The Phosphorylation of Kv1.3: A Modulatory Mechanism for a Multifunctional Ion Channel.

The voltage-gated potassium channel Kv1.3 plays a pivotal role in a myriad of biological processes, including cell proliferation, differentiation, and apoptosis. Kv1.3 undergoes fine-tuned regulation, and its altered expression or function correlates with tumorigenesis and cancer progression. Moreover, posttranslational modifications (PTMs), such as phosphorylation, have evolved as rapid switch-like moieties that tightly modulate channel activity. In addition, kinases are promising targets in anticancer therapies. The diverse serine/threonine and tyrosine kinases function on Kv1.3 and the effects of its phosphorylation vary depending on multiple factors. For instance, Kv1.3 regulatory subunits (KCNE4 and Kvß) can be phosphorylated, increasing the complexity of channel modulation. Scaffold proteins allow the Kv1.3 channelosome and kinase to form protein complexes, thereby favoring the attachment of phosphate groups. This review compiles the network triggers and signaling pathways that culminate in Kv1.3 phosphorylation. Alterations to Kv1.3 expression and its phosphorylation are detailed, emphasizing the importance of this channel as an anticancer target. Overall, further research on Kv1.3 kinase-dependent effects should be addressed to develop effective antineoplastic drugs while minimizing side effects. This promising field encourages basic cancer research while inspiring new therapy development.

Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury.

CONTEXT.­: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. OBJECTIVE.­: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN.­: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. RESULTS.­: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. CONCLUSIONS.­: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

Diffuse trophoblast damage is the hallmark of SARS-CoV-2-associated fetal demise.

Placental pathology in SARS-CoV-2-infected pregnancies seems rather unspecific. However, the identification of the placental lesions due to SARS-CoV-2 infection would be a significant advance in order to improve the management of these pregnancies and to identify the mechanisms involved in a possible vertical transmission. The pathological findings in placentas delivered from 198 SARS-CoV-2-positive pregnant women were investigated for the presence of lesions associated with placental SARS-CoV-2 infection. SARS-CoV-2 infection was investigated in placental tissues through immunohistochemistry, and positive cases were further confirmed by in situ hybridization. SARS-CoV-2 infection was also investigated by RT-PCR in 33 cases, including all the immunohistochemically positive cases. Nine cases were SARS-CoV-2-positive by immunohistochemistry, in situ hybridization, and RT-PCR. These placentas showed lesions characterized by villous trophoblast necrosis with intervillous space collapse and variable amounts of mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition. Such lesions ranged from focal to massively widespread in five cases, resulting in intrauterine fetal death. Two of the stillborn fetuses showed some evidence of SARS-CoV-2 positivity. The remaining 189 placentas did not show similar lesions. The strong association between trophoblastic damage and placenta SARS-CoV-2 infection suggests that this lesion is a specific marker of SARS-CoV-2 infection in placenta. Diffuse trophoblastic damage, massively affecting chorionic villous tissue, can result in fetal death associated with COVID-19 disease.

T1 Rectal Adenocarcinoma: a Different Way to Measure Tumoral Invasion Based on the Healthy Residual Submucosa with Its Prognosis and Therapeutic Implications.

BACKGROUND: Surgical treatment of early rectal cancer T1 is either local excision or total mesorectal excision. The choice of surgery is based on the risk of metastatic lymph node involvement. The most important factor to consider is the degree of submucosal invasion. We present a different way to measure tumoral invasion derived from the measurement of the healthy residual submucosa with its prognosis and therapeutic implications METHODS: Observational study of tumor submucosal invasion in patients undergoing transanal endoscopic microsurgery was conducted. Parameters evaluated are submucosal invasion, measuring the healthy residual submucosa at the point of maximum invasion; macroscopic morphology of the tumor; presence of muscularis mucosa, muscularis propria, and measurement of submucosa in the tumor area and the healthy area. The classification proposed is compared with the ones previously published. RESULTS: Eighty consecutive patients diagnosed with T1 rectal cancer underwent transanal endoscopic microsurgery. Seventeen tumors (21.3%) were polypoid. En bloc resection was achieved in 77 (96.3%). The muscularis mucosa was present in 28 (35%), and the muscularis propria in 77 (96.3%) (p < 0.001). The healthy residual submucosa in the tumor area measured 2,343 ± 1,869 µm. Agreement was moderate with the Kikuchi classification (kappa 0.58) and very good with the Kudo classification (kappa 0.87). CONCLUSIONS: We describe a method for measuring submucosal invasion in T1 rectal cancer which does not depend on the morphology of the lesion or on the presence of the muscularis mucosa. It can be applied to all T1 classifications of the digestive tract in which the muscularis propria is present.

Remodeling of Kv7.1 and Kv7.5 Expression in Vascular Tumors.

Voltage-dependent potassium (Kv) channels contribute to the excitability of nerves and muscles. In addition, Kv participates in several cell functions, including cell cycle progression and proliferation. Kv channel remodeling has been associated with neoplastic cell growth and cancer. Kv7 channels are expressed in blood vessels, and they participate in the maintenance of vascular tone and are implicated in myocyte proliferation. Although evidence links Kv7 remodeling to different types of cancer, its expression in vascular tumors has never been studied. Endothelium-derived vascular neoplasms range from indolent lesions to highly aggressive and metastasizing cancers. Here, we show that Kv7.1 and Kv7.5 are evenly distributed in tunicas as well as the endothelium of healthy veins and arteries. The layered structure of vessels is lost in vascular tumors. By studying eight vascular tumors with different origins and characteristics, we found that Kv7.1 and Kv7.5 expression was changed in vascular cancers. While both channels were generally downregulated, Kv7.5 expression was clearly correlated with neoplastic malignancy. The vascular tumors did not contract; therefore, the role of Kv7 channels is probably related to proliferation rather than controlling vascular tone. Our results identify vascular Kv7 channels as targets for cancer detection and anticancer therapies.

Frequency of low-level and high-level mosaicism in sporadic retinoblastoma: genotype-phenotype relationships.

Somatic mutational mosaicism is a common feature of monogenic genetic disorders, particularly in diseases such as retinoblastoma, with high rates of de novo mutations. The detection and quantification of mosaicism is particularly relevant in these diseases, since it has important implications for genetic counseling, patient management, and probably also on disease onset and progression. In order to assess the rate of somatic mosaicism (high- and low-level mosaicism) in sporadic retinoblastoma patients, we analyzed a cohort of 153 patients with sporadic retinoblastoma using ultra deep next-generation sequencing. High-level mosaicism was detected in 14 out of 100 (14%) bilateral patients and in 11 out of 29 (38%) unilateral patients in whom conventional Sanger sequencing identified a pathogenic mutation in blood DNA. In addition, low-level mosaicism was detected in 3 out of 16 (19%) unilateral patients in whom conventional screening was negative in blood DNA. Our results also reveal that mosaicism was associated to delayed retinoblastoma onset particularly in unilateral patients. Finally we compared the level of mosaicism in different tissues to identify the best DNA source to identify mosaicism in retinoblastoma patients. In light of these results we recommended analyzing the mosaic status in all retinoblastoma patients using accurate techniques such as next-generation sequencing, even in those cases in which conventional Sanger sequencing identified a pathogenic mutation in blood DNA. Our results suggest that a significant proportion of those cases are truly mosaics that could have been overlooked. This information should be taking into consideration in the management and genetic counseling of retinoblastoma patients and families.

Isolated pulmonary interstitial glycogenosis associated with alveolar growth abnormalities: A long-term follow-up study.

INTRODUCTION: Pulmonary interstitial glycogenosis (PIG) is a rare infant interstitial lung disease characterized by an increase in the number of interstitial mesenchymal cells, presenting as enhanced cytoplasmic glycogen, and is considered to represent the expression of an underlying lung development disorder. METHODS: This study describes the clinical, radiological, and functional characteristics and long-term outcomes (median 12 years) of nine infants diagnosed with isolated PIG associated with alveolar simplification in the absence of other diseases. RESULTS: All patients presented with tachypnea. Additionally, seven patients had breathing difficulties and hypoxemia. Abnormalities in chest-computerized tomography (CT) with a pattern of ground-glass opacity, septal thickening, and air trapping were observed in all individuals, with images suggesting abnormal alveolar growth (parenchymal bands and architectural distortion). All lung biopsies showed alveolar simplification associated with an increased number of interstitial cells, which appeared as accumulated cytoplasmic glycogen. In the follow-up, all patients were asymptomatic. The respiratory function test was normal in only two patients. Five children showed an obstructive pattern, and two children showed a restrictive pattern. Chest-CT, performed after an average of 6.5 years since the initial investigation, revealed a partial improvement of the ground-glass opacity pattern; however, relevant alterations persisted. CONCLUSION: Although the patients with PIG in the absence of other associated pathologies had a good clinical outcome, significant radiographic alterations and sequelae in lung function were still observed after a median follow-up of 12 years, suggesting that PIG is a marker of some other persistent abnormalities in lung growth, which have effects beyond the symptomatic period.

Implication of Voltage-Gated Potassium Channels in Neoplastic Cell Proliferation.

Voltage-gated potassium channels (Kv) are the largest group of ion channels. Kv are involved in controlling the resting potential and action potential duration in the heart and brain. Additionally, these proteins participate in cell cycle progression as well as in several other important features in mammalian cell physiology, such as activation, differentiation, apoptosis, and cell volume control. Therefore, Kv remarkably participate in the cell function by balancing responses. The implication of Kv in physiological and pathophysiological cell growth is the subject of study, as Kv are proposed as therapeutic targets for tumor regression. Though it is widely accepted that Kv channels control proliferation by allowing cell cycle progression, their role is controversial. Kv expression is altered in many cancers, and their participation, as well as their use as tumor markers, is worthy of effort. There is an ever-growing list of Kv that remodel during tumorigenesis. This review focuses on the actual knowledge of Kv channel expression and their relationship with neoplastic proliferation. In this work, we provide an update of what is currently known about these proteins, thereby paving the way for a more precise understanding of the participation of Kv during cancer development.

Insulinoma: A Rare Cause of Hypoglycemia in Childhood.

BACKGROUND Insulinomas are pancreatic neuroendocrine tumors that cause non-ketotic hypoglycemia due to hyperinsulinism; they are extremely rare, especially in children. CASE REPORT We present a case of a sporadic insulinoma in an 11-year-old boy who had episodes of self-limited drowsiness and behavior changes over a 3-month period, thought to be caused by psychological issues. Non-ketotic hypoglycemia was confirmed at our center. A fasting blood test found inappropriately elevated insulin levels during hypoglycemia, undetectable ß-hydroxybutyrate, and increased C-peptide levels in line with insulin levels. Anti-insulin antibodies were negative and antidiabetic drugs untraceable. The glucagon-stimulation test was positive. Growth hormone, adrenocorticotropin hormone, and phosphorus and calcium metabolism were normal. Dual-phase computed tomography detected a lesion compatible with an insulinoma. Endoscopic ultrasound showed a homogenous lesion at the junction of the body and tail of the pancreas. Histologic analysis of a fine-needle aspiration biopsy was compatible with neuroendocrine neoplasia. Preoperatively, a fractional diet avoiding fast-absorbing carbohydrates maintained normal glucose blood levels. Enucleation was not possible, so the lesion was resected along with portions of the body and tail of the pancreas. The well-differentiated tumor measured 15 mm x 13 mm. Postoperative blood glucose levels were correct, allowing a normal diet. CONCLUSIONS In children with unspecific symptoms compatible with hypoglycemia, blood glucose must be evaluated to confirm low blood glucose levels. Determining blood ketone levels is important for the differential diagnosis. The diagnostic approach to pediatric insulinoma represents a challenge for multidisciplinary teamwork.

Pulmonary Interstitial Glycogenosis: A Reversible Underlying Condition Associated With D-Transposition of the Great Arteries and Severe Persistent Pulmonary Hypertension.

Transposition of the great arteries with intact ventricular septum and persistent pulmonary hypertension (TGA-IVS PPHN) is a rare association with a poor prognosis. We report the case of a term newborn with TGA-IVS PPHN successfully managed with perioperative extracorporeal membrane oxygenation (ECMO) and aggressive pulmonary vasodilation therapy that underwent successful arterial switch procedure. A lung biopsy obtained during the surgical procedure showed pulmonary interstitial glycogenosis, a reversible condition. Concerns over left ventricle deconditioning after ECMO could be minimized with appropriate management and monitoring of the ductus arteriosus and appropriate timing of surgery.

Involvement of potassium channels in the progression of cancer to a more malignant phenotype.

Potassium channels are a diverse group of pore-forming transmembrane proteins that selectively facilitate potassium flow through an electrochemical gradient. They participate in the control of the membrane potential and cell excitability in addition to different cell functions such as cell volume regulation, proliferation, cell migration, angiogenesis as well as apoptosis. Because these physiological processes are essential for the correct cell function, K+ channels have been associated with a growing number of diseases including cancer. In fact, different K+ channel families such as the voltage-gated K+ channels, the ether à-go-go K+ channels, the two pore domain K+ channels and the Ca2+-activated K+ channels have been associated to tumor biology. Potassium channels have a role in neoplastic cell-cycle progression and their expression has been found abnormal in many types of tumors and cancer cells. In addition, the expression and activity of specific K+ channels have shown a significant correlation with the tumor malignancy grade. The aim of this overview is to summarize published data on K+ channels that exhibit oncogenic properties and have been linked to a more malignant cancer phenotype. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Emerging role for the voltage-dependent K+ channel Kv1.5 in B-lymphocyte physiology: expression associated with human lymphoma malignancy.

Kv, which play a role in the immune system, are remodeled during carcinogenesis. Leukocytes present a limited Kv repertoire, with Kv1.3 and Kv1.5 as isoforms that are involved in neoplastic processes, such as proliferation and migration. In this study, we identified Kv1.5 in B-lymphocytes, characterized its role in proliferation and migration, and analyzed Kv1.3 and Kv1.5 expression in human non-Hodgkin lymphomas. DLBCL, F, MCL, ALCL, and T, along with control N specimens, were analyzed. Kv1.3 and Kv1.5 were found to be remodeled differentially; whereas Kv1.3 expression did not correlate with the state of dedifferentiation or the nature of lymphomatous cells, Kv1.5 abundance correlated inversely with clinical aggressiveness. Whereas indolent F expressed noticeable levels of Kv1.5, aggressive DLBCL showed low Kv1.5 levels. In addition, control LNs expressed heterogeneous high levels of Kv1.3, which could indicate some reactivity, whereas Kv1.5 abundance was low and quite homogeneous. Our data show that Kv1.5 is a determinant of human B cell proliferation and migration, thereby identifying this channel as a new target for immunomodulation. Our work also provides new insights into the use of Kv1.3 and Kv1.5 as potential targets during tumorigenesis.

Association of ventricular noncompaction and histiocytoid cardiomyopathy: case report and review of the literature.

We report an association between ventricular noncompaction and histiocytoid cardiomyopathy. Both entities are rare, and only 2 cases of their association have been reported previously in the medical literature. Ventricular noncompaction is believed to be caused by an arrest of the normal endomyocardial development, resulting in a thin and compacted epicardial layer and a thickened noncompacted endocardial layer. Histiocytoid cardiomyopathy is a rare arrhythmogenic disorder characterized by aggregates of oncocytic cells involving predominantly the subendocardium. These cells are thought to be abnormal Purkinje cells. In our case, the histiocytoid cells showed strong cytoplasmic expression for the skeletal muscle transcription factor MyoD1, which could be attributed to cross reactivity with an undetermined cytoplasmic antigen.

Increased voltage-dependent K+ channel Kv1.3 and Kv1.5 expression correlates with leiomyosarcoma aggressiveness.

Voltage-dependent K+ channels (Kv) are involved in the proliferation and differentiation of mammalian cells, since Kv antagonists impair cell cycle progression. Although myofibers are terminally differentiated, some myoblasts may re-enter the cell cycle and proliferate. Since Kv1.3 and Kv1.5 expression is remodeled during tumorigenesis and is involved in smooth muscle proliferation, the purpose of this study was to analyze the expression of Kv1.3 and Kv1.5 in smooth muscle neoplasms. In the present study, we examined human samples of smooth muscle tumors together with healthy specimens. Thus, leiomyoma (LM) and leiomyosarcoma (LMS) tumors were analyzed. Results showed that Kv1.3 was poorly expressed in the healthy muscle and indolent LM specimens, whereas aggressive LMS showed high levels of Kv1.3 expression. Kv1.5 staining was correlated with malignancy. The findings show a remodeling of Kv1.3 and Kv1.5 in human smooth muscle sarcoma. A correlation of Kv1.3 and Kv1.5 expression with tumor aggressiveness was observed. Thus, our results indicate Kv1.5 and Kv1.3 as potential tumorigenic targets for aggressive human LMS.

Differential expression of Kv1.3 and Kv1.5 voltage-dependent K+ channels in human skeletal muscle sarcomas.

Because Kv1.3 and Kv1.5 K(+) channels are remodeled during tumorigenesis and participate in skeletal muscle proliferation, we analyzed their expression in human skeletal muscle sarcomas. Aggressive alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) were studied. Kv1.5 expression was moderate in adult muscle and low in ERMS, whereas it was notable in ARMS and embryonic samples. Kv1.3 expression showed no major differences between RMS and healthy samples. We found a correlation of Kv1.3 and Kv1.5 expression with the tumor malignancy.

[Fatal rickets in the fetus and undiagnosed maternal celiac disease]. / Raquitismo fetal mortal y celiaquía materna no diagnosticada.

Celiac disease is a relatively frequent enteropathy associated with a wide range of clinical manifestations, due in part to malabsorption. In women, it has been associated with obstetric and gynecological alterations such as repeated miscarriages, intrauterine growth delay, premature delivery, and low birth weight. We present the case of a woman with undiagnosed celiac disease who gave birth to a stillborn foetus via normal delivery after 34 weeks of gestation. The foetus presented severe morphological alterations due to hypomineralization which were compatible with rickets. In the medical literature congenital rickets secondary to maternal celiac disease due to malabsorption is rare. We discuss the current knowledge on maternofoetal phospho-calcium metabolism and relate active celiac disease with severe hypocalcaemia during pregnancy and fatal rickets in the foetus. We recommend screening for celiac disease in pregnant women with signs of malabsorption or impaired fetal development.

Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human fetus.

Voltage-dependent K(+) channels (Kv) control repolarization and membrane potential in electrically excitable cells. In addition, Kv channels are involved in the maintenance of vascular smooth muscle tone, insulin release, epithelial K(+) transport, cell proliferation and leukocyte activation. Kv1.3 and Kv1.5 are widely distributed throughout the body and are involved in a variety of physiological processes taking place in the immune system, brain and muscle. Since the developmental pattern of Kv channels has an essential role in the maturing human, we aimed to study Kv1.3 and Kv1.5 channels in 8-10 week human fetal tissues. We chose that gestational age because all organs are in place and the nervous system, although not fully developed. However, the human embryo is undergoing major changes, which will lead to a defined adult pattern. Our results indicated that numerous tissues expressed Kv1.3 and Kv1.5. While Kv1.3 overlapped with the central and peripheral nervous systems, Kv1.5 was mostly localized in the central nervous system. In addition, both channels were abundantly expressed in the hematopoietic fetal liver. Finally, Kv1.5 heavily stained skeletal muscle and heart, whereas Kv1.3 was slightly present. This is the first study to analyze Kv1.3 and Kv1.5 in human during the beginning of fetal development.