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Pemphigus vulgaris (PV) is a blistering autoimmune disease that affects the skin and mucous membranes. The precise mechanisms by which PV antibodies induce a complete loss of cohesion of keratinocytes are not fully understood. But it is accepted that the process starts with antibody binding to desmosomal targets which leads to its disassembly and subsequent structural changes to cell-cell adhesions. In vitro immunofluorescence imaging of desmosome molecules has been used to characterize this initial phase, often qualitatively. However, there remains an untapped potential of image analysis in providing us more in-depth knowledge regarding ultrastructural changes after antibody binding. Currently, there is no such effort to establish a quantitative framework from immunofluorescence images in PV pathology. We take on this effort here in a comprehensive study to examine the effects of antibodies on key adhesion molecules and the cytoskeletal network, aiming to establish a correlation of ultrastructural changes in cell-cell adhesion with antibody pathogenicity. Specifically, we introduced a data-driven approach to quantitatively evaluate perturbations in adhesion molecules, including desmoglein 3, E-cadherin, as well as the cytoskeleton, following antibody treatment. We identify distinct immunofluorescence imaging signatures that mark the impact of antibody binding on the remodeling of the adhesion molecules and introduce a pathogenicity score to compare the relative effects of different antibodies. From this analysis, we showed that the biophysical response of keratinocytes to distinct PV associated antibodies is highly specific, allowing for accurate prediction of their pathogenicity. For instance, the high pathogenicity scores of the PVIgG and AK23 antibodies show strong agreement with their reported PV pathology. Our data-driven approach offers a more detailed framework for the action of autoantibodies in pemphigus and has the potential to pave the way for the development of effective novel diagnostic methods and therapeutic strategies., Competing Interests: COMPETING INTERESTS None to declare.

In order to replace conventional diesel, biodiesel from various feedstocks is being researched for diesel engines. This study explores novel biodiesel blends produced from unconventional resources such as mentha piperita (peppermint), pontederia crassipes (water hyacinth), tamarindus indica (tamarind), and trichosanthes cucumerina (snake gourd) to assess the outcomes of a diesel engine. The fuel samples are designated as MP20, PC20, TC20, and TI20, which consist of 80% biodiesel and 20% diesel. The assessment is carried out on a four-stroke, one-cylinder diesel engine that is water-cooled and set to operate at 1500 rpm with a 17.5 compression ratio under various engine loading scenarios with quarter-incremental loading from one-fourth to full loading conditions. The fuel samples are injected with 220 bar injection pressure into the combustion chamber 23° before TDC. An extensive analysis of engine parameters is performed using engine configuration, fuel characteristics, and applied boundary conditions. This comprises brake-specific energy consumption (BSEC), fuel consumption (BSFC), thermal efficiency (BTE), cylinder pressure (CP), heat release rate (HRR), particulate matter (PM), nitrogen oxide (NOx), and carbon dioxide (CO 2 ) emissions. At 100% load, the biodiesel blends show an increase in BSFC (2.8-12.6%) and BSEC (1.1-7.1%) but a minor decrease in CP (0.9-6.9%), HRR (0.8-16.2%), and BTE (1.2-2.9%). For biodiesel blends at full engine load, the emissions of PM (8.9-21.4%), NOx (1.4-16.2%) and CO 2 (2.4-7.9%) are all significantly reduced. The results emphasize the distinct benefits of biodiesel blends, demonstrating enhanced engine performance and substantial decreases in emissions, which supports the aim of providing sustainable energy solutions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Establishing a strong bond between the pulp capping agent and the restorative material is crucial to the success of the procedure. Without this bond, there is a risk of bacterial infiltration into the pulp, leading to treatment failure. In the past, calcium hydroxide was commonly used for such treatments, but it faced challenges, including poor adhesion to dentin, dissolution over time, and the development of multiple tunnel defects. Mineral trioxide aggregate (MTA), introduced to dentistry in 1993, offered an alternative but came with drawbacks like challenging handling and extended setting times. However, in recent times, several new calcium silicate-based materials have emerged to address MTA's limitations. Two notable examples are Biodentine and MTA Plus. Biodentine, for instance, exhibits excellent sealing ability, while MTA Plus distinguishes itself with a finer particle size compared to traditional MTA. These innovative materials offer promising solutions to enhance the efficacy of pulp capping procedures., Aim: Therefore, in this research, we conducted a comparative analysis of the shear bond strength (SBS) between composite resin and three materials-MTA, MTA Plus, and Biodentine. We examined the effects of applying two distinct adhesive systems in order to evaluate their influence on the bond strength., Materials and Methods: A total of 60 acrylic blocks were evenly distributed into three groups, each containing 20 blocks-group I received Biodentine, group II was assigned MTA, and group III received MTA Plus. The respective test materials were compacted into the holes within the blocks. Following this, the samples were incubated for a period of 72 hours. Subsequently, the samples were divided into two subgroups, each consisting of 10 blocks-the self-etch and the total-etch subgroup. The SBS values were then carefully measured for analysis., Result: The SBS of the Biodentine group demonstrated a significantly higher value when compared to the other groups. It's worth noting that when the self-etch adhesive system was employed, the SBS of all the groups experienced a significant reduction., Conclusion: Biodentine cement proves to be an effective choice for pulp capping procedures, regardless of the specific adhesive system employed. Notably, the total-etch adhesive system consistently yields higher bond strength when compared to the self-etch adhesive system., How to Cite This Article: Kumar V, Showkat I, Manuja N, et al. Comparative Evaluation of Shear Bond Strength of Tricalcium Silicate-based Materials to Composite Resin with Two Different Adhesive Systems: An In Vitro Study. Int J Clin Pediatr Dent 2023;16(S-3):S272-S277., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2023; The Author(s).)

Autoimmune diseases tend to cluster in families, suggesting genetic predisposition to autoimmunity associated with familial background. We have previously reported similarities in gene expression patterns and PTPN22 polymorphisms between alopecia areata (AA) patients and their healthy relatives, but not unrelated healthy controls. However, the spectrum of disease promoting (or preventing) pathways that may be activated in blood relatives of AA patients remains to be defined. Here, we investigated the extent to which cytokines associated with the Th1 and Th17 pathway are differentially expressed in the blood of patients with AA and its clinical subtypes in comparison to both healthy relatives as well as unrelated healthy controls. A comprehensive set of Th1- and Th17-related cytokines were evaluated by ELISA. We found a significant elevation of the Th17 inducer IL-23, the Th17 product IL-17A, the Th1 hallmark cytokine IFNγ, and TNFα, a Th1 cytokine with relevance to the Th17 pathway in AA patients, regardless of disease subtype, compared to healthy individuals. On further examination, we found that healthy family members grouped together with patients in terms of elevated Th1- and Th17-pathway cytokines in an inheritance-specific manner, distinct from unrelated controls. The elevation of Th17-associated cytokines in healthy controls related to AA patients indicates that Th1 and Th17 dysregulation in AA may be genetically based. Of note, one unrelated control displayed elevated levels of IL-17A and IL-23 similar to those detected in patients. One year after initial blood draw, areas of beard hair loss consistent with the diagnosis of AA were reported by this individual, indicating that the elevation in Th17-related cytokines may have predictive value.

Aim: To evaluate the effect of different add-ons on the flexural strength (FS) of glass ionomer cement (GIC)., Materials and Methods: Around 72 samples were fabricated and divided among the following six different groups: group I-control (conventional GIC-nonmodified), group II-GIC powder modified with 3% titanium dioxide (TiO 2 ) and liquid is unmodified, group III-powder modified with 10% nanohydroxyapatite (nHA) and liquid is unmodified, group IV-powder is unmodified and Liquid is modified with 10% chitosan (CH), group V-powder is modified with 3% TiO 2 and liquid is modified with 10% CH, and group VI-powder is modified with 10% nHA and liquid is modified with 10% CH. The samples were then subjected to a three-point bending test on a universal testing machine for the evaluation of FS. The results obtained were analyzed statistically using the analysis of variance (ANOVA) test., Result: The mean FS value of group V depicts significantly high FS among all groups (29.42 ± 3.35). A significant difference was present in FS amongst all the groups that is groups V>II>IV>VI>III>I., Conclusion: Glass ionomer cement (GIC) powder can be modified with nHA, nanotitanium, and GIC liquid can be modified with CH to improve its FS., Clinical Significance: Glass ionomer cement (GIC) supplemented with additives like nanoparticles (NPs) and CH can be used as an enhanced filling material due to its potential antibacterial properties and in areas with a high masticatory load., How to Cite This Article: Showkat I, Chaudhary S, Sinha AA, et al. Comparative Evaluation of Flexural Strength of Conventional Glass Ionomer Cement and Glass Ionomer Cement Modified with Chitosan, Titanium Dioxide Nanopowder and Nanohydroxyapatite: An In Vitro Study. Int J Clin Pediatr Dent 2023;16(S-1):S72-S76., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2023; The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Autoimmune blistering diseases such as bullous pemphigoid (BP) and pemphigus vulgaris (PV) are complex, multifactorial, and polygenic diseases, whose exact pathogenesis is difficult to pinpoint. Research aimed at elucidating the associated epidemiologic risk factors of these two diseases has been hampered by their rare disease status. Further, a lack of centralization and standardization of available data makes the practical application of this information challenging. In order to collate and clarify the available literature we comprehensively reviewed 61 PV articles from 37 different countries and 35 BP articles from 16 different countries addressing a range of disease relevant clinical parameters including age of onset, sex, incidence, prevalence, and HLA allele association. The reported incidence of PV ranged from 0.098 to 5 patients per 100,000 people, while BP ranged from 0.21 to 7.63 patients per 100,000. Prevalence of PV ranged from 0.38 to 30 per 100,000 people and BP ranged from 1.46 to 47.99 per 100,000. The mean age of onset in patients ranged from 36.5 to 71 years for PV and 64 to 82.6 years for BP. Female-to-male ratios ranged from 0.46 to 4.4 in PV and 1.01 to 5.1 in BP. Our analysis provides support for the reported linkage disequilibrium of HLA DRB1*0402 (an allele previously shown to be associated with PV) and DQB1*0302 alleles in Europe, North America, and South America. Our data also highlight that HLA DQB1*0503 (also known to be associated with PV) appears in linkage disequilibrium with DRB1*1404 and DRB1*1401, mainly in Europe, the Middle East, and Asian countries. The HLA DRB1*0804 allele was only associated with PV in patients of Brazilian and Egyptian descent. Only two HLA alleles were reported as associated with BP more than twice in our review, DQB1*0301 and DQA1*0505. Collectively, our findings provide detailed insights into the variation of disease parameters relevant to PV and BP that can be expected to inform future work aimed at unraveling the complex pathogenesis of these conditions across the globe., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rosi-Schumacher, Baker, Waris, Seiffert-Sinha and Sinha.)

Pemphigus vulgaris (PV) is a potentially life-threatening blistering disorder characterized by autoantibodies directed against cell-cell adhesion molecules that serves as an excellent model to study human autoimmune development. Numerous studies have identified specific Human Leukocyte Antigen (HLA) genes, in particular DRB1*0402 and DQB1*0503, that confer disease risk. Although HLA is required, it is not sufficient for the initiation of disease. As with all autoimmune diseases, the etio-pathogenesis of PV is complex, meaning it is multifactorial. Susceptibility is polygenic, and the search for non-HLA disease-linked genes continues. Moreover, twin studies across autoimmune conditions indicate that non-genetic environmental and lifestyle factors, which can be collectively grouped under the term "exposome", are also major contributors to disease development. The literature presents evidence for the potential role of multiple triggers such as medications, infections, stress, diet, immunizations, and sleep to influence the etiology, pathophysiology, and prognosis of PV. However, a clear understanding of the degree to which specific factors impact PV is lacking. In this investigation, we comprehensively review the environmental elements listed above and consider the strength of evidence for these factors. The overall goals of this work are to provide greater insights into the factors that influence disease susceptibility, disease development and disease course and ultimately help to better guide clinicians and inform patients in the management of PV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Adebiyi, Galloway, Augustin and Sinha.)

Background and Aim: Pemphigus vulgaris (PV) is known to have one of the strongest HLA associations among autoimmune diseases. DRB1*0402 and DQB1*0503 in particular are significantly overrepresented in PV patients in certain worldwide populations. Yet, there remain significant gaps in our understanding regarding the precise link between PV-associated HLA molecules, the specificity of the autoimmune response, and clinical expression. In this study we assessed correlations between factors including HLA genotype, ethnicity, autoantibody levels, and lesion distribution in a cohort of 293 patients., Methods and Population: Participants were recruited from multiple outpatient dermatology clinic settings and patient support meetings in the USA. On intake, patients provided venous blood samples and answered questionnaires regarding their current disease activity., Results: Eighty-one percent of patients typed as either DRB1*0402 or DQB1*0503 with a high prevalence of DRB1*0402 in patients of Ashkenazi Jewish or Caucasian (non-Jewish) descent (86% and 42%, respectively) and DQB1*0503 in patients of Southeast Asian descent (78%). Patients typing as HLA DRB1*0402 had higher levels of anti-desmoglein (Dsg)3 antibodies (204.6 +/- 340.5 IU/ml) than patients without DRB1*0402 (138.5 +/- 236.4 IU/ml) (p=0.03) and had mucosal only lesions more often than cutaneous only or mucocutaneous lesions. Patients typing as DQB1*0503 had higher levels of anti-Dsg1 antibodies (47.3 +/- 59.8 IU/ml) compared to other groups (27.8 +/- 43.7 IU/ml) (p=0.06) and higher rates of mucocutaneous disease than other lesion types. We also report an unexpected HLA association of DRB1*0804 in PV patients of African descent. Sixty-four percent of this population carried the DRB1*0804 allele, and presented with highly elevated levels of anti-Dsg3 (p=0.02). However, neither African heritage nor the presence of DRB1*0804 correlated with a predilection to any specific lesion morphology. Patients that carried neither DRB1*0402, nor DQB1*0503 or DRB1*0804 had the lowest levels of anti-Dsg3 antibodies (60.0 +/- 80.0 IU/ml) and the highest rate of solely cutaneous disease compared to carriers of these alleles., Conclusion: Our data illuminate the broader impact of genetic factors on disease development by showing that differences in HLA expression among patients and ethnicities play a large role in driving distinct patterns of antibody selection and disease phenotype in PV. These findings provide insights regarding clinical heterogeneity, and are relevant to developing improved, patient tailored management strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Baker, Seiffert-Sinha and Sinha.)

The pemphigus group of autoimmune blistering diseases encompasses pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Lesion location in pemphigus has been elegantly postulated by the Desmoglein Compensation Hypothesis (DCH), which references the distribution of desmoglein (Dsg) proteins in the epidermis along with a patient's autoantibody profile to describe three different lesion phenotypes: PF is characterized by subcorneal lesions in the presence of anti-Dsg1 antibodies only, while lesions in PV are suprabasilar and accompanied by anti-Dsg3 antibodies only in mucosal PV, or both anti-Dsg3 and anti-Dsg1 in the case of mucocutaneous PV. While the validity of this hypothesis has been supported by several studies and is prominently featured in textbooks of dermatology, a number of logical inconsistencies have been noted and exceptions have been published in several small-scale studies. We sought to comprehensively assess the extent to which patient clinical and autoantibody profiles contradict the DCH, and characterize these contradictions in a large sample size of 266 pemphigus patients. Remarkably, we find that roughly half of active PV and PF patients surveyed present with a combination of lesion morphology and anti-Dsg3/1 levels that contradict the DCH, including: patients with a cutaneous only PV presentation, mucocutaneous disease in the absence of either Dsg3, Dsg1, or both, and mucosal disease in the absence of Dsg3 or presence of Dsg1. We also find stark differences in fidelity to the DCH based on ethnicity and HLA-association, with the lowest proportion of adherence in previously understudied populations. These findings underscore the need to expand our understanding of pemphigus morphology beyond the DCH, in particular for populations that have not been a focus in previous investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sielski, Baker, DePasquale, Attwood, Seiffert-Sinha and Sinha.)

Background: Peripheral venous access in patients with sickle cell disease (SCD) can become difficult over time due to frequent access and scarring. Infusion ports provide reliable central venous access. Deep venous thrombosis (DVT) and infections are complications associated with SCD and infusion ports., Methods: We performed a 17.5-year single-institution retrospective chart review (January 2000 to July 2018) with literature review regarding use of infusion ports in patients with SCD., Results: We identified 32 patients with infusion ports placed for a total of 63 devices (48 for chronic transfusion [CT] and 15 for poor venous access [PVA], not on CT) for a total of 99,272 catheter days. The mean age at first insertion was 8 years (range 1-20 years). Complications included malfunction, infection, thrombosis, difficult access, and pain over infusion port site. The rate of infection was 0.2 per 1000 catheter days. Thrombosis was identified in three devices (5%) in three patients (9%), with a rate of 0.03 per 1000 catheter days. There was no difference in complications by site in either the left or right subclavian vein (p = 1). The rate of premature removal was 0.36 per 1000 catheter days, which was higher among patients with infusion ports solely for PVA (0.87 per 1000 catheter days) compared with those placed for CT (0.29 per 1000 catheter days)., Conclusion: Infusion ports in patients with SCD was associated with low rates of thrombosis, infection, and malfunction, and may be considered as an alternative to frequent intravenous access, especially in patients requiring CT., (© 2021 Wiley Periodicals LLC.)

The skin is vital for protecting the body and perceiving external stimuli in the environment. Ability to adapt between environments is in part based on skin phenotypic plasticity, indicating evolved homeostasis between skin and environment. This homeostasis reflects the greater relationship between the body and the environment, and disruptions in this balance may lead to accumulation of susceptibility factors for autoimmune conditions like psoriasis. In this study, we examined the relationship between rapid, lineage-specific evolution of human skin and formation of psoriatic skin responses at the transcriptome level. We collected skin tissue biopsies from individuals with psoriasis and compared gene expression in psoriatic plaques to non-plaque psoriatic skin. We then compared these data with non-psoriatic skin transcriptome data from multiple primate species. We found 67 genes showing human-specific skin expression that are also differentially regulated in psoriatic skin; these genes are significantly enriched for skin barrier function, immunity and neuronal development. We identified six gene clusters with differential expression in the context of human evolution and psoriasis, suggesting underlying regulatory mechanisms in these loci. Human and psoriasis-specific enrichment of neuroimmune genes shows the importance of the ongoing evolved homeostatic relationship between skin and external environment. These results have implications for both evolutionary medicine and public health, using transcriptomic data to acknowledge the importance of an individual's surroundings on their overall health., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

It is becoming increasingly clear that mechanical stress in adhesive junctions plays a significant role in dictating the fate of cell-cell attachment under physiological conditions. Targeted disruption of cell-cell junctions leads to multiple pathological conditions, among them the life-threatening autoimmune blistering disease pemphigus vulgaris (PV). The dissociation of cell-cell junctions by autoantibodies is the hallmark of PV, however, the detailed mechanisms that result in tissue destruction remain unclear. Thus far, research and therapy in PV have focused primarily on immune mechanisms upstream of autoantibody binding, while the biophysical aspects of the cell-cell dissociation process leading to acantholysis are less well studied. In work aimed at illuminating the cellular consequences of autoantibody attachment, it is reported that externally applied mechanical stress mitigates antibody-induced monolayer fragmentation and inhibits p38 MAPK phosphorylation activated by anti-Dsg3 antibody. Further, it is demonstrated that mechanical stress applied externally to cell monolayers enhances cell contractility via RhoA activation and promotes the strengthening of cortical actin, which ultimately mitigates antibody-induced cell-cell dissociation. The study elevates understanding of the mechanism of acantholysis in PV and shifts the paradigm of PV disease development from a focus solely on immune pathways to highlight the key role of physical transformations at the target cell., (© 2021 Wiley-VCH GmbH.)

D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) or a single gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2). Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) is a type of D-2-HGA that has been previously reported in ten patients (OMIM 614875), three of whom had somatic mosaicism for R132 variants in isocitrate dehydrogenase 1 ( IDH1 ). We describe a 3-year-old boy with MC-HGA who subsequently developed acute myeloid leukemia (AML) and was found to have an IDH1 R132C mutation in a leukemic bone marrow sample. Further testing revealed presence of somatic mosaicism for IDH1 R132C variant, suggesting an association of IDH1 in inducing myeloid leukemogenesis.

Aim: Metastatic prostate cancer is responsible for a large proportion of deaths worldwide. The aim of this study was to identify metastatic cells and determine if stromal invasion by cancer cells differs from those during metastasis., Methods & Results: Tissue biopsy/prostatectomy samples, visualized by transmission electron microscopy, identified that metastatic cells are a lineage of stem cells, which have dedifferentiated into cancerous columnar/cuboidal cells. These cells demonstrate nuclear plasticity; the loss of nuclear membranes and boundary between nucleus and cytoplasm; and the presence of electron dense molecules, which can readily pass through basement membranes and enter the capillary, ready for dissemination to metastatic sites., Conclusion: This is the first study to demonstrate differences between invasive and metastatic cell types., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript., (© 2020 Akhouri A Sinha.)

Competing Interests: The author declares no competing interest.

Background: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management., Objective: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations., Methods: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus., Results: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion., Limitations: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available., Conclusions: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus., (Copyright © 2020. Published by Elsevier Inc.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Despite advancements in the diagnosis and treatment of acute lymphoblastic leukemia (ALL), a need for improved strategies to decrease morbidity and improve cure rates in relapsed/refractory ALL still exists. Such approaches include the identification and implementation of novel targeted combination regimens, and more precise upfront patient risk stratification to guide therapy. New curative strategies rely on an understanding of the pathobiology that derives from systematically dissecting each cancer's genetic and molecular landscape. Zebrafish models provide a powerful system to simulate human diseases, including leukemias and ALL specifically. They are also an invaluable tool for genetic manipulation, in vivo studies, and drug discovery. Here, we highlight and summarize contributions made by several zebrafish T-ALL models and newer zebrafish B-ALL models in translating the underlying genetic and molecular mechanisms operative in ALL, and also highlight their potential utility for drug discovery. These models have laid the groundwork for increasing our understanding of the molecular basis of ALL to further translational and clinical research endeavors that seek to improve outcomes in this important cancer.

Background: Vascular complications such as pulmonary hypertension (PH) occur at an increased rate following splenectomy in patients with various hemolytic blood disorders including thalassemia. The goal of this retrospective cross-sectional analysis was to assess the independent association of splenectomy with an elevated tricuspid regurgitation velocity (TRV) in people with homozygous sickle cell disease (HbSS). TRV is a noninvasive screening test for PH and a surrogate marker of prognosis in sickle cell disease (SCD)., Procedure: Data were obtained from the multicenter Walk-PHaSST (treatment of pulmonary hypertension and sickle cell disease with sildenafil therapy) study of PH (NCT00492531). We compared TRV in the cohort of patients with HbSS who were surgically splenectomized with patients who were not surgically splenectomized., Results: We found no significant differences in TRV between the two groups., Conclusions: The lack of difference in TRV between the two groups is most likely because members of the comparator nonsurgical group in many cases experienced autoinfarction of the spleen in childhood. Splenectomy does not seem to confer additional risk for the development of a higher TRV in HbSS, unlike in patients with thalassemia or other hemolytic anemias. This could be an important consideration when weighing the risks and benefits of splenectomy in patients with HbSS., (© 2019 Wiley Periodicals, Inc.)

Bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) are rare chronic autoimmune disorders characterized by subepidermal blistering. For the United States, there is a limited amount of studies in BP and MMP that address disease demographics and clinical data. In order to more comprehensively examine disease demographics and clinical factors, we performed a retrospective analysis of patient-reported data of 138 BP and 165 MMP patients enrolled in the International Pemphigus & Pemphigoid Foundation (IPPF) disease registry from 2010-2016. Patient-reported data was compared to Physician/Investigator reported data generated in our own local patient population (Western New York; 19 BP and 43 MMP patients). We confirm a female predominance in BP (M:F ratio 1:2.1) and MMP (M:F ratio 1:4.3), and a late onset within the 6th decade of life (average age at diagnosis, 59.1 ± 17.5 years for BP and 54.8 ± 11.2 years for MMP). MMP patients were significantly more likely to have a delay in diagnosis >12 months than BP patients (38 vs. 21%, respectively). Similar to other autoimmune conditions, a large number of BP (34%) and MMP (35%) patients present with other co-existing autoimmune disorders, with the most common being thyroid disease for both groups. Increased illness activity was paralleled by an increase in severe limitations of daily activities. The vast majority of of both BP and MMP patients received high intensity immunosuppression (49%). However, the majority of BP patients reported therapy with prednisone combined with other immunosuppressants (40%), while the majority of MMP patients received immunosuppressants other than prednisone (55%). With the exception of age at diagnosis, the clinical and demographic findings from both the national and local datasets were largely consistent with each other, and support those reported in other countries., (Copyright © 2019 Lee, Seiffert-Sinha, Attwood and Sinha.)

Background/aim: Identification of prostatic stem cells in primary prostate tissue sections, organ cultures of prostate and cell lines requires a range of techniques that allows characterization of stem cells for their potential use in the treatment of patients. Isolated cells usually round-up and develop changes in shape, size and cellular characteristics. The aim of this study was to provide a range of methods for identifying prostatic stem cells and characterizing them with regard to ultrastructure, nuclear morphology, cytoplasmic organelles, and/or expression stem cell marker CD133., Materials and Methods: Prostate biopsy and prostatectomy specimens were used for studying prostatic stem cells and their known marker CD133 in tissue sections by light and/or electron microscopy. Inverted capsule embedding was used to study archival metastatic prostate in pelvic nodes and Du145 cell line in a monolayer culture., Results: Staining for CD133 positively identified stem cells that were found in benign prostatic hyperplasia, benign prostate, and prostate cancer cells. Paraffin embedded sections showed a single type of stem cells, whereas methylene blue-stained Epon sections showed both light and dark stem cells. Electron microscopy showed that both basal and stem cells were closely associated with the basement membrane (basal lamina). Stem cells had smooth plasma and nuclear membranes, a prominent nucleolus, small mitochondria, and few ribosomes. Du145 cells were separated by intercellular spaces in monolayer culture., Conclusion: The inverted capsule embedding method allowed the study of metastasized prostate cancer in pelvic lymph nodes. Our approach enabled the assessment of stem cells in tissue sections by light and electron microscopy., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cutaneous lesions feature prominently in lupus erythematosus (LE). Yet lupus and its cutaneous manifestations exhibit extraordinary clinical heterogeneity, making it imperative to stratify patients with varying organ involvement based on molecular criteria that may be of clinical value. We conducted several in silico bioinformatics-based analyses integrating chronic cutaneous lupus erythematosus (CCLE)-skin and blood expression profiles to provide novel insights into disease mechanisms and potential future therapy. In addition to substantiating well-known prominent apoptosis and interferon related response in both tissue environments, the overrepresentation of GO categories in the datasets, in the context of existing literature, led us to model a "disease road-map" demonstrating a coordinated orchestration of the autoimmune response in CCLE reflected in three phases: (1) initiation, (2) amplification, and (3) target damage in skin. Within this framework, we undertook in silico interactome analyses to identify significantly "over-connected" genes that are potential key functional players in the metabolic reprogramming associated with skin pathology in CCLE. Furthermore, overlapping and distinct transcriptional "hot spots" within CCLE skin and blood expression profiles mapping to specified chromosomal locations offer selected targets for identifying disease-risk genes. Lastly, we used a novel in silico approach to prioritize the receptor protein CCR2, whose expression level in CCLE tissues was validated by qPCR analysis, and suggest it as a drug target for use in future potential CCLE therapy.

Background: The basal compartment of the prostatic acinus harbors stem and basal cells, whereas the luminal compartment contains cuboidal and columnar cells. Mutation in the genes of stem cells is required for benign (normal) prostate to develop into prostatic adenocarcinoma. Stem/basal cells survive androgen deprivation therapy in humans and castrated mice to repopulate glandular cells by proliferation when stimulated by androgen. We hypothesized that using different embedding and staining methods, it would be possible to identify two types of stem cells in human prostate by localization of CD133., Materials and Methods: Prostate biopsy or prostatectomy pieces from 13 untreated and eight diethylstilbestrol-treated men with prostate cancer were sectioned, stained by methylene blue and CD133 was localized by immunogold technique., Results: Methylene blue stained basic proteins in dark basal cells, but not in light cells. Light basal cells expressed androgen receptors and dark cells estrogen receptors. Light and dark cells expressed CD133, indicating them to be stem cells. Light stem cells produced the lineage of columnar/cuboidal cells. Estrogen-dependent dark cells produced a lineage of columnar/cuboidal cells, that also expressed estrogen receptors., Conclusion: Our analysis indicates that stem/basal cells are privileged cells in the basal compartment. Stem cells are not under the regulation of steroid hormones, whereas their lineage of cuboidal/columnar cells are. The lineage of androgen-dependent cells are columnar/cuboidal cells and the lineage of estrogen-dependent cells are also columnar/cuboidal cells. Epon-embedding and methylene blue staining showed two types of CD133-positive stem cells in prostate. Paraffin sections did not show two types of stem cells in prostate and bone marrow leukemia cells. Our study indicates the continuity of embryonic stem cells into adult prostate as organ-specific stem cells. To our knowledge, this is the first study to identify two types of stem cells in human prostate., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Emerging data and innovative technologies are re-shaping our understanding of the scope and specificity of the autoimmune response in Pemphigus vulgaris (PV), a prototypical humorally mediated autoimmune skin blistering disorder. Seminal studies identified the desmosomal proteins Desmoglein 3 and 1 (Dsg3 and Dsg1), cadherin family proteins which function to maintain cell adhesion, as the primary targets of pathogenic autoAbs. Consequently, pathogenesis in PV has primarily considered to be the result of anti-Dsg autoAbs alone. However, accumulating data suggesting that anti-Dsg autoAbs by themselves cannot adequately explain the loss of cell-cell adhesion seen in PV, nor account for the disease heterogeneity exhibited across PV patients has spurred the notion that additional autoAb specificities may contribute to disease. To investigate the role of non-Dsg autoAbs in PV, an increasing number of studies have attempted to characterize additional targets of PV autoAbs. The recent advent of protein microarray technology, which allows for the rapid, highly sensitive, and multiplexed assessment of autoAb specificity has facilitated the comprehensive classification of the scope and specificity of the autoAb response in PV. Such detailed deconstruction of the autoimmune response in PV, beyond simply tracking anti-Dsg autoAbs, has provided invaluable new insights concerning disease mechanisms and enhanced disease classification which could directly translate into superior tools for prognostics and clinical management, as well as the development of novel, disease specific treatments.

Delivering molecules onto the plasma membrane of single cells is still a challenging task in profiling cell signaling pathways with single cell resolution. We demonstrated that a large quantity of molecules could be targeted and released onto the membrane of individual cells to trigger signaling responses. This is achieved by a porous pen nanodeposition (PPN) method, in which a multilayer porous structure, serving as a reservoir for a large amount of molecules, is formed on an atomic force microscope (AFM) tip using layer-by-layer assembly and post processing. To demonstrate its capability for single cell membrane drug delivery, PPN was employed to induce a calcium flux triggered by the binding of released antibodies to membrane antigens in an autoimmune skin disease model. This calcium signal propagates from the target cell to its neighbors in a matter of seconds, proving the theory of intercellular communication through cell-cell junctions. Collectively, these results demonstrated the effectiveness of PPN in membrane drug delivery for single cells; to the best of our knowledge, this is the first technique that can perform the targeted transport and delivery in single cell resolution, paving the way for probing complex signaling interactions in multicellular settings.