Liquid biopsy for molecular characterization of diffuse large B-cell lymphoma and early assessment of minimal residual disease.

Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next-generation sequencing (NGS) approach (EuroClonality-NDC), we evaluated the clinical and prognostic value of ctDNA in a series of R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) patients at baseline (n = 68) and after two cycles (n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography [PET/CT]). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high-risk International Prognostic Index and a trend to shorter 2-year progression-free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5-log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2-year PFS of 76% vs. 0%, p < 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2-year PFS of 83% vs. 38%; p < 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2-year PFS of 84% vs. 17% vs. 0%, p < 0.001). EuroClonality-NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.

Characterization of Human B Cell Hematological Malignancies Using Protein-Based Approaches.

The maturation of B cells is a complex, multi-step process. During B cell differentiation, errors can occur, leading to the emergence of aberrant versions of B cells that, finally, constitute a malignant tumor. These B cell malignancies are classified into three main groups: leukemias, myelomas, and lymphomas, the latter being the most heterogeneous type. Since their discovery, multiple biological studies have been performed to characterize these diseases, aiming to define their specific features and determine potential biomarkers for diagnosis, stratification, and prognosis. The rise of advanced -omics approaches has significantly contributed to this end. Notably, proteomics strategies appear as promising tools to comprehensively profile the final molecular effector of these cells. In this narrative review, we first introduce the main B cell malignancies together with the most relevant proteomics approaches. Then, we describe the core studies conducted in the field and their main findings and, finally, we evaluate the advantages and drawbacks of flow cytometry, mass cytometry, and mass spectrometry for the profiling of human B cell disorders.

In Silico Transcriptomic Expression of MSR1 in Solid Tumors Is Associated with Responses to Anti-PD1 and Anti-CTLA4 Therapies.

Immuno-oncology has gained momentum with the approval of antibodies with clinical activities in different indications. Unfortunately, for anti-PD (L)1 agents in monotherapy, only half of the treated population achieves a clinical response. For other agents, such as anti-CTLA4 antibodies, no biomarkers exist, and tolerability can limit administration. In this study, using publicly available genomic datasets, we evaluated the expression of the macrophage scavenger receptor-A (SR-A) (MSR1) and its association with a response to check-point inhibitors (CPI). MSR1 was associated with the presence of macrophages, dendritic cells (DCs) and neutrophils in most of the studied indications. The presence of MSR1 was associated with macrophages with a pro-tumoral phenotype and correlated with TIM3 expression. MSR1 predicted favorable overall survival in patients treated with anti-PD1 (HR: 0.56, FDR: 1%, p = 2.6 × 10-5), anti PD-L1 (HR: 0.66, FDR: 20%, p = 0.00098) and anti-CTLA4 (HR: 0.37, FDR: 1%, p = 4.8 × 10-5). When specifically studying skin cutaneous melanoma (SKCM), we observed similar effects for anti-PD1 (HR: 0.65, FDR: 50%, p = 0.0072) and anti-CTLA4 (HR: 0.35, FDR: 1%, p = 4.1 × 10-5). In a different dataset of SKCM patients, the expression of MSR1 predicted a clinical response to anti-CTLA4 (AUC: 0.61, p = 2.9 × 10-2). Here, we describe the expression of MSR1 in some solid tumors and its association with innate cells and M2 phenotype macrophages. Of note, the presence of MSR1 predicted a response to CPI and, particularly, anti-CTLA4 therapies in different cohorts of patients. Future studies should prospectively explore the association of MSR1 expression and the response to anti-CTLA4 strategies in solid tumors.

Clinical and Immunologic Characteristics of Colorectal Cancer Tumors Expressing LY6G6D.

The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D (LY6G6D) gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage. In the present work, we interrogated public genomic datasets including TCGA to evaluate the genomic and immunologic cell profile present in tumors with high expression of LY6G6D. We used data from TCGA, among others, and the Tumor Immune Estimation Resource (TIMER2.0) platform for immune cell estimations and Spearman correlation tests. LY6G6D expression was exclusively present in CRC, particularly in the microsatellite stable (MSS) subtype, and was associated with left-side tumors and the canonical genomic subgroup. Tumors with mutations of APC and p53 expressed elevated levels of LY6G6D. This protein was expressed in tumors with an inert immune microenvironment with an absence of immune cells and co-inhibitory molecules. In conclusion, we described clinical, genomic and immune-pathologic characteristics that can be used to optimize the clinical development of agents against this target. Future studies should be performed to confirm these findings and potentially explore the suggested clinical development options.

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.

Effectiveness of a cardiac rehabilitation program on biomechanical, imaging, and physiological biomarkers in elderly patients with heart failure with preserved ejection fraction (HFpEF): FUNNEL + study protocol.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) have a low functional status, which in turn is a risk factor for hospital admission and an important predictor of survival in HFpEF. HFpFE is a heterogeneous syndrome and recent studies have suggested an important role for careful, pathophysiological-based phenotyping to improve patient characterization. Cardiac rehabilitation has proven to be a useful tool in the framework of secondary prevention in patients with HFpEF. Facilitating decision-making and implementing cardiac rehabilitation programs is a challenge in public health systems for HFpEF management. The FUNNEL + study proposes to evaluate the efficacy of an exercise and education-based cardiac rehabilitation program on biomechanical, physiological, and imaging biomarkers in patients with HFpEF. METHODS: A randomised crossover clinical trial is presented among people older than 70 years with a diagnosis of HFpEF. The experimental group will receive a cardiac rehabilitation intervention for 12 weeks. Participants in the control group will receive one educational session per week for 12 weeks on HFpEF complications, functional decline, and healthy lifestyle habits. VO2peak is the primary outcome. Biomechanical, imaging and physiological biomarkers will be assessed as secondary outcomes. Outcomes will be assessed at baseline, 12 weeks, and 24 weeks. DISCUSSION: Identifying objective functional parameters indicative of HFpEF and the subsequent development of functional level stratification based on functional impairment ("biomechanical phenotypes") may help clinicians identify cardiac rehabilitation responders and non-responders and make future clinical decisions. In this way, future pharmacological and non-pharmacological interventions, such as exercise, could be improved and tailored to improve quality of life and prognosis and reducing patients' hospital readmissions, thereby reducing healthcare costs. TRIAL REGISTRATION: NCT05393362 (Clinicaltrials.gov).

Usefulness of daptomycin lock therapy in children with catheter-related bacteremia after failed vancomycin lock therapy.

PURPOSE: Catheter-related bacteremia (CRB) is a significant cause of morbidity, resource expenditure and prolonged hospital stays in patients with long-term catheters, whose numbers have increased considerably in recent years. Antibiotic lock therapy reaches high concentrations in the catheter, allowing good penetration into the biofilm, being vancomycin the most commonly used one in gram-positive infections. Several authors have recently reported the superior in vitro efficacy of daptomycin compared with vancomycin, especially for eradicating biofilms. Although there is some data on the use of daptomycin for antibiotic lock in animal models and adults, there are no data on its use in children. METHODS: A descriptive study was conducted in a tertiary hospital, including patients younger than 16 years in whom daptomycin lock therapy was employed between 2018 and 2022. RESULTS: We report three pediatric patients in whom CRB was confirmed on admission by paired blood cultures positive for CoNS sensitive to vancomycin, daptomycin and linezolid. All patients started vancomycin lock therapy and systemic antibiotic therapy with proven sensitivity for the isolated bacteria, without achieving negative blood cultures. Due to the persistence of positive cultures, vancomycin lock therapy was replaced by daptomycin, and blood cultures turned negative, with no relapses or need for catheter removal. CONCLUSION: The use of daptomycin lock therapy could be considered in children with CoNS catheter infection, especially when other antibiotic lock therapy had failed.

Differences in Tridimensional Shoulder Kinematics between Asymptomatic Subjects and Subjects Suffering from Rotator Cuff Tears by Means of Inertial Sensors: A Cross-Sectional Study.

Background: The aim of this study was to analyze differences in three-dimensional shoulder kinematics between asymptomatic subjects and patients who were diagnosed with rotator cuff tears. Methods: This cross-sectional study recruited 13 symptomatic subjects and 14 asymptomatic subjects. Data were obtained from three inertial sensors placed on the humerus, scapula and sternum. Kinematic data from the glenohumeral, scapulothoracic and thoracohumeral joints were also calculated. The participants performed shoulder abductions and flexions. The principal angles of movements and resultant vectors in each axis were studied. Results: The glenohumeral joint showed differences in abduction (p = 0.001) and flexion (p = 0.000), while differences in the scapulothoracic joint were only significant during flexion (p = 0.001). The asymptomatic group showed higher velocity values in all sensors for both movements, with the differences being significant (p < 0.007). Acceleration differences were found in the scapula during abduction (p = 0.001) and flexion (p = 0.014), as well as in the sternum only during shoulder abduction (p = 0.022). Conclusion: The results showed kinematic differences between the patients and asymptomatic subjects in terms of the mobility, velocity and acceleration variables, with lower values for the patients.

Autonomous competences and quality of professional life of paediatric nurses in primary care, their relationship and associated factors: A cross-sectional study.

AIMS AND OBJECTIVES: To identify the autonomous competences and quality of professional life of paediatric nurses in primary care, their relationship and possible associated factors. BACKGROUND: The autonomous competences of paediatric nurses vary among healthcare providers in Catalonia, Spain. Autonomy is related to quality of professional life, but little is known about autonomous competences and other factors contributing to paediatric nurses' quality of professional life. DESIGN: A cross-sectional study following the STROBE statement. METHODS: Data from 206 paediatric primary care nurses were analysed. A self-administered survey consisting of an ad hoc questionnaire and a validated instrument to measure quality of professional life (QPL-35 questionnaire) was conducted. Descriptive, bivariate and general multivariate regression analyses were used to identify the relationship between autonomous competences and quality of professional life, and its predicting factors. RESULTS: 47.6% nurses reported a medium level of autonomous competences, 46.6% a high level, and 5.8% a low level. Quality of professional life was medium-high for the domains perception of managerial support and global perception of workload and for the item disconnect from work after work shift, and very high and high values for the domain intrinsic motivation and for the item quality of work life, respectively. Autonomous competences and perceived autonomy were factors associated with quality of professional life. Other associated factors were academic background, specific training and being a paediatric nurse specialist. CONCLUSIONS: Paediatric nurses in primary care have a medium-high level of autonomous competences and they perceive a high level of autonomy. Autonomous competences and level of perceived autonomy are predictors of quality of professional life. RELEVANCE TO CLINICAL PRACTICE: Enhancing paediatric nurses' autonomous competences and academic background, receiving specific training and being paediatric nurse specialists might improve their quality of professional life, healthcare quality and outcomes for the child population.

Treatment of minor health problems by primary care nurses: A cross-sectional study.

AIMS: To assess the results of a nursing-led program to treatment of minor health issues from Catalan health institute primary care teams during 2019 and 2020. BACKGROUND: In 2009, the Catalan health institute implemented a nursing program to deal with minor health problems. This nursing-led program includes an algorithm for each of the minor health problems and arose as a strategy to reorganise the flow of demand for care in primary care. DESIGN: A cross-sectional design. METHODS: Multicentric cross-sectional study. 392 primary care teams from the Catalan health institute participated in the study. STROBE guideline was followed in reporting this study. Patients attending any of the participating centres requesting a same-day consultation for minor health issues were registered. RESULTS: A total of 21,215,278 consultations were recorded: 18,284,105 for adult and 2,931,173 for paediatric patients. Minor health issue resolved by the nurse was achieved in 50.9% of adult patients and 55.4% of paediatric patients. The highest rates of resolution in adults (>85%) were as follows: burns, emergency contraception and injuries. The highest resolution rates (>84%) were as follows: burns, breastfeeding difficulties and infant colic. 87.7% of prescriptions issued by nurses were accepted by the family physician. CONCLUSIONS: The nursing-led program to treat minor health issues has been shown to present acceptable resolution for nurses in a large primary care setting. Nurses have been carrying out prescription activities with very favourable results. RELEVANCE TO CLINICAL PRACTICE: This study demonstrates that care provided to patients by nurses for minor health issues requiring preferential resolution is effective. Our results are useful in that they confirm both the effectiveness of the nursing-led program for minor health issues and the pharmacological prescriptions produced during patient appointments. PATIENT OR PUBLIC CONTRIBUTION: Patient's data were obtained through a program records system after the minor health issues appointments.

Impact of Functional Polymorphisms on Drug Survival of Biological Therapies in Patients with Moderate-to-Severe Psoriasis.

Biological therapies (BTs) indicated for psoriasis are highly effective; however, not all patients obtain good results, and loss of effectiveness is the main reason for switching. Genetic factors may be involved. The objective of this study was to evaluate the influence of single-nucleotide polymorphisms (SNPs) on the drug survival of tumor necrosis factor inhibitors (anti-TNF) medications and ustekinumab (UTK) in patients diagnosed with moderate-to-severe psoriasis. We conducted an ambispective observational cohort study that included 379 lines of treatment with anti-TNF (n = 247) and UTK (132) in 206 white patients from southern Spain and Italy. The genotyping of the 29 functional SNPs was carried out using real-time polymerase chain reaction (PCR) with TaqMan probes. Drug survival was evaluated with Cox regression and Kaplan-Meier curves. The multivariate analysis showed that the HLA-C rs12191877-T (hazard ratio [HR] = 0.560; 95% CI = 0.40-0.78; p = 0.0006) and TNF-1031 (rs1799964-C) (HR = 0.707; 95% CI = 0.50-0.99; p = 0.048) polymorphisms are associated with anti-TNF drug survival, while TLR5 rs5744174-G (HR = 0.589; 95% CI = 0.37-0.92; p = 0.02), CD84 rs6427528-GG (HR = 0.557; 95% CI = 0.35-0.88; p = 0.013) and PDE3A rs11045392-T together with SLCO1C1 rs3794271-T (HR = 0.508; 95% CI = 0.32-0.79; p = 0.002) are related to UTK survival. The limitations are the sample size and the clustering of anti-TNF drugs; we used a homogeneous cohort of patients from 2 hospitals only. In conclusion, SNPs in the HLA-C, TNF, TLR5, CD84, PDE3A, and SLCO1C1 genes may be useful as biomarkers of drug survival of BTs indicated for psoriasis, making it possible to implement personalized medicine that will reduce financial healthcare costs, facilitate medical decision-making and improve patient quality of life. However, further pharmacogenetic studies need to be conducted to confirm these associations.

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway and Their Relationship with High Blood Pressure Risk.

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin-angiotensin-aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41-0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47-1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40-0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12-1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease.

Guanylation Reactions for the Rational Design of Cancer Therapeutic Agents.

The modular synthesis of the guanidine core by guanylation reactions using commercially available ZnEt2 as a catalyst has been exploited as a tool for the rapid development of antitumoral guanidine candidates. Therefore, a series of phenyl-guanidines were straightforwardly obtained in very high yields. From the in vitro assessment of the antitumoral activity of such structurally diverse guanidines, the guanidine termed ACB3 has been identified as the lead compound of the series. Several biological assays, an estimation of AMDE values, and an uptake study using Fluorescence Lifetime Imaging Microscopy were conducted to gain insight into the mechanism of action. Cell death apoptosis, induction of cell cycle arrest, and reduction in cell adhesion and colony formation have been demonstrated for the lead compound in the series. In this work, and as a proof of concept, we discuss the potential of the catalytic guanylation reactions for high-throughput testing and the rational design of guanidine-based cancer therapeutic agents.

Total gastrectomy due to emphysematous and necrotizing gastritis associated with Sarcina ventriculi in an 18-year-old patient.

An 18-year-old woman with no pathological history, admitted to Emergency Department with abdominal pain and vomiting after consuming alcohol and cannabis in the last 36 hours. On physical examination, she presented with abdominal distention, signs of peritoneal irritation and sepsis. Abdominal computed tomography showed gastric, esophageal and duodenal distension, gastric and portal pneumatosis and the presence of free intra-abdominal fluid. An exploratory laparotomy was performed revealing extensive gastric necrosis. Then, total gastrectomy with stapled Roux-en-Y anastomosis was required. Histopathology of the gastric tissue confirmed extensive images of transmural emphysematous and necrotizing gastritis, and allowed to identify established Sarcina ventriculi infection.

Gastrointestinal infection by Mycobacterium avium with an unusual endoscopic presentation.

A 38-year-old male with medical history of HIV group C3 with voluntary abandonment of antiretroviral therapy, was hospitalized due to general deterioration, abdominal pain, diarrhea and rectal bleeding without signs of acute abdomen. The patient presented anemia, renal and hepatic dysfunction, and metabolic acidosis. Abdominal CT and CT angiography were performed without observing signs of perforation or active bleeding. In the same year, he was also diagnosed of intestinal Cryptosporidiosis, cutaneous Kaposi's sarcoma and disseminated infection by Mycobacterium avium (MA) with lung, liver and bone marrow involvement. Panendoscopy was performed, showing violaceous lesions on the soft palate. In the stomach and duodenum, he presented multiple, large, well-defined and occasionally confluent red-violet lesions Colonoscopy did not show macroscopic alterations.

Endoscopic management of intraluminal gastric band erosion using a laser lithotripsy probe.

Intraluminal erosion of adjustable and non adjustable gastric bands generally occurs years after placement. Different endoscopic techniques have been described for the management of bands that erode the gastric wall, using endoscopic scissors, rigid endoscopic guides wire coupled to a mechanical lithotripter or even less frequently used devices such as the Gastric Band Cutter System to cut it. We present a clinical case in which we used a lithotripsy laser probe to break the band with great effectiveness without complications.

COVID-19 and the Use of Angiotensin II Receptor Blockers in Older Chronic Hypertensive Patients: Systematic Review and Meta-Analysis.

Angiotensin II-converting enzyme inhibitors (ACEIs) and selective angiotensin II receptor antagonists (ARAIIs) are widely used antihypertensive agents. Their use has generated controversy due to their possible influence on the health status of chronic patients infected with COVID-19. The objective of this work is to analyze the influence of COVID-19 on chronic hypertensive patients treated with ACEI and ARAII inhibitors. A systematic review and meta-analysis in the databases Pubmed, Pro-Quest and Scopus were carried out. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search equation descriptors were obtained from the Medical Subject Headings (MeSH) thesaurus. The search equation was: "Older AND hypertension AND (COVID-19 OR coronavirus) AND primary care" and its equivalent in Spanish. Nineteen articles were obtained, with n = 10,806,159 subjects. Several studies describe the COVID-19 association with ACEI or ARAII treatment in hypertension patients as a protective factor, some as a risk factor, and others without a risk association. In the case of ACEI vs. ARAII, the risk described for the former has an odds ratio (OR) of 0.55, and for ARAII, an OR of 0.59. Some authors talk about mortality associated with COVID-19 and ACEI with a half ratio (HR) of 0.97, and also associated ARAIIs with an HR of 0.98. It is recommended to maintain the use of the renin-angiotensin-aldosterone axis in the context of the COVID-19 disease.

Clinical considerations for the design of PROTACs in cancer.

Degradation of targeted proteins using proteolysis targeting chimeras (PROTACs) has gained momentum. A PROTAC is a bifunctional molecule that consists of three parts: a ligand that interacts with the protein to be degraded, another ligand that binds to an E3 ubiquitin ligase and a linker that connects both. Identification of the right proteins as targets to be degraded and a ligase that is highly expressed in tumors compare with normal tissue is mandatory, as can augment efficacy reducing toxicity. In this article we review the current development stage of PROTACs in cancer to categorize the best PROTAC construction. Targets including BCL2, CDK4 and MCL1 were highly expressed in all tumors; MCL1 was significantly increased in breast cancer and lung adenocarcinoma and CDK4 in colon adenocarcinoma. Degradation of CDK9, AURKA or PLK1, followed by BCL2, MCL1, PTPN11, BRD4, PTK2, showed a high dependency. Most ligases evaluated were not highly present in tumors except for MDM2 in breast, lung, prostate and gastric cancer. In non-transformed tissue MDM2 was the most abundant ligase, followed by cIAP and CRBN, and those with low expression included XIAP and VHL. MDM2 ligase coupled with inhibitors of the targets BCL2, BRD4, CDK9, PLK1 and MCL1 in stomach tumor, and MDM2 with PIK3C3 inhibitors in breast cancer, seems to be the best therapeutic strategy. Our results suggest potential options for the design of PROTACS in specific medical indications.

Circulating levels of calprotectin, a signature of neutrophil activation in prediction of severe respiratory failure in COVID-19 patients: a multicenter, prospective study (CalCov study).

OBJECTIVE: Severe COVID-19 is characterized by a dysregulated immune response in which neutrophils play a critical role. Calprotectin reflects neutrophil activation and is involved in the self-amplifying thrombo-inflammatory storm in severe COVID-19. We aimed to evaluate the role of calprotectin in early prediction of severity in COVID-19 patients. METHODS: This was a multicenter prospective observational study enrolling consecutive adult COVID-19 patients. On arrival to emergency department, blood samples were collected for laboratory tests, including serum calprotectin. The primary outcome was severe respiratory failure requiring invasive mechanical ventilation and the secondary outcome was need for Intensive Care Unit (ICU) admission. RESULTS: Study population included 395 patients, 57 (14.4%) required invasive mechanical ventilation and 100 (25.3%) were admitted to ICU. Median serum calprotectin levels were significantly higher in intubated (3.73 mg/L vs. 2.63 mg/L; p < 0.001) and ICU patients (3.48 mg/L vs. 2.60 mg/L; p = 0.001). Calprotectin showed a significant accuracy to predict the need for invasive mechanical ventilation (ROC AUC 0.723) and ICU admission (ROC AUC 0.650). In multivariate analysis, serum calprotectin was an independent predictor of invasive mechanical ventilation (OR 1.161) and ICU admission (OR 1.068). CONCLUSION: Serum calprotectin can be used as an early predictor of severity in COVID-19 patients.

Design and implementation of a standard care programme of therapeutic exercise and education for breast cancer survivors.

BACKGROUND: Breast cancer survivors (BCS) face several symptoms and are at higher risk of weight gain following diagnosis. Current literature shows that both exercise and diet play a key role in recovery of BCS. However, there is a gap between current guidelines and the real-world context. The aim of this article is to describe the process behind a free, not-for-profit community-based therapeutic exercise and education programme (TEEP) for BCS in the clinical setting. METHODS: The "Onco-Health Club" (OHC) consists of therapeutic exercise (TE) intervention aimed at ameliorating cancer-related fatigue (CRF) and improving QoL and physical function. TE is supplemented with nutritional education, providing information about the Mediterranean diet. To this end, patients are recruited from an oncologist and are referred to a physiotherapist and a nutritionist for baseline assessment. TEEP consists of a 3-month intervention, delivered twice a week in a group format with 1 h of TE and 30 min of nutritional education. BCS then have a final assessment and are advised to continue with a healthy lifestyle. Data about referral, compliance and assessment were collected. RESULTS: From May 2017 to February of 2020, a total of 158 patients were recruited from 8 cohorts and 142 initially started the OHC. From 119 that joined the program, 96 patients were considered to have finished it with good adherence (assistance > 80%). BCS significantly improved their QoL, as well as upper and lower limb's function, and increased their level of physical activity. CRF tended to decrease (p = 0.005). CONCLUSIONS: This study obtained data on recruitment, compliance, and possible limitations of these kinds of programmes in a real-world context. Further research is needed in order to optimize patient engagement and compliance, as well as to determine the transferability of these programmes in the clinical setting. TRIAL REGISTRATION: NCT03879096, Registered 18th March 2019. Retrospectively registered.