Rare Orphan Disease Research Articles

Prader-Willi syndrome: guidance for children and transition into adulthood.

Prader-Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues, especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.

Persistent Pruritic Linear Streaks of Adult-Onset Still's Disease: Reconsidering the Yamaguchi Criteria.

Objective Adult-onset Still's disease (AOSD) is a rare orphan disease, the diagnosis of which remains challenging. This study aimed to identify additional clues for establishing early diagnosis beyond the existing criteria. Methods A retrospective longitudinal cohort study was conducted at two community hospitals in Japan between March 2012 and December 2022. The clinical characteristics and medical histories of patients with AOSD were extracted from the clinical records. The primary outcome was to identify the key manifestations of AOSD for an early diagnosis beyond the existing criteria. Results Twenty-one patients (mean age, 58 years) were included in the study. Fever was the first symptom in 13 out of 21 patients (62%). Six out of 21 patients (29%) presented with a pruritic rash only, while two out of 21 (10%) initially presented with a sore throat. All patients visited more than one medical institution. The median time to reach a correct diagnosis was 41 days (IQR 19-138). Nineteen out of 20 patients (95%) exhibited a pruritic rash, identified as persistent pruritic linear streaks, with a median duration of 21 days (IQR 12-64) before the diagnosis of AOSD as a cutaneous manifestation. Conclusions Persistent pruritic linear streaks were a key feature in the context of an early diagnosis of AOSD, offering an option for reconsidering and revising the existing classification criteria.

Entrectinib in the treatment of ROS1-positive lung cancer

The possibilities in the treatment of patients with non–small cell lung cancer are constantly expanding – thanks to high-performance genomic profiling methods, we are discovering new targets in the tumor for drug action, as a result, new targeted drugs appear, some of them have several application points. Multipurpose drugs have a number of advantages and therefore have become the main direction of drug development. Entrectinib is an oral low molecular weight multikinase inhibitor that blocks three targets at once – the receptors of tyrosine kinases ROS1, NTRK1/2/3 and ALK, in 2023 was approved by the Ministry of Health of the Russian Federation for the treatment of adult patients with ROS1-positive metastatic non-small cell lung cancer. This form of lung cancer is classified as a rare orphan disease, which usually occurs in younger people (about 50 years old), more often in women and non-smokers. Until recently , we had the only active targeted drug – crizotinib. It provided a sufficiently high immediate effect and long-term control of the disease. However, his intracranial activity was not evaluated prospectively, and a retrospective analysis showed modest results. Entrectinib is distinguished from its competitor by high intracranial activity, and, as is known, metastatic brain damage in patients with activating mutations is quite common. With comparable indicators of objective response, its duration and time to progression, entrectinib provides a high level of intracranial control and reduces the risks of progression in the central nervous system in patients who did not have brain metastases at the beginning of therapy. In addition, entrectinib demonstrates good tolerability.

Anaesthesia management in anti-synthetase syndrome, a rare orphan disease - A case study.

Anaesthesia management in anti-synthetase syndrome, a rare orphan disease - A case study.

Нейрошкірний меланоз (хвороба Рокітанського) як рідкісна причина епілептичних нападів у педіатричній практиці

Neurocutaneous melanosis is a rare disease belonging to the group of phakomatoses, characterized by the presence of giant melanocytic nevi on the skin and melanocytic infiltration of the parenchyma and meninges, as well as a high risk of neurological complications and malignancy. Purpose - to analyze the information of modern specialized literature on the etiology, pathogenesis, approaches to diagnosis and treatment of a rare orphan disease - neurocutaneous melanosis (Rokitansky's disease) and to describe clinical cases of this disease. A review of the scientific literature and a personal case of diagnosis and treatment of two patients are given. In the first case, the clinical history of a boy aged 1 year and 4 months is presented with neurocutaneous melanosis and Dandy-Walker anomaly, complicated by frequent drug-resistant epileptic seizures. In the second case, a description of the medical history of a 14-year-old boy with newly diagnosed neurocutaneous melanosis complicated by progressive obstructive hydrocephalus and generalized tonic-clonic seizures is presented. MRI features deserve special attention, namely specific changes in the T2-weighted mode, which reveals typical areas of hyperintense signal in the brain parenchyma and from the dura mater (leptomelanosis). It is the neuroimaging data with a high probability that gives reason to assume the correct diagnosis, reducing time and costs for additional examinations. There is no pathogenetic treatment for this disease. For the symptomatic treatment of obstructive hydrocephalus, surgical intervention is used, and in the presence of epileptic seizures, anticonvulsant therapy is used. Conclusions. The given clinical observation confirms the complexity of the diagnostic search for orphan diseases of the nervous system. Objective examination data and neuroimaging methods (CT and MRI of the brain and spinal cord) play a key role in the diagnosis of neurocutaneous melanosis. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone

Myopathy is the main adverse effect of the widely prescribed statin drug class. Statins exert their beneficial effect by inhibiting HMG CoA-reductase, the rate-controlling enzyme of the mevalonate pathway. The mechanism of statin myopathy is yet to be resolved, and its treatment is insufficient. Through homozygosity mapping and whole exome sequencing, followed by functional analysis using confocal microscopy and biochemical and biophysical methods, we demonstrate that a distinct form of human limb girdle muscular disease is caused by a pathogenic homozygous loss-of-function missense mutation in HMG CoA reductase (HMGCR), encoding HMG CoA-reductase. We biochemically synthesized and purified mevalonolactone, never administered to human patients before, and establish the safety of its oral administration in mice. We then show that its oral administration is effective in treating a human patient with no significant adverse effects. Furthermore, we demonstrate that oral mevalonolactone resolved statin-induced myopathy in mice. We conclude that HMGCR mutation causes a late-onset severe progressive muscular disease, which shows similar features to statin-induced myopathy. Our findings indicate that mevalonolactone is effective both in the treatment of hereditary HMGCR myopathy and in a murine model of statin myopathy. Further large clinical trials are in place to enable the clinical use of mevalonolactone both in the rare orphan disease and in the more common statin myopathy.

Perspective of Patients and Stakeholders as Members of a Research Team

Systemic sclerosis (SSc) is a rare orphan disease, characterized by skin thickening, vascular insufficiency, and fibrosis of internal organs. SSc affects about 100,000 people in the United States. This study explored perceived benefits and challenges of patient partners and stakeholders, who were team members on a project to revise and test a self-management program (Taking Charge of Systemic Sclerosis). Five patient partners, 1 stakeholder from the Scleroderma Foundation and 1 stakeholder from a state chapter of the Scleroderma Foundation were interviewed. Conversations were audio recorded and transcribed verbatim and analyzed. Four themes emerged from the analysis with corresponding subthemes: contributions to study, benefits of involvement, challenges, and project leadership. The themes and subthemes were generally similar to those expressed in other studies. However, additional benefits from engagement were identified: acceptance, increased knowledge of SSc, and helping others. Participants reported feeling supported and valued as members of the team and that their opinions mattered which is in contrast with findings from other studies.

Features of the diagnosis of Gaucher disease

Type II Gaucher disease is a rare orphan disease and its diagnosis is accompanied by certain difficulties for practitioners. The problem is low clinical alertness and lack of experience with rare patients. In addition, the disease requires tests for the content of enzymatic activity and determination of the severity of the pathological process.

Organization of pharmaceutical provision of patients with pulmonary hypertension on the example of Kyiv

In Ukraine, pharmaceutical provision of patients with pulmonary hypertension (PH) as a rare (orphan) disease is one of the important components of the State policy. Despite the permanent reform of the medical and pharmaceutical sector, a significant number of problems in the formation of a balanced system for providing the necessary medicinal products (MP) to orphan patients have not yet been resolved.
 The purpose of the study is to study the process of pharmaceutical provision of patients with PH, using the example of Kyiv.
 Information on MP purchases for patients in Kyiv, included in the Unified Clinical Protocol for Emergency, Primary, Secondary (Specialized) Medical Care Pulmonary Hypertension in Adults for the State and local budgets for 2018–2021, has been chosen as the object of the study. We have used system-review, documentary, and marketing research methods.
 The result of the analysis of the annual need for 2018–2021 in INN, necessary for the pharmaceutical provision of Kyiv patients with PH, has shown that the annual decrease in funding compared to 2018, namely: in 2019– by 17.54%, in 2020– by 32.52%, in 2021 – by 50.08%, due to a decrease in the cost of INN Sildenafil (Sildenafilum) by an average of 89.21% annually, compared with the cost in 2018.
 At the same time, the state of providing MP for patients with PH in Kyiv for the period 2018–2021 indicates that the total need for them was met at the expense of the State Budget of Ukraine and the budget of Kyiv for the implementation of the City Target Program «Health of Kievans» in 2018 – by 81.46%, and in 2019 – by 91.67% of the need.
 The supply of MP ordered for 2020 for the treatment of PH at the expense of the State Budget took place only at the end of 2021. Only Iloprost (Iloprostum) of the six supplies of INN ordered was completed, which accounted for 82.27% of the declared need.
 In 2021, only Sildenafil (Sildenafilum) was purchased at the expense of the State Budget of Ukraine, which is 8% of the need to provide treatment for patients with PH in the city of Kyiv. The City Target Program «Health of Kievans» for 2021 does not provide for expenses in the «Pulmonary Hypertension» direction.
 Thus, the results of a study of the organization of pharmaceutical support for Kyiv residents with PH indicate that there are no financial guarantees for the provision of free medical care to patients with rare (orphan) diseases.

The analysis of the legislative framework regarding pharmaceutical provision of orphan patients in Ukraine

A rare (orphan) disease is a disease that threatens a person’s life or chronically progresses; it leads to a reduction in life expectancy or disability, which prevalence among the population is not more than 1 : 2000 in Ukraine and not more than 1 : 5000-8000 in other countries. Aim. To analyze the current legal framework on pharmaceutical provision of orphan patients in Ukraine. Materials and methods. The current regulatory framework on pharmaceutical provision of orphan patients in Ukraine was analyzed by constructing and studying the hierarchy of legislative acts regulating the issues of management of orphan (rare) diseases in the world and in Ukraine. Results and discussion. The article describes the main stages of the legislation formation, starting from the USA in 1983 to the EU and Ukraine in 2021. The practical value of the article consists in the current list of normative acts regulating the provision of patients with orphan diseases. The scientific significance is in the use of the results of previous studies of others domestic researchers (2016). The analysis of the legislation and the main issues of providing orphan patients allowed us to formulate the basic problems of the national healthcare system listed in the article. Conclusions. The current state of the legal regulation of orphan patients in Ukraine has been studied. It has been found that the legislative regulation of the issue under study has been actively carried out over the past 7 years by implementing the adopted Law of Ukraine, resolutions of the Cabinet of Ministers and orders of the Ministry ofHealth. The results of the study of international experience in introducing the basic concepts of orphan diseases and orphan patients into the healthcare system in the United States (since 1983), EU countries (since 1999), Japan (since 1993), etc., have been summarized. It has been found that 275 nosologies of orphan diseases have been approved in Ukraine; they are grouped by 11 nosological categories, there are 104 nosologies (+40 %) more than in 2016. A positive trend towards intensification of the process of improving the provision of orphan patients in Ukraine has been revealed.

Еye manifestations of Gaucher’s disease

Gauchers disease is a rare autosomal recessive disease that belongs to the group of sphingolipidoses. This pathology is caused by a lysosomal enzyme glucocerebrosidase deficiency, which leads to its substrate, glucosylceramide, accumulation in macrophages, and leads to damage to the nervous system, parenchymal organs, and the hematopoietic system. The literature reported isolated cases of vision organ damages such as oculomotor function disorders and violations of the structure of the vitreous, retina, cornea, choroid, and conjunctiva. During diagnosis, these clinical symptoms may cause interpretation and, possibly, substitution therapy evaluating difficulties. Retinal changes in Gauchers disease are poorly understood, but they are an important symptom of this disease, which dynamically visualizes and evaluates the substrate deposition in the preretinal and intraretinal layers. The effectiveness of replacement therapy based on the presence of retinal lesions remains controversial.
 Herein, presented the description of a clinical case of a 10-year-old boy with ocular manifestations of Gauchers disease, a rare orphan disease. The comprehensive ophthalmological examination results revealed preretinal changes in whitish foci in the paramacular zone, microstructural changes in the central retina according to optical coherence tomography, and moderate changes in retinal functions according to electroretinogram, as well as visual field defects and decreased light sensitivity. The revealed changes indicate a violation of metabolic processes in the retinal layers of the eye, which leads to retinal foci (gosher) formation. Noninvasive visualization of these deposits helps assess the disease course and the substitution therapy effectiveness. The management of patients with Gauchers disease requires an interdisciplinary approach with the mandatory involvement of an ophthalmologist.

Thoracic involvement and imaging patterns in IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a rare orphan disease. Lung, pleura, pericardium, mediastinum, aorta and lymph node involvement has been reported with variable frequency and mostly in Asian studies. The objective of this study was to describe thoracic involvement assessed by high-resolution thoracic computed tomography (CT) in Caucasian patients with IgG4-RD. Thoracic CT scans before treatment were retrospectively collected through the French case registry of IgG4-RD and a single tertiary referral centre. CT scans were reviewed by two experts in thoracic imagery blinded from clinical data. 48 IgG4-RD patients with thoracic involvement were analysed. All had American College of Rheumatology/European League Against Rheumatism classification scores ≥20 and comprehensive diagnostic criteria for IgG4-RD. CT scan findings showed heterogeneous lesions. Seven patterns were observed: peribronchovascular involvement (56%), lymph node enlargement (31%), nodular disease (25%), interstitial disease (25%), ground-glass opacities (10%), pleural disease (8%) and retromediastinal fibrosis (4%). In 37% of cases two or more patterns were associated. Asthma was significantly associated with peribronchovascular involvement (p=0.04). Among eight patients evaluated by CT scan before and after treatments, only two patients with interstitial disease displayed no improvement. Thoracic involvement of IgG4-RD is heterogeneous and likely underestimated. The main thoracic CT scan patterns are peribronchovascular thickening and thoracic lymph nodes.

Pantothenate kinase-associated neurodegeneration (Hallerworden–Spatze disease): clinical aspects, diagnosis, treatment (literature review and own data)

Aim. To analyze current data of scientific literature on the etiology, pathogenesis, approaches to the diagnosis and treatment of rare orphan disease – pantothenate kinase-associated neurodegeneration and to describe the clinical case of this disease. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare inherited autosomal recessive disorder caused by mutations in the PANK2 gene, which is located at the chromosomal locus: 20p13-p12.3. The article presents a literature review and a case report of the diagnosis and treatment of 8-year-old girl with pantothenate kinase-associated neurodegeneration who suffered from progressive motor impairment. Among the dominant clinical manifestations is a growing extrapyramidal motor disorder, the so-called “dystonic storm”, which can range from severe sensorimotor motor deficits in infants and young children to mild parkinsonism in adults. MRI signs in the form of specific changes in the T2-weighted mode, which detects typical areas of hyperintensive signal in globus pallidus, surrounded by a border of hypointensive signal (“tiger’s eye”) are particular important. Neuroimaging data most likely make possible to suspect a correct diagnosis, reducing the time and cost of additional examinations. There is no pathogenetic treatment of this disease now. The main directions of currently available symptomatic drug therapy are described. Clinical trials of detoxifying drugs that reduce iron levels in the body (chelation) and surgical treatments are currently underway. Conclusions. The presented clinical observation once again confirms the complexity of the diagnostic search for orphan diseases of the nervous system. A key place in the diagnosis of pantothenate kinase-associated neurodegeneration belongs to the neuroimaging methods and molecular genetic testing data.

Epidermolysis bullosa dystrophica pretibialis - Clinical snapshot and management of a rare orphan disease.

If blistering occurs in childhood, the possibility of hereditary epidermolysis bullosa should be considered even if the symptoms are mild. Besides clinical and histological examination, molecular genetic screening is diagnostically relevant. For localized forms, symptomatic, topical therapy options are currently still the primary choice. Of particular interest is the new option of topical therapy with diacerein 1% cream. In the case of a pronounced clinical picture with extracutaneous organ involvement, multidisciplinary management is required. In the future, new forms of therapy such as autologous epidermal stem cell transplantation and gene therapeutic procedures may be applied. Human genetic counselling is indispensable.

Idiopathic hypersomnia: a homogeneous or heterogeneous disease?

IntroductionIdiopathic hypersomnia (IH) is a rare orphan disease characterized by excessive daytime sleepiness, frequently accompanied by prolonged nocturnal sleep and difficulties awakening, termed sleep inertia or sleep drunkenness. Severe sleepiness usually causes a greater handicap than manifestations of narcolepsy. MethodsForty-three IH patients (17 male, mean age 42.8 ± SD 12.2 years, range 20–67), diagnosed in the past 20 years according to ICSD-2 or ICSD-3 criteria were invited for clinical examination to evaluate the course, manifestations and severity of the disease, as well as clinical comorbidities. The patients completed a set of questionnaires scoring sleepiness, sleep inertia, fatigue, depression, anxiety, circadian preference, and quality of life. ResultsIH patients were divided according to the duration of nocturnal sleep at the time of their diagnosis into two cohorts: (1) with normal sleep duration (n = 25, 58.1%) and (2) with long sleep duration (n = 18, 41.9%). The mean duration of ad libitum sleep per 22 h in the second cohort was 732.0 ± 115.4 min (range 603–1100), and women markedly prevailed (n = 14, 77.8%). Age at disease onset was younger in the group with long sleep duration (21.2 ± 11.4 years versus 28.1 ± 13.6 years, p = 0.028), their MSLT latency was longer (7.2 ± 3.7 min versus 5.1 ± 1.7 min, p = 0.005), a history of sleep inertia prevailed (p = 0.005), and daily naps were mostly non-refreshing (p = 0.014). Additionally, questionnaires in the group with long sleep duration showed more severe sleep inertia (p = 0.007), fatigue (p = 0.004), and a tendency towards evening chronotype (p = 0.001). ConclusionsIH patients with long sleep duration differ clinically as well as by objective measures at the time of diagnosis and in long-term follow up from IH patients without long 24-h sleep time. In our opinion they represent an independent clinical entity to be considered in the revised ICSD-3 criteria.

Antineoplastic effect of a novel nanosized curcumin on cutaneous T cell lymphoma.

Cutaneous T cell lymphomas (CTCLs) are a group of heterogeneous, life-threatening, extra-nodal and lymphoproliferative T cell neoplasms. Since chronic inflammation serves a key role in CTCL progression, curcumin, a natural pigment with proven anti-inflammatory and antineoplastic properties, as well as minimal toxicity, may be used as a therapeutic agent. In the present study, two formulations of curcumin (standard ethanolic and a Pluronic®P-123/F-127 micellar solution) were compared regarding their cytotoxic efficacy and speed of internalization in three CTCL cell lines, namely HuT-78, HH and MJ. In addition, the modulating effect of curcumin on selected proteins involved in the proliferation and progression of the disease was determined. The results indicated the superiority of the Pluronic®P-123/F-127 micellar curcumin over the standard ethanol solution in terms of cellular internalization efficiency as determined by spectrophotometric analysis. Notably, the presence of commonly used media components, such as phenol red, may interfere when interpreting the cytotoxicity of curcumin, due to their overlapping absorbance peaks. Therefore, it was concluded that phenol red-free media are superior over media with phenol red in order to correctly measure the cytotoxic efficacy and cell penetration of curcumin. Depending on the cell line, the IC50 values of micellar curcumin varied from 29.76 to 1.24 µΜ, with HH cells demonstrating the highest sensitivity. This cell line had the lowest expression levels of the Wilms' tumor-1 transcription factor. Performing western blot analyses of treated and untreated CTCL cells, selective signal transduction changes were recorded for the first time, thus making curcumin nano-formulation an attractive and prospective option with therapeutic relevance for CTCL as a rare orphan disease.

Alpha-mannosidosis in children: analysis of the observations and treatment options

The article is devoted to a rare (orphan) disease from the group of lysosomal storage diseases — alpha-mannosidosis, associated with the accumulation of mannose-containing oligosaccharides in the tissues and cells of the body. The authors analyze the literature data and proposals of the International working group for the diagnosis of alpha-mannosidosis. The article presents the examination results of 15 patients with alpha-mannosidosis aged from 1 to 12 years. The diagnosis was based on the combination of phenotypic traits and extremely low activity of the lysosomal enzyme of alpha-mannosidase in peripheral blood lymphocytes. The molecular genetic verification of the diagnosis was performed in 14 probands. The authors found that all the patients under observation had a typical Hurler-like phenotype, lighter than patients with Hurler syndrome. The children were divided into 2 groups according to the severity of the disease: severe (1 child) and moderate (14 children) forms. The disease had a progressive course. The enzyme replacement therapy with velmanase alpha (recombinant human alpha-mannosidase), developed and registered in the European countries, is not used in Russia due to the absence of registration. Early diagnosis and early start of enzyme replacement therapy is the best way to limit the progression of the disease, and effective genetic counseling helps to prevent it.

Rare genital malformations in women\u2019s health research: sociodemographic, regional, and disease-related characteristics of patients with Mayer-Rokitansky-K\xfcster-Hauser syndrome

BackgroundThe Mayer-Rokitansky-Küster-Hauser syndrome, MRKHS, is a rare (orphan) disease characterized by the aplasia or hypoplasia of the uterus and the vagina. In women's health research, little is known as to how much care provision for patients with MRKHS takes into account their socio-demographic together with their clinical characteristics. This work examines the patients’ socio-demographic characteristics, highlighting issues of inappropriate and deficient provision of care.MethodsThe study was carried out as part of the larger TransCareO project and included a group of N=129 MRKHS patients who underwent surgery between 2008 and 2012. Using a specially developed questionnaire, we analyzed MRKHS patients’ data found both in the clinical documentation of the Department for Women's Health, University Hospital of Tübingen and the patient surveys of the Center for Rare Genital Malformations (CRGM/ ZSGF). Patients who took part in interviews were compared with non-respondents.ResultsPatient respondents and non-respondents did not differ as to the parameters of interest. In most cases, primary amenorrhea was reported as an admission reason. In 24% of patients, a medical intervention (hymenal incision or hormone treatment) already occurred before admission to the Center in Tübingen and proper diagnosis of MRKHS. About one third received in advance inappropriate treatment. During the therapy, more than half of the patients were in a solid partnership. 10% of the family anamneses documented the occurrence of urogenital malformations.ConclusionsCare provision for MRKHS patients is largely characterized by delayed proper diagnosis and in part, by inappropriate treatment attempts; there are also indications of regional differences. Anamnestic clues such as an asymptomatic amenorrhea or renal abnormalities of unclear origin still fail to result early enough in referral to a center on the basis of suspected MRKHS diagnosis. Urogenital malformations in the family are more common in patients than in the general population. For patients, a wide range of burdens are associated with the diagnosis. Abnormalities compared to their female peers occur, for instance, in the partnership status: MRKHS patients have more rarely a partner.

A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice.

BackgroundNumerous currently incurable human diseases have been causally linked to mutations in connexin (Cx) genes. In several instances, pathological mutations generate abnormally active Cx hemichannels, referred to also as “leaky” hemichannels. The goal of this study was to assay the in vivo efficacy of a potent antagonist antibody targeting Cx hemichannels.MethodsWe employed the antibody to treat Cx30A88V/A88V adult mutant mice, the only available animal model of Clouston syndrome, a rare orphan disease caused by Cx30 p.A88V leaky hemichannels. To gain mechanistic insight into antibody action, we also performed patch clamp recordings, Ca2+ imaging and ATP release assay in vitro.FindingsTwo weeks of antibody treatment sufficed to repress cell hyperproliferation in skin and reduce hypertrophic sebaceous glands (SGs) to wild type (wt) levels. These effects were obtained whether mutant mice were treated topically, by application of an antibody cream formulation, or systemically, by intraperitoneal antibody injection. Experiments with mouse primary keratinocytes and HaCaT cells revealed the antibody blocked Ca2+ influx and diminished ATP release through leaky Cx30 p.A88V hemichannels.InterpretationOur results show anti-Cx antibody treatment was effective in vivo and sufficient to counteract the effects of pathological connexin expression in Cx30A88V/A88V mice. In vitro experiments suggest antibodies gained control over leaky hemichannels and contributed to restoring epidermal homeostasis. Therefore, regulating cell physiology by antibodies targeting the extracellular domain of Cxs may enforce an entirely new therapeutic strategy. These findings support the further development of antibodies as drugs to address unmet medical needs for Cx-related diseases.FundFondazione Telethon, GGP19148; University of Padova, SID/BIRD187130; Consiglio Nazionale delle Ricerche, DSB.AD008.370.003\\TERABIO-IBCN; National Science Foundation of China, 31770776; Science and Technology Commission of Shanghai Municipality, 16DZ1910200.

Immunotherapy for mesothelioma: a critical review of current clinical trials and future perspectives.

At the clinical level the role of immunotherapy in cancer is currently at a pivotal point. Therapies such as checkpoint inhibitors are being approved at many levels in cancers such as non-small cell lung cancer (NSCLC). Mesothelioma is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Various clinical trials for checkpoint inhibitors have been conducted in this rare disease, and suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. Most recently approved as a salvage therapy in mesothelioma was granted in Japan, regulatory approval for their use in the clinic elsewhere lags. In this article we review the current pertinent clinical trials of immunotherapies in malignant mesothelioma, discuss the current issues that may affect the clinical outcomes of such therapies and further evaluate potential candidate new avenues that may become future targets for immunotherapy in this cancer.