Period Of Latency Research Articles

Urachal adenocarcinoma

Cancer of the urachus is very unusual. The lesion is a mucosecretory adenocarcinoma. The diagnosis is usually established late, and has a serious prognosis because of a long clinical latency. We report a case of metastatic adenocarcinoma of the urachus revealed by hematuria. A review of the literature allows us to demonstrate the rarity of this tumour and to demonstrate its various clinical, histological, radiological and therapeutical aspects.

Pulmonary tuberculosis with rhinosinusal and otic manifestations - diagnostic challenge

Abstract BACKGROUND. Unfortunately, tuberculosis is still being diagnosed among patients, independent of their age, gender, provenance or social category. The etiologic agent of tuberculosis is Mycobacterium tuberculosis, which is known to have a period of latency between the initial infection and the clinical manifestation. The most common localization is pulmonary, but it can affect, secondarily, other organs, especially in the ENT regions, mimicking other systemic diseases. MATERIAL AND METHODS. We are presenting a case of a 51-year-old female patient, who was referred to our ENT Clinic with the suspicion of Behcet’s disease with rhinosinusal manifestations. She had a pulmonary assessment in another hospital, as she was known with left lung bronchiectasis, but the sputum samples were negative. The clinical otorhinolaryngologic examination together with the rheumato-logical assessment and the result of the nasal mucosa biopsy were suggestive for Behcet’s disease and the patient received 6 weeks of Prednisolone. The specific immunologic tests (cANCA, pANCA, HLA B51) were negative. The patient returned to our clinic after 2 months, accusing symptomatology reacutization with right otorrhea and bilateral hearing loss aggravation. Nasal and rhinopharyngeal mucosa biopsies were repeated and the anatomopathological result was specific for tuberculosis. RESULTS. She was referred to the Pneumology Service where she received the diagnosis of pulmonary tuberculosis with rhinosinusal and otic manifestations. Currently, the patient is under tuberculostatic treatment. CONCLUSION. Extrapulmonary tuberculosis symptoms might be confused with other systemic diseases with rhinosinusal manifestations. Thorough examination and multidisciplinary approach are mandatory in order to establish a correct diagnosis followed by an appropriate treatment.

Exosome-encapsulated microRNAs as promising biomarkers for Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease that locks into long clinical latency and low curative ratio. Therefore, early diagnosis before the clinical phase is quite essential and may be effective for therapeutic prevention. Peripheral blood or cerebrospinal fluid biomarkers symbolizing functional neuronal impairment are gradually applied to diagnose AD in research studies. Exosomes have generated immense interest in the diagnosis field of neurodegenerative disorders after confirmation of their roles as mediators, delivering important proteins and microRNAs (miRNAs) in intercellular communication. Compelling research results reveal that miRNAs released from exosomes modulate expression and function of amyloid precursor proteins and tau proteins. These findings open up possibility that dysfunctional exosomal miRNAs may influence AD progression. In this review, we summarized the existing knowledge of exosomal miRNAs and their involvement in AD, emphasizing their potential to serve as diagnostic biomarkers during the preclinical phase of AD.

Abstract LB-312: Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency

Abstract While thousands of breast cancer cells disseminate and home to bone marrow (BM) until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. Signals and mechanisms determining failure or success of disseminated cancer cells (DCCs) are largely unknown and there is no in vivo model available to study the spontaneous progression and genomic evolution from early bone marrow infiltration to manifestation of bone metastasis, as spontaneous or transgenic mouse models do not generate bone metastases. We therefore profiled DCCs from BM of breast cancer patients long before manifestation of metastasis by RNAseq to identify signals supporting survival or outgrowth of DCCs and identified IL6/PTEN/PI3K signaling as candidate pathway for DCC activation. Since early DCCs often display close-to-normal genomes we used mammary epithelial cells ex vivo isolated from reduction mammoplasties and immortalized pre-malignant breast cancer cell lines as model for functional testing in vitro. Using specific activators and inhibitors of IL6 signaling revealed that IL6 trans, but not classical signaling, regulates stemness of mammary epithelial cells. Moreover, knock-down of PTEN revealed that PI3K/PTEN pathway activation renders cells independent of IL6 trans-signaling. Interestingly, gp130 expression, a pre-requisite for IL6 trans-signaling was found to be down-regulated by bone marrow stromal and endosteal, but not vascular niche cells, and as a consequence the number of cells with stem-like ability was significantly reduced. Consistent with a bottleneck function of microenvironmental DCC control, we found PIK3CA mutations highly associated with late-stage metastatic DCCs and CTCs while generally absent in early DCCs. Our data suggest that the initial steps of metastasis formation depend on microenvironmental signals and are not cancer cell-autonomous. Citation Format: Melanie Werner-Klein, Ana Grujovic, Milan Obradovic, Martin Hoffmann, Xin Lu, Stefan Kirsch, Steffi Treitschke, Cäcilia Köstler, Kathrin Weidele, Christoph Irlbeck, Catherine Botteron, Christian Werno, Bernhard Polzer, Miodrag Guzvic, Stefan Buchholz, Petra Rümmele, Norbert Heine, Stefan Rose-John, Christoph A. Klein. Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-312.

Vitis Methods to Understand and Develop Strategies for Diagnosis and Sustainable Control of Grapevine Trunk Diseases.

Vitis vinifera is affected by many diseases every year, depending on causal agents, susceptibility of cultivars, and climate region. Some are caused by a single agent, such as gray mold caused by Botrytis cinerea or powdery mildew caused by Erysiphe necator. Others result from the actions of a complex of pathogens such as grapevine trunk diseases (GTDs). GTDs are presently among the most devastating diseases in viticulture worldwide because both the economic losses and the long-term sustainability of vineyards are strongly affected. The complexity of GTDs results from the diversity of associated fungi, the undetermined period of latency within the vine (asymptomatic status), the erratic foliar symptom expression from one year to the next, and, probably correlated with all of these points, the lack of efficient strategies to control them. Distinct methods can be beneficial to improve our knowledge of GTDs. In vitro bioassays with cell suspensions, calli, foliar discs, full leaves, or plantlets, and in vivo natural bioassays with cuttings, grafted plants in the greenhouse, or artificially infected ones in the vineyard, can be applied by using progressive integrative levels of in vitro and in vivo, depending on the information searched. In this review, the methods available to understand GTDs are described in terms of experimental procedures, main obtained results, and deliverable prospects. The advantages and disadvantages of each model are also discussed.

Are Longer Periods of Latency After the Diagnosis of Preeclampsia Associated With Readmission? [31G

INTRODUCTION: To determine if longer periods of latency after the diagnosis of preeclampsia with severe features is associated with postpartum readmission or complications. METHODS: This was a nested case control study of all patients with severe preeclampsia at an academic medical center from 2014 until 2017. The primary outcome was readmission within six weeks of discharge. The primary exposure was pregnancy latency after the diagnosis of preeclampsia with severe features until delivery. Secondary exposures were the differing severe features or complications of preeclampsia which the patients were diagnosed with during their antepartum admission. Controls were randomly selected from the patients who had been diagnosed with preeclampsia with severe features in a 2:1 ratio. Median latency, baseline characteristics, severe features, and complications of preeclampsia were compared between patients who were readmitted and those who were not. RESULTS: Of the 18,645 deliveries over this time period, 950 were complicated by preeclampsia with severe features. Of these deliveries, 39 were readmitted. The median gestational age on admission was 37 weeks and one day. Contrary to our hypothesis, readmission was more likely with shorter latencies (mean rank 65 vs 45, p<0.01). Pregestational diabetes was a risk factor for readmission (OR 3.2, p=0.04); Antepartum headache (OR 0.36, p=0.02), parenteral antihypertensives (OR .30, p<0.01), oral antihypertensives (OR 0.25, p<0.01), antepartum magnesium sulfate (OR 0.07, p<0.01) during the initial admission were protective. CONCLUSION: Analyzing the factors that contribute to readmission in preeclamptic patients allow us to be cognizant of factors that may lead to increased maternal morbidity and mortality.

AVALIAÇÃO DO EFEITO DA SALINIDADE NA CINÉTICA DE DESOXIGENAÇÃO NO ENSAIO DA DBO

A demanda bioquímica de oxigênio (DBO) é um parâmetro típico utilizado para avaliar a poluição de águas superficiais. Sua determinação está baseada no consumo de oxigênio durante a biodegradação aeróbia de compostos orgânicos. O objetivo deste trabalho foi avaliar a influência da salinidade na redução do coeficiente de desoxigenação (k) no ensaio de DBO e as consequências para uma análise de DBO5. Os resultados mostraram que a presença de salinidade afetou os resultados de DBO de forma mais significativa durante o período de latência. O método Mínimos Quadrados mostrou-se o mais eficiente para a obtenção dos parâmetros k e L0. A adição de 15 g·L-1 de NaCl, para simular o efeito da salinidade sobre a amostra, reduziu o coeficiente k em 41,7 % e a DBO5 em 26 %. Logo, a salinidade foi um interferente no ensaio, subestimando o resultado da DBO5, devendo ser considerada em análises de amostras oriundas de ambientes expostos a variações na salinidade.

Allopurinol-induced DRESS syndrome in the elderly: an exceptional form of iatrogenesis

Introduction The Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a very rare iatrogenic accident that is characterized by its difficult diagnosis due to its clinical latency and heterogeneous clinic. The form induced by allopurinol remains exceptional and often ignored by clinicians, although potentially fatal. We are reporting an original observation of allopurinol-induced DRESS syndrome in elderly. Observation A 64-year-old woman who had been treated with allopurinol for gout for three weeks, was hospitalized for a diffuse, erythematous and maculopapular cutaneous rash, associated with fever at 39°C, dyspnea, generalized lymphadenopathy, and a hyperkeratotic and desquamative plantar eruption. The biology showed eosinophilia at 860/mm3 and cytolitic hepatitis without cholestasis or hepatocellular insufficiency with ASAT at 230 IU/l and alanine aminotransferase ( ALAT) at 280 IU/l. The infectious, immunological investigation, as well as the search for underlying malignant neoplasia or hematological malignancy were negative. The skin biopsy was inconclusive. The diagnosis of a DRESS syndrome induced by allopurinol was retained. The evolution was rapidly favorable after stopping allopurinol and treatment with systemic glucocorticoids. Conclusion The incidence of cutaneous reactions to allopurinol is estimated at 1.5/100,000 H/year. The DRESS syndrome, the most serious form of these reactions, remains exceptional. This particular form of toxicity deserves to be known by clinicians, especially since allopurinol is widely prescribed in the elderly.

AXL Is a Putative Tumor Suppressor and Dormancy Regulator in Prostate Cancer.

Prostate cancer bone metastasis remains lethal and incurable, and often arises years after elimination of the primary tumor. It is unclear what underlies the decades-long clinical latency before recurrence, but evidence points to the existence of dormant residual tumor cells that disseminated before the primary tumor was eliminated. To design therapies to prevent progression of disseminated tumor cells (DTC) into lethal metastases, it is crucial to understand the mechanism(s) underlying this dormancy. The current study functionally validated our previous observation that implicated the GAS6/AXL axis in mediating DTC dormancy in the bone marrow. AXL-null and AXL-overexpressing prostate cancer cell lines were generated to determine if AXL was necessary and/or sufficient for dormancy. Characterization of these cells in vitro and using in vivo mouse models of DTC growth demonstrated that AXL was indeed sufficient to induce dormancy, but was unable to maintain it long-term and was not absolutely required for a dormancy period. Clinically, AXL expression correlated with longer survival in prostate cancer patients, and AXL was not expressed by cancer cells in primary or metastatic tissue. These data point to a tumor-suppressive role for AXL in prostate cancer, and future work is required to determine if AXL is expressed on human bone marrow DTCs. IMPLICATIONS: The ability of AXL to initiate but not maintain dormancy, coupled with its dispensability, suggests that targeting AXL alone will not prevent lethal metastatic outgrowth, and likely a cooperative network of factors exists to mediate long-term cellular dormancy.

Novel Mechanism for Surface Layer Shedding and Regenerating in Bacteria Exposed to Metal-Contaminated Conditions.

Surface layers (S-layers) are components of the cell walls throughout the Bacteria and the Archaea that provide protection for microorganisms against diverse environmental stresses, including metal stress. We have previously characterized the process by which S-layers serve as a nucleation site for metal mineralization in an archaeon for which the S-layer represents the only cell wall component. Here, we test the hypothesis originally proposed in cyanobacteria that a “shedding” mechanism exists for replacing S-layers that have become mineral-encrusted, using Lysinibacillus sp. TchIII 20n38, metallotolerant gram-positive bacterium, as a model organism. We characterize for the first time a mechanism for resistance to metals through S-layer shedding and regeneration. S-layers nucleate the formation of Fe-mineral on the cell surface, depending on physiological state of the cells and metal exposure times, leading to the encrustation of the S-layer and changes in the cell morphology as observed by scanning electron microscopy. Using Nanoscale Secondary Ion Mass Spectrometry, we show that mineral-encrusted S-layers are shed by the bacterial cells after a period of latency (2 days under the conditions tested) in a heterogeneous fashion likely reflecting natural variations in metal stress resistance. The emerging cells regenerate new S-layers as part of their cell wall structure. Given the wide diversity of S-layer bearing prokaryotes, S-layer shedding may represent an important mechanism for microbial survival in metal-contaminated environments.

Clinic Pathological Study of an Eccrine Spiradenoma

Eccrine Spiradenoma (ES) is an exceedingly rare sweat-gland tumor, it usually presents as a solitary lesion and painful nodule. ES is a kind of neoplasm with distinct histological characteristics and nonspecific clinical manifestations. Most ES cases have a benign course; however, malignant transformation would occur after a long period of latency. The diagnosis mostly depends on the clinic symptom, histological features and immunohistochemistry. Here, we report a case of ES and literature review. The aim of this study is to understand clinic and histological features for ES.

Absence of FLT3 mutations in Iranian adult T-cell leukemia/lymphoma patients.

Background: Adult T cell leukemia lymphoma (ATLL) is a rare disease, significantly linked to the infection by the human T-cell lymphotropic virus 1(HTLV-1). ATLL is typically preceded by decades of clinical latency during which infected cells accumulate selectable traits leading to a malignant transformation. Amongst all the HTLV-1 infected carriers only about 3-5% will develop ATLL. Despite the intensive attempt to improve the overall survival, ATLL remains one of worse prognosis among the hematologic malignancies. FMS like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are mutations which are frequent among leukemic patients. We aimed to investigate the frequency of FLT3 mutation status in patients with acute type of ATLL which has not been studied yet. Methods: In this case control study 38 patients with acute type of ATLL were retrospectively analyzed between February 2015 and February 2017. Forty HTLV-1 positive patients were also used as control cases. Genomic DNA was extracted according to phenolchloroform protocol and two restriction fragment length polymorphism (RFLP) PCR reactions were set up to detect FLT3/ ITD and FLT3/TKD mutations. Differences between variables were evaluated by the chi-square test and t test for categorical and continuous variables, respectively. SPSS software v. 15 was used for statistical analysis. All P values were two sided and values less than 0.05 were considered to be significant. Results: No FLT3 mutations were detected in acute type of ATLL patients. So far, not many studies have shown the frequency of FLT3 mutation in ATLL patients Conclusion: Therefore, we conclude that although FLT3 mutations are rather unusual in the acute type of ATLL patients, but other alternative mechanisms associated with ATLL remain to be further investigated. This study was a novel project regarding the analysis of FLT3 mutation in the field of ATLL research.

Intravenous Immunoglobulin Therapy Administered Early after Narcolepsy Type 1 Onset in Three Patients Evaluated by Clinical and Polysomnographic Follow-Up

Narcolepsy type 1 is a rare disabling sleep disorder mainly characterized by excessive daytime sleepiness and cataplexy, an emotion-triggered sudden loss of muscle tone. Patients have a selective degeneration of hypocretin-producing neurons in the dorsolateral posterior hypothalamus with growing evidence supporting the hypothesis of an autoimmune mechanism. Few case studies that reported intravenous immunoglobulin therapy (IVIg) suggest the efficacy of IVIg when administered early after disease onset, but the results are controversial. In these retrospective case observations, IVIg cycles were initiated within one to four months after cataplexy onset in a twenty-seven-year-old man, a ten-year-old girl, and a seven-year-old boy, all three with early onset typical narcolepsy type 1. Efficacy of treatment (three IVIg cycles of 1 g/kg administered at four-week intervals) was evaluated based on clinical, polysomnographic, and multiple sleep latency test (mean latency and SOREM) follow-up. Two patients reported decreased cataplexy frequency and ameliorated daytime sleepiness, but no significant amelioration of polysomnographic parameters was observed. Given the possibility of spontaneous improvement of cataplexy frequency with self-behavioral adjustments, these observations would need to be confirmed by larger controlled studies. Based on the present study and current literature, proof of concept is still missing thus prohibiting the consideration of IVIg as an efficient treatment option.

Technical Note: Characterization of clinical linear accelerator triggering latency for motion management system development

Latencies for motion management systems have previously been presented as guidelines for system development and implementation. These guidelines consider the overall system latency, including data acquisition, algorithm processing, and linac triggering time. However, during system development, the triggering latency of the clinical linear accelerator is often considered fixed. This paper presents a method to decouple the linac-only triggering latency from the total system latency such that latency can be considered in terms of only the linac-independent aspects of the system. The linac-only latency was investigated by considering the time at which a linac response was observed relative to the time at which a beam-on/off triggering signal was sent to the linac. The relative time between the two signals was analyzed using a multichannel oscilloscope with input signals from a custom gating box to manually trigger the beam state as well as a diode positioned at beam isocenter to monitor the linac response. The beam-on/off latency was measured at multiple energies (6/18 MV) and repetition rates (100-600 MU/min) to investigate beam setting dependencies. The measured latency was observed to be dependent on the accelerator settings for repetition rate and energy, with beam-on latencies decreasing with increasing repetition rate and decreasing energy. In contrast, the opposite trend was present for the observed beam-off latency. At 600 MU/min, beam-on/off latencies were observed to be 3.37/1.45 ms for a 6 MV beam and 6.02/0.73 ms for an 18 MV beam. Negative latencies were possible for beam-off measurements due to the mechanical latency being less than the pulse separation at given repetition rates. The linac latency associated with triggering the beam-on/off was determined to have a minor contribution to the total allowable system latency; thus, the majority of the total system latency can be attributed to linac-independent factors.

DeepHINT: understanding HIV-1 integration via deep learning with attention.

Human immunodeficiency virus type 1 (HIV-1) genome integration is closely related to clinical latency and viral rebound. In addition to human DNA sequences that directly interact with the integration machinery, the selection of HIV integration sites has also been shown to depend on the heterogeneous genomic context around a large region, which greatly hinders the prediction and mechanistic studies of HIV integration. We have developed an attention-based deep learning framework, named DeepHINT, to simultaneously provide accurate prediction of HIV integration sites and mechanistic explanations of the detected sites. Extensive tests on a high-density HIV integration site dataset showed that DeepHINT can outperform conventional modeling strategies by automatically learning the genomic context of HIV integration from primary DNA sequence alone or together with epigenetic information. Systematic analyses on diverse known factors of HIV integration further validated the biological relevance of the prediction results. More importantly, in-depth analyses of the attention values output by DeepHINT revealed intriguing mechanistic implications in the selection of HIV integration sites, including potential roles of several DNA-binding proteins. These results established DeepHINT as an effective and explainable deep learning framework for the prediction and mechanistic study of HIV integration. DeepHINT is available as an open-source software and can be downloaded from https://github.com/nonnerdling/DeepHINT. Supplementary data are available at Bioinformatics online.

Targeting USP7 Identifies a Metastasis-Competent State within Bone Marrow–Resident Melanoma CTCs

Systemic metastasis is the major cause of death from melanoma, the most lethal form of skin cancer. Although most patients with melanoma exhibit a substantial gap between onset of primary and metastatic tumors, signaling mechanisms implicated in the period of metastatic latency remain unclear. We hypothesized that melanoma circulating tumor cells (CTC) home to and reside in the bone marrow during the asymptomatic phase of disease progression. Using a strategy to deplete normal cell lineages (Lin-), we isolated CTC-enriched cell populations from the blood of patients with metastatic melanoma, verified by the presence of putative CTCs characterized by melanoma-specific biomarkers and upregulated gene transcripts involved in cell survival and prodevelopment functions. Implantation of Lin- population in NSG mice (CTC-derived xenografts, i.e., CDX), and subsequent transcriptomic analysis of ex vivo bone marrow-resident tumor cells (BMRTC) versus CTC identified protein ubiquitination as a significant regulatory pathway of BMRTC signaling. Selective inhibition of USP7, a key deubiquinating enzyme, arrested BMRTCs in bone marrow locales and decreased systemic micrometastasis. This study provides first-time evidence that the asymptomatic progression of metastatic melanoma can be recapitulated in vivo using patient-isolated CTCs. Furthermore, these results suggest that USP7 inhibitors warrant further investigation as a strategy to prevent progression to overt clinical metastasis.Significance: These findings provide insights into mechanism of melanoma recurrence and propose a novel approach to inhibit systematic metastatic disease by targeting bone marrow-resident tumor cells through pharmacological inhibition of USP7.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/18/5349/F1.large.jpg Cancer Res; 78(18); 5349-62. ©2018 AACR.

Aliivibrio salmonicida requires O-antigen for virulence in Atlantic salmon (Salmo salar L.)

Aliivibrio salmonicida is the causative agent of cold-water vibriosis, a hemorrhagic septicemia of salmonid fish. The bacterium has been shown to rapidly enter the fish bloodstream, and proliferation in blood is seen after a period of latency. Although the pathogenesis of the disease is largely unknown, shedding of high quantities of outer-membrane complex VS-P1, consisting of LPS and a protein moiety, has been suggested to act as decoy and contribute to immunomodulation. To investigate the role of LPS in the pathogenesis, we constructed O-antigen deficient mutants by knocking out the gene encoding O-antigen ligase waaL. As this gene exists in two copies in the Al. salmonicida genome, we constructed single and double in-frame deletion mutants to explore potential effects of copy number variation. Our results demonstrate that the LPS structure of Al. salmonicida is essential for virulence in Atlantic salmon. As the loss of O-antigen did not influence invasive properties of the bacterium, the role of LPS in virulence applies to later stages of the pathogenesis. One copy of waaL was sufficient for O-antigen ligation and virulence in experimental models. However, as a non-significant decrease in mortality was observed after immersion challenge with a waaL single mutant, it is tempting to suggest that multiple copies of the gene are beneficial to the bacterium at lower challenge doses. The loss of O-antigen was not found to affect serum survival in vitro, but quantification of bacteria in blood following immersion challenge suggested a role in in vivo survival. Furthermore, fish challenged with the waaL double mutant induced a more transient immune response than fish challenged with the wild type strain. Whether the reduction in virulence following the loss of waaL is caused by altered immunomodulative properties or impaired survival remains unclear. However, our data demonstrate that LPS is crucial for development of disease.

Abstract A41: Ovarian cancer as an infectious disease. Targeting of mitochondrial activity to prevent and treat recurrent ovarian cancer

Abstract Targeting of the mechanisms responsible for ovarian cancer recurrence and chemoresistance serves the two most pressing needs for the clinical management of this disease: prevent recurrence in women who are in remission and provide effective treatment for patients who have recurred (1). Ovarian cancer recurrence is due to the presence of a relatively small population of cancer cells (floating in the abdominal cavity as spheroids and circulating in the bloodstream) that were not removed during surgery and was able to survive chemotherapy treatment (2-4). These cells, after a period of latency, grow back and cause recurrent and chemoresistant ovarian cancer. Recent evidences suggest that spheroids’ and cancer cells’ resistance to conventional chemotherapy is due to their ability to increase mitochondrial respiration as a way to survive the highly hostile tumor microenvironment caused by chemotherapy and hypoxia (5-9). To prevent recurrence and to treat chemoresistance we need to: 1) find the “Achille’s heel” of the small population of cancer cells that are capable of escaping chemotherapy and kill them, and 2) use therapeutic strategies that are already FDA approved because their known toxicology and pharmacology makes them ideal repurposed drugs rapidly implementable in the clinics. We propose that: a) ovarian cancer spheroids and chemoresistant metastasis share the unique Achille’s heel of having high dependency upon mitochondrial activity, b) targeting of mitochondrial activity leads to effective killing of ovarian cancer cells in spheroids and in chemoresistant metastasis with no toxicity on normal cells, and c) the FDA-approved antimitochondrial antibiotics inhibit cancer cells’ mitochondrial activity and can safely and effectively be used to prevent ovarian cancer recurrence and to treat chemoresistance (10, 11). This research is clinically relevant in that antimitochondrial antibiotics can be quickly implemented in the clinic as a mantainance therapy for women in remission and as a combination therapy for patients with recurrent and chemoresistant ovarian cancer. Of note, several antimitochondrial antibiotics have long half-life, are well tolerated, and are affordable, rendering them the ideal repurposed drug.

Sulfur dioxide exposure reduces the quantity of CD19+ cells and causes nasal epithelial injury in rats

BackgroundReactive airway dysfunction syndrome (RADS), also called irritant-induced asthma, is a type of occupational asthma that can occur within a very short period of latency. The study sought to investigate the influence of sulfur dioxide (SO2) exposure on CD19+ cells and nasal epithelial injury.MethodsWe investigated the effects of SO2 on CD19 expression and morphological changes of nasal epithelia in rats. In the study, 20 rats were randomly divided into the SO2 exposure group that were exposed to 600 ppm SO2, 2 h/day for consecutive 7 days, and the control group that were exposed to filtered air).ResultsInhalation of high concentration of SO2significantly reduced CD19 expression at both the mRNA transcript and protein levels, and reduced the percentages of CD19+ cells and CD19+/CD23+ cells in the nasal septum. However, inhalation of high concentration of SO2 did not affect immunoglobulin (Ig) G, IgA and IgE levels in the serum and nasal septum. More importantly, SO2 exposure also caused mild structural changes of the nasal septum.ConclusionOur results reveal that inhalation of a high concentration of SO2 reduces CD19 expression and causes structural change of the nasal septum in rats.

Understanding the role of interactions between host and Mycobacterium tuberculosis under hypoxic condition: an in silico approach

BackgroundMycobacterium tuberculosis infection in humans is often associated with extended period of latency. To adapt to the hostile hypoxic environment inside a macrophage, M. tuberculosis cells undergo several physiological and metabolic changes. Previous studies have mostly focused on inspecting individual facets of this complex process. In order to gain deeper insights into the infection process and to understand the coordination among different regulatory/ metabolic pathways in the pathogen, the current in silico study investigates three aspects, namely, (i) host-pathogen interactions (HPIs) between human and M. tuberculosis proteins, (ii) gene regulatory network pertaining to adaptation of M. tuberculosis to hypoxia and (iii) alterations in M. tuberculosis metabolism under hypoxic condition. Subsequently, cross-talks between these components have been probed to evaluate possible gene-regulatory events as well as HPIs which are likely to drive metabolic changes during pathogen’s adaptation to the intra-host hypoxic environment.ResultsThe newly identified HPIs suggest the pathogen’s ability to subvert host mediated reactive oxygen intermediates/ reactive nitrogen intermediates (ROI/ RNI) stress as well as their potential role in modulating host cell cycle and cytoskeleton structure. The results also indicate a significantly pronounced effect of HPIs on hypoxic metabolism of M. tuberculosis. Findings from the current study underscore the necessity of investigating the infection process from a systems-level perspective incorporating different facets of intra-cellular survival of the pathogen.ConclusionsThe comprehensive host-pathogen interaction network, a Boolean model of M. tuberculosis H37Rv (Mtb) hypoxic gene-regulation, as well as a genome scale metabolic model of Mtb, built for this study are expected to be useful resources for future studies on tuberculosis infection.