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Dissemination of multiple myeloma into the bone marrow proceeds through sequential steps mediated by a variety of adhesion molecules and chemokines that eventually results in the extravasation of malignant plasma cells into this protective niche. Selectins are a class of C-type lectins that recognize carbohydrate structures exposed on blood borne cells and participate in the first step of the extravasation cascade, serving as brakes to slow down circulating cells enabling them to establish firm adhesion onto the endothelium. Myeloma cells enriched for the expression of selectin ligands present an aggressive disease in vivo that is refractory to bortezomib treatment and can be reverted by small molecules targeting E-selectin. In this study, we have defined the molecular determinants of the selectin ligands expressed on myeloma cells. We show that PSGL-1 is the main protein carrier of sialyl Lewis a/x -related structures in myeloma. PSGL-1 decorated with sialyl Lewis a/x is essential for P-selectin binding but dispensable for E-selectin binding. Moreover, sialylation is required for E-selectin engagement whereas high affinity binding to P-selectin occurs even in the absence of sialic acid. This study provides further knowledge on the biology of selectin ligands in myeloma, opening the way to their clinical application as diagnostic tools and therapeutic targets., (© 2024. The Author(s).)

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy whose progression largely depends on the lymph node and bone marrow microenvironment. Indeed, CLL cells actively proliferate in specific regions of these anatomical compartments, known as proliferation centers, while being quiescent in the blood stream. Hence, CLL cell adhesion and migration into these protective niches are critical for CLL pathophysiology. CLL cells are lodged in their microenvironment through a series of molecular interactions that are mediated by cellular adhesion molecules and their counter receptors. The importance of these adhesion molecules in the clinic is demonstrated by the correlation between the expression levels of some of them, in particular CD49d, and the prognostic likelihood. Furthermore, novel therapeutic agents, such as ibrutinib, impair the functions of these adhesion molecules, leading to an egress of CLL cells from the lymph nodes and bone marrow into the circulation together with an inhibition of homing into these survival niches, thereby preventing disease progression. Several adhesion molecules have been shown to participate in CLL adhesion and migration. Their importance also stems from the observation that they are involved in promoting, directly or indirectly, survival signals that sustain CLL proliferation and limit the efficacy of standard and novel chemotherapeutic drugs, a process known as cell adhesion-mediated drug resistance. In this respect, many studies have elucidated the molecular mechanisms underlying cell adhesion-mediated drug resistance, which have highlighted different signaling pathways that may represent potential therapeutic targets. Here, we review the role of the microenvironment and the adhesion molecules that have been shown to be important in CLL and their impact on transendothelial migration and cell-mediated drug resistance. We also discuss how novel therapeutic compounds modulate the function of this important class of molecules.

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies.

Sialylation is the terminal addition of sialic acid to underlying glycans. It plays a prominent role in cell adhesion and immune regulation. Sialylated structures found on adhesion molecules, such as CD49d, mediate the interactions between cancer cells and the microenvironment, facilitating metastatic seeding in target organs. Chronic lymphocytic leukemia (CLL) is a clonal B-cell malignancy characterized by the accumulation of CD5-positive B cells in the peripheral blood, bone marrow and lymph nodes. CLL cells proliferate mainly in the lymph node "proliferation centers", where the microenvironment provides pro-survival signals. Thus, migration and homing into these protective niches play a crucial role in CLL biology. In recent years, therapeutic strategies aimed at inducing the egress of CLL cells from the lymph nodes and bone marrow into the circulation have been highly successful. In this study, the sialylation status of 79 untreated and 24 ibrutinib-treated CLL patients was characterized by flow cytometry. Moreover, the effect of sialic acid removal on migration was tested by a transwell assay. Finally, we examined the sialylation status of CD49d by Western blot analysis. We found that CLL cells are highly sialylated, particularly those characterized by an "activated" immune phenotype. Notably, sialylation regulates CLL migration through the post-translational modification of CD49d. Finally, we showed that therapeutic agents that induce CLL mobilization from their protective niches, such as ibrutinib, modulate sialic acid levels. We propose that sialylation is an important regulator of CLL trafficking and may represent a novel target to further improve CLL therapy.

Multiple myeloma (MM) is a plasma cell disorder that develops in the bone marrow (BM) and is characterized by uncontrolled proliferation and the ability to disseminate to different sites of the skeleton. Sialofucosylated structures, particularly Sialyl Lewis a/x (SLe a/x ), facilitate the homing of MM cells into the BM, leading to resistance to bortezomib in vivo. Platelets have been shown to play an important role in tumor metastasis. Platelets can bind to the surface of cancer cells, forming a "cloak" that protects them from the shear stress of the bloodstream and natural killer (NK) cell-mediated cytotoxicity. In this study, we showed that the presence of SLe a/x induced a strong binding of MM cells to P-selectin, leading to specific and direct interactions with platelets, which could be inhibited by a P-selectin-blocking antibody. Importantly, platelets surrounded SLe a/x -enriched MM cells, protecting them from NK cell-mediated cytotoxicity. The interactions between the platelets and MM cells were also detected in BM samples obtained from MM patients. Platelet binding to SLe a/x -enriched MM cells was increased in patients with symptomatic disease and at relapse. These data suggest an important role of SLe a/x and platelets in MM disease progression and resistance to therapy.

Weight loss is a therapeutic solution for many metabolic disorders, such as obesity and its complications. Bariatric surgery aims to achieve lasting weight loss in all patients who have failed after multiple dietary attempts. Among its many benefits, it has been associated with the regression of non-alcoholic fatty liver disease (NAFLD), which is often associated with obesity, with evidence of substantial improvement in tissue inflammation and fibrosis. These benefits are mediated not only by weight loss, but also by favorable changes in systemic inflammation and in the composition of the gut microbiota. Changes in microbial metabolites such as short-chain fatty acids (SCFAs), capable of acting as endocrine mediators, and bile acids (BAs) as well as modifications of the gut-brain axis, are among the involved mechanisms. However, not all bariatric surgeries show beneficial effects on the liver; those leading to malabsorption can cause liver failure or a marked worsening of fibrosis and the development of cirrhosis. Nevertheless, there are still many unclear aspects, including the extent of the benefits and the magnitude of the risks of bariatric surgery in cirrhotic patients. In addition, the usefulness and the safety of these procedures in patients who are candidates to or who have undergone liver transplant need solid supporting evidence. This paper aims to review literature data on the use of bariatric surgery in the setting of chronic liver disease.

Primary care physicians who care for adults with intellectual disability often lack experience with the population, and patients with intellectual disability express dissatisfaction with their care. Establishing a secure primary care relationship is particularly important for adults with intellectual disability, who experience health disparities and may rely on their physician to direct/coordinate their care. The authors conducted semistructured interviews with 22 family physicians with the goal of identifying educational needs of family physicians who care for people with intellectual disability. Interviews were transcribed and coded using tools from grounded theory. Several themes related to educational needs were identified. Physician participants identified themes of "operating without a map," discomfort with patients with intellectual disability, and a need for more exposure to/experience with people with intellectual disability as important content areas. The authors also identified physician frustration and lack of confidence, compounded by anxiety related to difficult behaviors and a lack of context or frame of reference for patients with intellectual disability. Primary care physicians request some modification of their educational experience to better equip them to care for patients with intellectual disability. Their request for experiential, not theoretical, learning fits well under the umbrella of cultural competence (a required competency in U.S. medical education).

Phenylketonuria (PKU) is one of the most common inborn errors of metabolism and is due to a deficit of phenylalanine hydroxylase, the enzyme that converts phenylalanine (Phe) into tyrosine (Tyr). The resultant hyperphenylalaninemia (HPA) leads to severe neurological impairment, whose pathogenesis has not been entirely elucidated. Treatment of PKU consists essentially in lifelong protein restriction and, in mild cases, in tetrahydrobiopterin supplementation. However, compliance to both strategies, particularly to the long-term diet, is low and therefore other therapies are desirable. We explored a gene therapy approach aimed at long-term correction of the pathologic phenotype of BTBR-PahEnu2 mice, a mouse model of PKU. To this aim, we developed a helper-dependent adenoviral (HD-Ad) vector expressing phenylalanine hydroxylase and administered it to 3-week-old PKU mice. This resulted in complete normalization of Phe and Tyr levels and reversal of coat hypopigmentation that lasted throughout the observation period of six months. The spatial learning deficits observed in PKU mice were also reversed and hippocampus levels of the N-methyl-D-Aspartate and 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid receptor subunits returned to normal. Long-term potentiation, which is impaired in PKU mice, was also restored by treatment. Therefore, HD-Ad vector-mediated gene therapy is a promising approach to PKU treatment.

Hyperphenylalaninemias are genetic diseases prevalently caused by mutations in the phenylalanine hydroxylase (PAH) gene. The wild-type PAH enzyme is a homotetramer regulated by its substrate, cofactor and phosphorylation. We reproduced a full-length wild-type protein and seven natural full-length PAH variants, p.I65M, p.N223Y, p.R297L, p.F382L, p.K398N, p.A403V, and p.Q419R, and analyzed their biochemical and biophysical behavior. All mutants exhibited reduced enzymatic activity, namely from 38% to 69% of wild-type activity. Biophysical characterization was performed by size-exclusion chromatography, light scattering and circular dichroism. In the purified wild-type PAH, we identified the monomer in equilibrium with the dimer and tetramer. In most mutants, the equilibrium shifted toward the dimer and most tended to form aggregates. All PAH variants displayed different biophysical behaviors due to loss of secondary structure and thermal destabilization. Specifically, p.F382L was highly unstable at physiological temperature. Moreover, using confocal microscopy with the number and brightness technique, we studied the effect of BH4 addition directly in living human cells expressing wild-type PAH or p.A403V, a mild mutant associated with BH4 responsiveness in vivo. Our results demonstrate that BH4 addition promotes re-establishment of the oligomerization equilibrium, thus indicating that the dimer-to-tetramer shift in pA403V plays a key role in BH4 responsiveness. In conclusion, we show that the oligomerization process and conformational stability are altered by mutations that could affect the physiological behavior of the enzyme. This endorses the hypothesis that oligomerization and folding defects of PAH variants are the most common causes of HPAs, particularly as regards mild human phenotypes., (2011 Elsevier B.V. All rights reserved.)

The collection of information about events in the healthcare sector has been documented internationally for more than 25 years. Incident reporting is used for the structured acquisition of information about adverse events to improve patient and healthcare staff safety, prepare corrective action, and prevent event recurrence in the future. The establishment of an incident reporting system requires that the staff involved should be capable of recognizing events which require reporting. The aim of this work was to encourage operators to use the incident reporting system and gradually achieve 100% compliance in the reporting of adverse events and corrective and preventive actions taken. The project was carried out by the staff of one NephroCare dialysis center. The parameters observed were how many times the Variance Report was used, how problems were analyzed, and how many times and by what means the medical and nursing staff took action to correct problems. Ten months from the start of the project 100% reporting was achieved. All selected adverse advents were correctly reported and corrective or preventive action was taken to improve patient care and dialysis center organization. Only effective feedback on the results achieved in terms of safety and tangible improvements by staff will allow the number of reports to be kept high, and maintain participants' compliance with the incident reporting system over the long term.

Objectives: The aim of this study was to test the null hypothesis that the presence in the rectum of an endorectal ultrasound probe during transrectal voiding ultrasonography (TRVUS) would have no significant effect on uroflowmetry parameters., Patients and Methods: We studied 43 randomly selected men undergoing TRVUS of the prostate for non-neurogenic lower urinary tract symptoms. Uroflowmetry was performed immediately before and during the TRVUS. Results were compared with a paired Student's t test; the null hypothesis was confirmed by p values >0.05., Results: Forty patients were able to void with the endorectal probe inserted, and 95% described this micturition as representative of their usual voiding behavior. No significant statistical difference was found between uroflowmetry parameters before and during TRVUS, confirming our null hypothesis., Conclusion: Our data suggest that uroflowmetry in combination with TRVUS can be a reliable tool for evaluating disorders of micturition in males, at least in selected cases.

We reported recently that neonatal supplementation with 52 micromol vitamin A reduced infant mortality by 64%; acute side effects were limited to a 3% excess rate of a bulging fontanelle. The current study was conducted to identify developmental changes at 3 y of age associated with neonatal vitamin A supplementation or a bulging fontanelle. Children who had a bulging fontanelle (n = 91) and 432 children who had normal fontanelles after receiving vitamin A or placebo were evaluated with the Bayley Scales of Infant Development. Mean scores for the mental, psychomotor, and behavioral rating scale (BRS) plus 3 subscales of the BRS were not significantly different for treatment-fontanelle-specific groups. In regression models predicting each score, a bulging fontanelle had a small negative effect in all models; when 1 child who was injured from birth was removed from the analysis the effect of a bulging fontanelle was not significant in any model (P > or = 0.35). Vitamin A supplementation had a small beneficial effect on all developmental scores, which was significant for one of the BRS subscales (orientation-engagement) and also for a second (motor quality) when the outlier child was removed. Compared with children with normal fontanelles in the placebo group, children with a bulging fontanelle in the vitamin A group tended to grow less (-0.5 cm, P = 0.33), whereas those with normal fontanelles in the vitamin A group grew significantly more (0.68 cm, P < 0.05), over the first 3 y of life. This study provides no evidence that neonatal vitamin A supplementation is associated with biologically significant adverse growth or developmental sequelae.

Premature infants weighing less than 1550 gm at birth were randomly assigned to receive one of three formulas identical in composition except for protein content (2.2, 2.7, and 3.2 gm.100 kcal-1) to determine the effects on growth, protein nutritional status, and behavior. Data collected for 2 weeks from the time of achieving an enteral energy intake of 100 kcal.kg-1.day-1 included measurements of weight, length, head circumference, and skin-fold thickness, and concentrations of plasma amino acids, serum total protein, prealbumin, retinol-binding protein, and urea nitrogen. In a subset of infants, behavior was assessed at the end of the feeding study with the Neonatal Behavior Assessment Scale. Except for the concentrations of plasma amino acids, there were no significant differences in growth or in other biochemical measurements among the three groups, but there were significant differences in the orientation, habituation, and stability clusters of the behavior assessment. Further, there were significant correlations between the plasma amino acid values and the behavioral clusters. These preliminary data suggest a relationship between protein intake in the neonatal period and behavioral outcome at the end of the feeding period in the absence of differences in growth and gross markers of protein nutritional status. The behavioral items noted to differ among the groups may indicate later cognitive outcome; detailed studies about behavioral responses to neonatal dietary intakes and later outcome seem indicated.

While DSM-II contains more diagnostic categories related specifically to children than did the earlier DSM-I, clinical utilization studies of the various categories have not been extensive. The present study reports data on the distribution of diagnoses of childhood disorders and analyzes relationships among several diagnostic categories and subject variables. Results indicate that clinicians are using a wide range of DSM-II diagnoses for childhood disorders, including some which were intended for use with adults as well as those which were designed specifically for children. Transient Situational Disorders and Behavior Disorders are assigned almost equally to two-thirds of the sample. Chi-square analyses revealed a relationship between diagnostic categories and subject variables of age and sex. These data suggest that boys, particularly between the ages of 6 and 13, are more frequently than girls categorized as Behavior Disorder, and that the Transient Situational Disorder category is overutilized for adolescents, both male and female.

The authors delineate and discuss in detail those psychological and familial factors that have implications in treatment and in fostering the optimal emotional and physical health of children and adolescents with diabetes mellitus.

This device field study investigated children's understanding of the cerebral computed tomography scan procedure. Two groups of 10 children each (ages 5-8 and 9-11) were interviewed to determine their thoughts and feelings about the procedure and the information they would like to have before the procedure. The two groups were compared and statistically significant results were found between them. The older group evidenced higher levels of conceptual understanding of the procedure. The findings indicate the necessity of taking into account the cognitive level of the child when designing and using educational materials.