch regulation of growth-related gene expression in infant rats.

During short-term periods of separation of rat pups from their mothers, the loss of certain sensory signals suppresses the increase in ornithine decarboxylase (ODC) gene expression induced by the growth-promoting hormones prolactin (PRL) and growth hormone (GH). Here, we identify a molecular mechanism through which maternal separation (MS) curtails ODC expression. Our results demonstrate that the absence of specific tactile stimuli provided by the mother limits PRL-evoked stimulation of ODC biosynthesis by interfering with sn-1,2-diacylglycerol's (DAG) ability to activate protein kinase Calpha (PKCalpha) and consequently c-myc mRNA and max mRNA expression. The proteins encoded by these proto-oncogenes function as direct transactivators of the ODC gene. As ODC activity is obligatory for normal cell replication and differentiation, PKCalpha activation by DAG represents an important control point at which 'nurturing touch' regulates growth and development of the neonate. Such a mechanism can explain the maladaptive consequences of disrupting mother-infant tactile interactions as occurs in isolated premature babies. Also, it could provide a basis for developing therapeutic interventions to maximize growth potential in children failing-to-thrive despite normal maternal care.

Factors associated with adherence to the Mediterranean diet in the adult population.

Our aim was to analyze the variables associated with adherence to the Mediterranean diet in the adult population. We conducted a cross-sectional study in an established cohort of 1,553 healthy study participants (mean age=55 ± 14 years; 60.3% women). Mediterranean diet adherence was evaluated based on a 14-item questionnaire and the Mediterranean diet adherence screener, which defines adequate adherence as a score of ≥ 9. Physical activity was evaluated using the 7-day physical activity record. Sociodemographic, biological, and anthropometric variables were also evaluated. The differences between Mediterranean diet compliers and noncompliers are defined by the consumption of fruit, red meats, carbonated beverages, wine, fish/shellfish, legumes, pasta, and rice (P<0.01). Adherence was lower among individuals younger than 49 years of age. In the first age tertile, adherence was greater in women and in nonobese individuals, and the triglyceride levels were lower among compliers. In the second age tertile, the compliers exercised more and had a lower body fat percentage. In the third age tertile, the compliers also possessed less body fat. The logistic regression analysis revealed the following factors associated with improved Mediterranean diet adherence: more physical exercise (odds ratio=1.588), older age (odds ratio=2.162), and moderate alcohol consumption (odds ratio=1.342). The factors associated with improved Mediterranean diet adherence included female sex, age older than 62 years, moderate alcohol consumption, and more than 17 metabolic equivalents (METs)/h/wk of physical exercise. Poorer adherence was associated with males and obesity.

Blood pressure circadian pattern and physical exercise assessment by accelerometer and 7-day physical activity recall scale.

BACKGROUND: The relationship between regular physical activity, measured objectively and by self-report, and the circadian pattern of 24-hour ambulatory arterial blood pressure (BP) has not been clarified. METHODS: We performed a cross-sectional study in a cohort of healthy patients. We included 1,345 patients from the EVIDENT study (mean age 55 ± 14 years; 59.3% women). Physical activity was assessed using the 7-day physical activity recall (PAR) questionnaire (metabolic equivalents (MET)/hour/week) and the Actigraph GT3X accelerometer (counts/minute) for 7 days; ambulatory arterial BP was measured with a radial tonometer (B-pro device). RESULTS: The dipper-pattern patients showed a higher level of activity than nondipper patients, as assessed by accelerometer and 7-day PAR. Physical activity measures correlated positively with the percent drop in systolic BP (SBP; ρ = 0.19 to 0.11; P < 0.01) and negatively with the systolic and diastolic sleep to wake ratios (ρ = -0.10 to -0.18; P < 0.01) and heart rate (ρ = -0.13; P < 0.01). In logistic regression, considering the circadian pattern (1, dipper; 0, nondipper) as the dependent variable, the odds ratio of the third tertile of counts/minute was 1.79 (95% confidence interval [CI], 1.35-2.38; P < 0.01) and of MET/hour/week was 1.33 (95% CI, 1.01-1.75; P = 0.04) after adjustment for confounding variables. CONCLUSIONS: Physical activity, as evaluated by both the accelerometer and the 7-day PAR, was associated with a more marked nocturnal BP dip and, accordingly, a lower SBP and diastolic BP sleep to wake ratio. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01083082.

Association of television viewing time with central hemodynamic parameters and the radial augmentation index in adults.

BACKGROUND: We conducted a study to explore the relationship between television viewing time and central hemodynamic parameters and the radial augmentation index (AIx) in adults. METHODS: Random sampling was used to select 732 individuals who attended primary-care centers as subjects for the study. The self-reported time that these individuals spent in viewing television was elicited with a questionnaire and included the number of hours that they spent watching television while sitting or lying down. The subjects' physical activity was estimated through accelerometers attached to their waists. Central hemodynamic parameters and the peripheral augmentation index adjusted for a heart rate of 75 bpm (PAIx75) were measured with pulse-wave application software (A-Pulse CASP). RESULTS: The subjects' systolic blood pressure (SBP) (central and peripheral), pulse pressure, and radial AIx showed significant differences between tertiles of television viewing time, with the lowest values in the first tertile (P < 0.01). After adjustment for age and sex, a multiple linear regression analysis showed an association of television viewing time with office SBP. Although the association of television viewing time with central SBP followed the same trend as for office BP, it did not reach statistical significance. After adjustment for age, sex, waist-to-height ratio, physical activity reflected by accelerometer data (counts/min), high-density lipoprotein cholesterol, smoking, antihypertensive and antidiabetic medication, and the use of lipid-lowering drugs, an increase in PAIx75 of 0.22 was estimated for each hour of increase in television viewing time (P < 0.01). CONCLUSIONS: Television viewing time was directly correlated with PAIx75 in an adult population. This correlation was maintained even after adjustment for physical activity, age, sex, and other cardiovascular risk factors.

Circulating levels of plasminogen activator inhibitor type-1, tissue plasminogen activator, and thrombomodulin in hemodialysis patients: biochemical correlations and role as independent predictors of coronary artery stenosis.

This study investigated the relationship between the circulating levels of the endothelial cell glycoproteins plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (TPA), and thrombomodulin (TM) and the major vascular risk factors described in dialysis patients. In addition, the role of these endothelial cell products as independent predictors of coronary artery disease (CAD) was analyzed. Levels of TM, TPA antigen (Ag), TPA activity, PAI-1 Ag, PAI-1 activity, TPA/PAI complexes, thrombin-antithrombin complexes, fibrinopeptide A, C-reactive protein (CRP), interleukin-1beta and tumor necrosis factor-alpha, lipids, apoproteins A1 and B, and albumin were measured in a group of 200 nondiabetic dialysis patients and 100 healthy matched volunteers. When compared with healthy controls, dialysis patients showed increased levels of CRP, TM, TPA, and PAI-1 and evidence of increased thrombin-dependent fibrin formation. Increased levels of active PAI-1 were associated to a great extent with major classic vascular risk factors and to a lesser extent with CRP and serum triglycerides. Forty-six patients (23%) had evidence of CAD. Variables associated with CAD in the univariate analysis included age, time on dialysis, male gender, number of packs of cigarettes per year, high BP, fibrinogen, apolipoprotein B, albumin, PAI-1 activity, CRP, thrombin-antithrombin complexes, and fibrinopeptide A. Logistic regression analysis found age, high-density lipoprotein cholesterol, gender, high BP, CRP, time on dialysis, and PAI-1 activity to be independent predictors of CAD. This model classified correctly 85% of patients as having CAD and showed adequate goodness of fit for all risk categories. Our data support a pathogenic link among activated inflammatory response, endothelial injury, and CAD in hemodialysis patients and suggest that assessment of circulating PAI-1 levels could be an additional tool to identify dialysis patients who are at risk for developing atheromatous cardiovascular disease.