Pathological Heterogeneity Research Articles

Nail Changes in the Chronic Kidney Failure – A Cross-Sectional Study

Background: Nail manifestations observed in chronic renal failure (CRF) patients are multifarious and heterogeneous in nature. The prime objective of the study is to evaluate the prevalence and features of various kinds of nail manifestations in the patients of CRF. CRF causes heterogeneous pathology of nail which may be or may not be associated with renal condition itself, complications related to it and its therapy. Objective: To study nail changes in the patients of CRF whether managing conservatively or on maintenance hemodialysis (HD). Patients and Methods: The study consists of 100 patients suffering from CRF. Nails of these 100 patients suffering from CRF were examined and different kinds of nails were appreciated and frequencies of the same type of nails in different patients were noted. Results: Nail changes found in chronic kidney disease are longitudinal ridges, half and half nails, leukonychia, pitting nails, onychomycosis, absence of lunula, splinter hemorrhage, and onycholysis as decreasing trend they observed. Conclusions: Nail changes that are seen on examination of patients with CRF managing on HD are very frequent and nail changes if found earlier can be an indicator for early diagnosis of systemic diseases.

Prognosis in moderate-severe traumatic brain injury in a Swedish cohort and external validation of the IMPACT models

BackgroundA major challenge in management of traumatic brain injury (TBI) is to assess the heterogeneity of TBI pathology and outcome prediction. A reliable outcome prediction would have both great value for the healthcare provider, but also for the patients and their relatives. A well-known prediction model is the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) prognostic calculator. The aim of this study was to externally validate all three modules of the IMPACT calculator on TBI patients admitted to Uppsala University hospital (UUH).MethodTBI patients admitted to UUH are continuously enrolled into the Uppsala neurointensive care unit (NICU) TBI Uppsala Clinical Research (UCR) quality register. The register contains both clinical and demographic data, radiological evaluations, and outcome assessments based on the extended Glasgow outcome scale extended (GOSE) performed at 6 months to 1 year. In this study, we included 635 patients with severe TBI admitted during 2008–2020. We used IMPACT core parameters: age, motor score, and pupillary reaction.ResultsThe patients had a median age of 56 (range 18–93), 142 female and 478 male. Using the IMPACT Core model to predict outcome resulted in an AUC of 0.85 for mortality and 0.79 for unfavorable outcome. The CT module did not increase AUC for mortality and slightly decreased AUC for unfavorable outcome to 0.78. However, the lab module increased AUC for mortality to 0.89 but slightly decreased for unfavorable outcome to 0.76. Comparing the predicted risk to actual outcomes, we found that all three models correctly predicted low risk of mortality in the surviving group of GOSE 2–8. However, it produced a greater variance of predicted risk in the GOSE 1 group, denoting general underprediction of risk. Regarding unfavorable outcome, all models once again underestimated the risk in the GOSE 3–4 groups, but correctly predicts low risk in GOSE 5–8.ConclusionsThe results of our study are in line with previous findings from centers with modern TBI care using the IMPACT model, in that the model provides adequate prediction for mortality and unfavorable outcome. However, it should be noted that the prediction is limited to 6 months outcome and not longer time interval.

Chronic constipation: modern view on the problem. A review

Chronic constipation is a frequently diagnosed heterogeneous pathology that significantly impairs the quality of life in all population groups and its frequency increases with age. It commonly affects up to 10 — 15 % of the population. There are numerous classifications of constipation due to a great number of disorders that cause it. The types of constipation are identified based on the etiology or mechanism of its development. Different criteria are used to specify the categorization of constipation, but it is still difficult to find one general classification including all types of constipation. The Rome IV criteria categorize disorders of chronic constipation into four subgroups. The treatment depends on the subtype. The significant increase of constipation cases is observed nowadays. This disorder is facilitated by a sedentary lifestyle, insufficient amount of fiber and fluid in the diet, a wide range of diseases that directly lead to the development of chronic constipation, congenital and acquired pathologies, abnormal intake of laxatives and opioids or a combination of these factors. Despite numerous publications on slow transit constipation, the latter is still the subject of research for many specialists. A lot of recent scientific works have been dedicated to the immunohistochemical studies of interstitial pacemaker cells. The numbers of markers they express were found. Consequently, the investigations of modern scientists are aimed to develop and implement new laboratory methods for determining the indications for surgical treatment depending on a diagnosed disorder of the intestinal neurophysiology. These methods will ensure a differentiated selection of patients for surgical treatment. The step approach to the diagnosis of chronic constipation allows choosing an adequate treatment method in order to improve symptoms, the quality of life, and patient satisfaction. The literature review indicates that surgery still remains the most radical treatment method for patients with slow transit constipation.

Host Lung Environment Limits Aspergillus fumigatus Germination through an SskA-Dependent Signaling Response.

ABSTRACTAspergillus fumigatus isolates display significant heterogeneity in growth, virulence, pathology, and inflammatory potential in multiple murine models of invasive aspergillosis. Previous studies have linked the initial germination of a fungal isolate in the airways to the inflammatory and pathological potential, but the mechanism(s) regulating A. fumigatus germination in the airways is unresolved. To explore the genetic basis for divergent germination phenotypes, we utilized a serial passaging strategy in which we cultured a slow germinating strain (AF293) in a murine-lung-based medium for multiple generations. Through this serial passaging approach, a strain emerged with an increased germination rate that induces more inflammation than the parental strain (herein named LH-EVOL for lung homogenate evolved). We identified a potential loss-of-function allele of Afu5g08390 (sskA) in the LH-EVOL strain. The LH-EVOL strain had a decreased ability to induce the SakA-dependent stress pathway, similar to AF293 ΔsskA and CEA10. In support of the whole-genome variant analyses, sskA, sakA, or mpkC loss-of-function strains in the AF293 parental strain increased germination both in vitro and in vivo. Since the airway surface liquid of the lungs contains low glucose levels, the relationship of low glucose concentration on germination of these mutant AF293 strains was examined; interestingly, in low glucose conditions, the sakA pathway mutants exhibited an enhanced germination rate. In conclusion, A. fumigatus germination in the airways is regulated by SskA through the SakA mitogen-activated protein kinase (MAPK) pathway and drives enhanced disease initiation and inflammation in the lungs.IMPORTANCE Aspergillus fumigatus is an important human fungal pathogen particularly in immunocompromised individuals. Initiation of growth by A. fumigatus in the lung is important for its pathogenicity in murine models. However, our understanding of what regulates fungal germination in the lung environment is lacking. Through a serial passage experiment using lung-based medium, we identified a new strain of A. fumigatus that has increased germination potential and inflammation in the lungs. Using this serially passaged strain, we found it had a decreased ability to mediate signaling through the osmotic stress response pathway. This finding was confirmed using genetic null mutants demonstrating that the osmotic stress response pathway is critical for regulating growth in the murine lungs. Our results contribute to the understanding of A. fumigatus adaptation and growth in the host lung environment.

Neurofilament Levels Are Reflecting the Loss of Presynaptic Dopamine Receptors in Movement Disorders.

Aims: Neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) are biomarkers for neuroaxonal damage. We assessed whether NfL and other biomarker levels in the CSF are correlated to the loss of presynaptic dopamine transporters in neurons as detected with dopamine transporter SPECT (DaTscan).Methods: We retrospectively identified 47 patients (17 Alzheimer’s dementia, 10 idiopathic Parkinson’s disease, 7 Lewy body dementia, 13 progressive supranuclear palsy or corticobasal degeneration) who received a DaTscan and a lumbar puncture. DaTscan imaging was performed according to current guidelines, and z-scores indicating the decrease in uptake were software based calculated for the nucleus caudatus and putamen. The CSF biomarkers progranulin, total-tau, alpha-synuclein, NfL, and pNfH were correlated with the z-scores.Results: DaTscan results in AD patients did not correlate with any biomarker. Subsuming every movement disorder with nigrostriatal neurodegeneration resulted in a strong correlation between putamen/nucleus caudatus and NfL (nucleus caudatus right p < 0.01, putamen right p < 0.05, left p < 0.05) and between pNfH and putamen (right p < 0.05; left p < 0.042). Subdividing in disease cohorts did not reveal significant correlations. Progranulin, alpha-synuclein, and total-tau did not correlate with DaTscan results.Conclusion: We show a strong correlation of NfL and pNfH with pathological changes in presynaptic dopamine transporter density in the putamen concomitant to nigrostriatal degeneration. This correlation might explain the reported correlation of impaired motor functions in PD and NfL as seen before, despite the pathological heterogeneity of these diseases.

Mapping tau burden and neuronal loss in MAPT-associated frontotemporal lobar degeneration.

Genetic mutations in the microtubule-associated protein tau (MAPT) cause frontotemporal lobar degeneration (FTLD-MAPT), associated with severe frontotemporal atrophy antemortem, and highly heterogeneous tau immunoreactivity postmortem, with differential involvement of 3-repeats (3R) or 4-repeats (4R) tau isoforms. To date, there are limited data objectively measuring tau burden in FTLD-MAPT, or directly comparing specific mutation groups. These novel data can help elucidate patterns of regional spread and associated neuronal loss, and shed light on pathologic heterogeneity in tauopathies. We digitally quantified burden of AT8-positive tau pathology using validated digital methods in a cohort of 35 FTLD-MAPT autopsy cases with 9 different mutations (4R mutations: P301L=16, IVS10+16=4, N279K=1; 3R mutations: G272V=5; L266V=2; 3R+4R mutations: R406W=3; L315R=2; G389R=1; S320F=1). We examined the relationship between quantitative measurements of tau burden and ordinal scores of neuronal loss (0-3) in a maximum of nine available grey matter (GM) regions. Regional analysis of tau burden was performed in a subset of six regions with most available data using linear mixed-effects modeling, adjusting for disease duration and neuronal loss. Overall, digitally quantified GM tau burden correlated positively with neuronal loss (beta=1.7, p<0.001), however a subset of GM samples (39/179, 22%) showed relatively low tau pathology in combination with severe neuronal loss. This was particularly prominent in specific mutations (χ2 =33.0, p<0.001) irrespective of region, i.e. in 7/11 (64%) GM samples of L315R, 11/24 (46%) of G272V, and 2/6 (33%) of S320F, and showed some regional variability (χ2 =34.9, p<0.001) across the cohort, occurring most frequently in the frontal (6/8, 75%) and temporal (9/20, 45%) pole. Regional analysis of tau burden in all FTLD-MAPT found that maximally affected regions were the parahippocampal gyrus (PHG), anterior cingulate cortex (ACC) and temporal pole (TP) (F=53.5, p<0.001). Sub-analyses found that 4R mutations were most affected in PHG and TP (F=29.7, p<0.001), while 3R mutations in ACC (F=13.0, p<0.001), and 3R+4R mutations in ACC and inferior parietal lobule (F=53.6, p<0.001). Heterogeneity in severity and distribution of pathology in FTLD-MAPT may in part be related to underlying mutation and tau isoform conformation, which may help improve the understanding of disease pathogenesis and progression.

Using amyloid PET as a biomarker to detect progression of early Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD), the most common form of dementia, is a complex polygenic disease with genetic, cellular, pathologic, and clinical heterogeneity. Recently, significant attempts have been made for identifying AD biomarkers for reliably tracking disease progression in its early asymptomatic stages. To this end, amyloid imaging technique has provided a breakthrough in deciphering the pathophysiology and accumulation of amyloid beta (Aβ) and hyperphosphorylated tau deposits in the brain. As such, our lab and multiple other research groups have used biomarker levels such as CSF Aβ tau, TREM2, and amyloid positivity for genetic association studies and identified novel genes and loci associated to AD. In a recent study, Raghavan et al., analyzed 4,314 participants and identified a novel locus for amyloidosis within RBFOX1 gene, however, this finding has not been replicated yet.MethodIn order to investigate the underlying genetic basis for brain amyloidosis in AD, we aim at systematically analyzing the largest collection of amyloid imaging (N=6,243), data across multiple ethnicities from multicenter cohorts (ADRC, A4, DIAN, ADNI, and ADNIDOD) as a quantitative trait to identify the functional variants and genes driving the association of AD.ResultResults and key findings will be presented at the AAIC meeting.ConclusionWe will leverage these datasets to generate prediction models for amyloid positivity and Mandelian Randomization (MR) analyses. Furthermore, the identification of AD‐specific molecular signatures and pathways will enable the characterization of appropriate therapeutic targets for the prevention and/or treatment of AD.

Neuropathology in the LifeAfter90 study: A new ethnically diverse cohort study of oldest‐old

Persons over the age of 90 are the fastest growing segment of the population in the US, yet there is a dearth of studies investigating the underlying neuropathology of cognitive impairment and dementias, in ethnically diverse, non-white decedents. The Life after 90 study began enrollment in July 2018 and is an ongoing cohort study of members of Kaiser Permanente Northern California aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Participants are examined every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer's Coordinating Center Neuropathology form v. 10. As of January 2021, 173 (26%) participants enrolled in autopsy (18% Asian, 12% African American, 12% Latino, and 10% as multiracial) with 8 deceased and neuropathological evaluations completed. Average age of death was 96 years (range 91 to 105), 5 (62.5%) were female, 3 Latino, 3 Caucasian, and 2 multiracial. At the final clinical exam, which was on average 4 months before death (range: 2-8), 2 participant had dementia (25%), 3 questionable/mild cognitive impairment (37.5%), and 3 cognitively normal (37.5%). With respect to a neuropathologic diagnosis of Alzheimer's disease (AD), 2 met criteria for intermediate likelihood (25%), 4 low (50%), and 2 were considered not to have AD (25%). Notably, none had high likelihood of AD. All participants had some level of neurofibrillary tangles with Braak stages between II and IV. Two participants lacked plaques (Amyloid-Beta or neuritic types), and the highest Thal phase was 4. Four participants (50%) had Lewy bodies (LBs), 1 in olfactory bulb/tract only, 2 Transitional, and 1 with Diffuse. Hippocampal sclerosis was not seen in any whereas TDP-43 inclusions were detected in 2 participants (25%). Diffuse LB, TDP-43 inclusions, and intermediate AD co-occurred in one (50%) of the dementia participants while all lacking in the other. Preliminary results of the first 8 deaths in this multiethnic cohort of oldest-old individuals indicate that numerous brain pathologies are present with advanced age. Further work with this study will examine the clinical impact of this pathological heterogeneity.

In vivo detection of damage in multiple sclerosis cortex and cortical lesions using NODDI

ObjectiveTo characterise in vivo the microstructural abnormalities of multiple sclerosis (MS) normal-appearing (NA) cortex and cortical lesions (CLs) and their relations with clinical phenotypes and disability using neurite orientation dispersion...

Experience in neuromuscular diseases in children and adolescents and their comorbidities in a tertiary hospital

IntroductionNeuromuscular diseases include a large group of heterogeneous and rare pathologies that affect different components of the motor unit. It is essential to optimize resources to know the prevalence of comorbidities in the most frequent groups to establish an early multidisciplinary approach in a specialized setting.Patients and methodsRetrospective descriptive study of pediatric and adolescent patients with neuromuscular diseases (NMDs). The Inclusion criteria were NMDs patients with motor neuron involvement divided into three groups, depending on the affected component of the motor unit. Group I: involvement of the motor neuron; Group II: peripheral neuropathies; Group III: myopathies. Demographic variables, association with comorbidities, need for respiratory support, and rehabilitative treatment were collected in each group.ResultsNinety-six patients who met the inclusion criteria were studied. In group I, when compared to the other two groups, a higher incidence of scoliosis (68.3%, p = 0.011), deformity of the rib cage (31.3%, p = 0.0001), chronic respiratory insufficiency (62.5%, p = 0.001) and bronchial aspiration (12.5%, p = 0.03) was detected. In this group, 50%of the patients required non-invasive mechanical ventilation (p = 0.0001). The in-hospital requirement for respiratory physiotherapy was higher in group I (75%, p = 0.001). We observed a higher incidence of scoliosis in Group III compared to Group II.ConclusionsNeuromuscular diseases with motor neuron involvement present more comorbidities and require an early approach after diagnosis to improve prognosis.

Clinical variants of chronic gastritis in childhood

Objective. To establish the features of various clinical variants of chronic gastritis in childhood.&#x0D; Material and methods. 415 children aged 617 years with chronic Hp-associated gastritis were examined. The clinical and anamnestic data, the results of laboratory, endoscopic and morphological studies of gastrobioptates were analyzed. Genetic typing of Hp was carried out with the determination of 16 pathogenicity factors. The persistence of human herpes viruses of types 6 and 8 and Epstein Barr viruses in the gastric mucosa was determined.&#x0D; Results. The clinical heterogeneity of chronic gastritis in children with the allocation of four topical variants was established: isolated duodenitis, duodenogastritis, antrum gastritis, pangastritis. It was found that with the first two, a high frequency of giardiasis is registered, with antrumgastritis and especially pangastritis, a significant contamination of the gastric mucosa with Hp is detected, mainly of CagA and VacA-positive strains. It is proved that the persistence of the type 6 human herpes virus does not affect the severity of inflammation, while the presence of the Epstein-Barr virus increases it. Colonization of the gastric mucosa by highly pathogenic Hp strains significantly increases the severity and activity of inflammation. It is shown that atrophy of the gastric mucosa in children is uncertain, and true atrophic gastritis occurs only in 0.61 % of cases.&#x0D; Conclusions. Chronic gastritis in children is a heterogeneous pathology, and its individual variants differ significantly in etiological factors including infectious, pathogenetic mechanisms and features of the morphology of gastric mucosa. This should be taken into account when carrying out medical support for patients.

Comparison of total and endometrial circulating cell-free DNA in women with and without endometriosis

Research questionDo women with laparoscopically confirmed endometriosis have higher plasma concentrations of circulating cell-free DNA (cirDNA) than those without endometriosis? DesignProspective study of women aged 18–45 years undergoing benign gynaecological laparoscopy at two tertiary hospitals. Venous blood was collected immediately before surgery, and women were allocated to the endometriosis or control groups based on surgical findings. Total plasma cirDNA and cirDNA integrity were measured by quantitative polymerase chain reaction (qPCR) targeting short (115 bases) and long (247 bases) ALU segments. Endometrial-derived cirDNA was measured by qPCR of bisulfite-treated cirDNA using primers selective for a FAM101A sequence uniquely unmethylated in endometrial tissue. Five cirDNA parameters were compared between the control and endometriosis cohorts: total cirDNA concentration, long-stranded cirDNA concentration, integrity ratio, endometrial cirDNA concentration and endometrial cirDNA proportion. ResultsTwenty-eight endometriosis and 15 control samples were included. Women with and without endometriosis had cirDNA concentrations of 2.24 ± 0.89 ng/ml and 2.56 ± 0.92 ng/ml, respectively. Analysis by phenotype of endometriosis revealed a significantly higher endometrial cirDNA concentration in women with superficial disease (n = 10) compared with deep endometriosis (n = 18) (mean difference 0.14 ng/ml; 95% CI 0.15 to 0.26; P = 0.025), but not with controls. ConclusionsNo significant differences were found in any of the cirDNA parameters between women with and without endometriosis. The low statistical power and heterogenous pelvic pathology in the control group render it difficult to determine whether the negative results reflect a true lack of increase in cirDNA in endometriosis.

Diabetes mellitus and cancer: a system of insulin-like growth factors

Diabetes mellitus and malignant tumors are among the most common and complex diseases. Epidemiological studies have shown a strong relationship between these pathologies. The causality of this relationship has not yet been unambiguously established, but a number of probable biological mechanisms have been proposed to explain it through the effects of hyperglycemia, hyperinsulinemia on the process of oncogenesis. An important role in this is played by the axis of insulin-like growth factors, their receptors and binding proteins (IGF / IGFR / IGFBP). The review provides data on the structural elements of the insulin / IGF / IGFR / IGFBP signaling axis and their internal relationships in diabetes mellitus and in the development of malignant tumors. Significant changes in the axis that occur during the formation of the diabetic environment prepare the background, which, under certain conditions, can lead to the stimulation or inhibition of tumor development. The considered signaling system, playing a significant role in the physiology of normal cells, often functions as a decisive factor in the survival of tumor cells, providing fine context-dependent regulation of many cellular processes associated with oncogenesis. However, despite many years of in-depth studies of the pathogenesis of diabetes mellitus and malignant tumors, the molecular mechanisms of the relationship between these pathologies are still largely unclear, and the internal heterogeneity of pathologies complicates research and interpretation of the results, leaving many questions.

Modeling Brain–Heart Crosstalk Information in Patients with Traumatic Brain Injury

BackgroundTraumatic brain injury (TBI) is an extremely heterogeneous and complex pathology that requires the integration of different physiological measurements for the optimal understanding and clinical management of patients. Information derived from intracranial pressure (ICP) monitoring can be coupled with information obtained from heart rate (HR) monitoring to assess the interplay between brain and heart. The goal of our study is to investigate events of simultaneous increases in HR and ICP and their relationship with patient mortality..MethodsIn our previous work, we introduced a novel measure of brain–heart interaction termed brain–heart crosstalks (ctnp), as well as two additional brain–heart crosstalks indicators [mutual information (mi_{ct}) and average edge overlap (ωct)] obtained through a complex network modeling of the brain–heart system. These measures are based on identification of simultaneous increase of HR and ICP. In this article, we investigated the relationship of these novel indicators with respect to mortality in a multicenter TBI cohort, as part of the Collaborative European Neurotrauma Effectiveness Research in TBI high-resolution work package.ResultsA total of 226 patients with TBI were included in this cohort. The data set included monitored parameters (ICP and HR), as well as laboratory, demographics, and clinical information. The number of detected brain–heart crosstalks varied (mean 58, standard deviation 57). The Kruskal–Wallis test comparing brain–heart crosstalks measures of survivors and nonsurvivors showed statistically significant differences between the two distributions (p values: 0.02 for mi_{ct}, 0.005 for ctnp and 0.006 for ωct). An inverse correlation was found, computed using the point biserial correlation technique, between the three new measures and mortality: − 0.13 for ctnp (p value 0.04), − 0.19 for ωct (p value 0.002969) and − 0.09 for mi_{ct} (p value 0.1396). The measures were then introduced into the logistic regression framework, along with a set of input predictors made of clinical, demographic, computed tomography (CT), and lab variables. The prediction models were obtained by dividing the original cohort into four age groups (16–29, 30–49, 50–65, and 65–85 years of age) to properly treat with the age confounding factor. The best performing models were for age groups 16–29, 50–65, and 65–85, with the deviance of ratio explaining more than 80% in all the three cases. The presence of an inverse relationship between brain–heart crosstalks and mortality was also confirmed.ConclusionsThe presence of a negative relationship between mortality and brain–heart crosstalks indicators suggests that a healthy brain–cardiovascular interaction plays a role in TBI.

Renal Cell Carcinoma in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which renal manifestations are prominent. There are three major renal lesions in TSC: angiomyolipomas, cysts, and renal cell carcinoma (RCC). Major recent advances have revolutionized our understanding of TSC-associated RCC, including two series that together include more than 100 TSC-RCC cases, demonstrating a mean age at onset of about 36 years, tumors in children as young as 7, and a striking 2:1 female predominance. These series also provide the first detailed understanding of the pathologic features of these distinctive tumors, which include chromophobe-like features and eosinophilia, with some of the tumors unclassified. This pathologic heterogeneity is distinctive and reminiscent of the pathologic heterogeneity in Birt–Hogg–Dube-associated RCC, which also includes chromophobe-like tumors. Additional advances include the identification of sporadic counterpart tumors that carry somatic TSC1/TSC2/mTOR mutations. These include unclassified eosinophilic tumors, eosinophilic solid cystic RCC (ESC-RCC), and RCC with leiomyomatous stroma (RCCLMS). A variety of epithelial renal neoplasms have been identified both in patients with tuberous sclerosis complex (TSC) and in the nonsyndromic setting associated with somatic mutations in the TSC1 and TSC2 genes. Interestingly, whether tumors are related to a germline or somatic TSC1/2 mutation, these tumors often display similar morphologic and immunophenotypic features. Finally, recent work has identified molecular links between TSC and BHD-associated tumors, involving the TFEB/TFE3 transcription factors.

PULMONARY SARCOMATOID CARCINOMA: A CASE REPORT AND REVIEW OF LITERATURE

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary sarcomatoid carcinomas are a rare subtype of poorly differentiated non-small cell lung cancer that accounts for less than 1 percent of primary lung malignancies. This case highlights the clinical presentation & diagnostic evaluation undertaken to identify this rare lung cancer. CASE PRESENTATION: A 77-year-old male with a medical history of tobacco abuse, hypertension & mutism was evaluated for pleuritic chest pain, cough and subjective fevers. Initial vitals were stable and pulmonary examination revealed focal expiratory wheezes auscultated on the right anterior chest with a prolonged expiratory phase throughout. CXR demonstrated a mass-like opacity in the inferior right hilum and the patient was treated with antibiotics for presumed community-acquired pneumonia. Chest CT was obtained due to persistent symptoms which showed a right hilar mass encasing the right pulmonary artery with calcific mediastinal lymphadenopathy. Bronchoscopy with endobronchial ultrasound was performed and samples for cytology were taken from the culprit endobronchial lesion. Lymph node surveillance revealed enlarged left paratracheal, right paratracheal & right hilar lymph nodes from which FNA samples were taken, respectively. Rapid onsite pathological evaluation demonstrated the presence of atypical cells and ultimately revealed sarcomatoid carcinoma. Oncology, radiation oncology, and palliative care were consulted. After a lengthy discussion concerning the treatment options, the patient & family elected to transition to comfort care. The patient was discharged home with hospice. DISCUSSION: Pulmonary sarcomatoid carcinoma is a rare non-small cell carcinoma accounting for approximately 0.1-0.4% of all primary pulmonary malignancies. The disease has a predilection for older males with a prolonged smoking history. Morphologically, sarcomatoid carcinoma is a heterogeneous group of neoplasms that originate from epithelial & mesenchymal tissue containing intermingled elements of carcinoma & sarcoma. There are five recognized subtypes: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma & pulmonary blastoma. Given the immense histological variability, a pathologic diagnosis frequently requires a generous tissue sample and can often pose a diagnostic challenge. The clinical course is aggressive with early metastasis rendering the overall prognosis is poor despite therapy. Surgical resection offers the best therapeutic option in early disease and remains the standard of care. Targeted therapies & immunotherapy remain a promising option, but additional research & clinical experience is needed in this patient population. CONCLUSIONS: This case highlights the clinical presentation & diagnostic evaluation undertaken to identify sarcomatoid carcinoma, a rare and aggressive lung cancer with heterogeneous pathology & limited response to traditional therapy. REFERENCE #1: Rajdev K, Siddiqui AH, Ibrahim U, Agarwal S, Ding J, Chalhoub M. Sarcomatoid Carcinoma of the Lung Presenting as Localized Bronchiectasis: A Case Report and Review of Literature. Respir Med Case Rep. 2018;24:143-146. Published 2018 May 17. doi:10.1016/j.rmcr.2018.05.016 REFERENCE #2: Shen XY, Lin ZF, Lin Q, et al. Pulmonary sarcomatoid carcinoma: a case report. Contemp Oncol (Pozn). 2013;17(2):210-213. doi:10.5114/wo.2013.34375 DISCLOSURES: No relevant relationships by Kari McCoy, source=Web Response No relevant relationships by Caroline Mears, source=Web Response No relevant relationships by Xian Qiao, source=Web Response

Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease.

The evident genetic, pathological, and clinical heterogeneity of Alzheimer's disease (AD) poses challenges for traditional drug development. We conducted a computational drug repurposing screen for drugs to treat apolipoprotein (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Aβ accumulation rescued electrophysiological, pathological, or cognitive deficits. Single-nucleus RNA-sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in apoE4-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.

Challenges for the Applications of Human Pluripotent Stem Cell-Derived Liver Organoids.

The current organoid culture systems allow pluripotent and adult stem cells to self-organize to form three-dimensional (3D) structures that provide a faithful recapitulation of the architecture and function of in vivo organs. In particular, human pluripotent stem cell-derived liver organoids (PSC-LOs) can be used in regenerative medicine and preclinical applications, such as disease modeling and drug discovery. New bioengineering tools, such as microfluidics, biomaterial scaffolds, and 3D bioprinting, are combined with organoid technologies to increase the efficiency of hepatic differentiation and enhance the functional maturity of human PSC-LOs by precise control of cellular microenvironment. Long-term stabilization of hepatocellular functions of in vitro liver organoids requires the combination of hepatic endodermal, endothelial, and mesenchymal cells. To improve the biological function and scalability of human PSC-LOs, bioengineering methods have been used to identify diverse and zonal hepatocyte populations in liver organoids for capturing heterogeneous pathologies. Therefore, constructing engineered liver organoids generated from human PSCs will be an extremely versatile tool in in vitro disease models and regenerative medicine in future. In this review, we aim to discuss the recent advances in bioengineering technologies in liver organoid culture systems that provide a timely and necessary study to model disease pathology and support drug discovery in vitro and to generate cell therapy products for transplantation.

Clinical Symptomatology and Laboratory Diagnosis of Nonalcoholic Chronic Fatty Liver Disease

Background: One of the leading causes for hepatocellular carcinoma is Nonalcoholic fatty liver diseases (NAFLD) that also increases incidence of mortality rates. Aim: To understand alterations biochemically and clinically in patients suffering from NAFLD since they are at stake of cirrhosis as well as nonalcoholic steatohepatitis (NASH) in case of Pakistani population. Methods: Patients suffering from NAFLD were selected for these case reaches that were all confirmed via ultrasonography. Candidates were tested negative for autoimmune or viral hepatitis serologic markers, no record was found with respect to liver disease related to metabolism, moreover candidates were also not administer any medication that has its impact on liver like Ursobil. Clinically and biochemically all the patients were tested for history, signs and symptoms and they depicted variables. Results: A enrollment of 80 candidates was carried out that included 38 female and 42 male, owing mean age of 40.4 years. The candidates with no diabetes and obesity were 26.4% and 18.3%, respectively. Late dinner sleep disorders and delayed sleep were the most detectable reasons in patients suffering from NAFLD. Moreover, thirst sensation, anxiety, bloating, and upper abdominal pain, warming sensation and defecation disturbances, were seen common in case of patients suffering from NAFLD. Conclusion: NAFLD is regarded as heterogeneous pathology with variety of clinical findings. It has been experienced that gastrointestinal problems as well as anxiety are most frequently seen in patients suffering from NAFLD. Keywords: NAFLD, hepatocellular carcinoma, cirrhosis

Multiplexed DNA-Directed Patterning of Antibodies for Applications in Cell Subpopulation Analysis

Antibodies provide the functional biospecificity that has enabled the development of sensors, diagnostic tools, and assays in both laboratory and clinical settings. However, as multimarker screening becomes increasingly necessary due to the heterogeneity and complexity of human pathology, new methods must be developed that are capable of coordinating the precise assembly of multiple, distinct antibodies. To address this technological challenge, we engineered a bottom-up, high-throughput method in which DNA patterns, comprising unique 20-base pair oligonucleotides, are patterned onto a substrate using photolithography. These microfabricated surface patterns are programmed to hybridize with, and instruct the multiplexed assembly of, antibodies conjugated with the complementary DNA strands. We demonstrate that this simple, yet robust, approach preserves the antibody-binding functionality in two common applications: antibody-based cell capture and label-free surface marker screening. Using a simple proof-of-concept capture device, we achieved high purity separation of a breast cancer cell line, MCF-7, from a blood cell line, Jurkat, with capture purities of 77.4% and 96.6% when using antibodies specific for the respective cell types. We also show that antigen-antibody interactions slow cell trajectories in flow in the next-generation microfluidic node-pore sensing (NPS) device, enabling the differentiation of MCF-7 and Jurkat cells based on EpCAM surface-marker expression. Finally, we use a next-generation NPS device patterned with antibodies against E-cadherin, N-cadherin, and β-integrin-three markers that are associated with epithelial-mesenchymal transitions-to perform label-free surface marker screening of MCF10A, MCF-7, and Hs 578T breast epithelial cells. Our high-throughput, highly versatile technique enables rapid development of customized, antibody-based assays across a host of diverse diseases and research thrusts.