Spontaneous Relapse Research Articles

Alopecia Areata: The Clinician and Patient Voice.

Alopecia areata (AA), an autoimmune disorder of hair follicles, results in varying degrees of scalp, facial, and body hair loss. In addition, it is associated with profound psychosocial and quality-of-life impairments, which can lead to anxiety and depression. The clinical course is unpredictable, with spontaneous remissions and relapses. There is no cure, and current treatments are limited by their efficacy, safety, and high relapse rates after discontinuation. This article reviews clinician and patient perspectives on AA, based on clinician and physician surveys, and discusses the unmet needs and gaps in care. J Drugs Dermatol. 2023;22(10 Suppl):s5-10.

Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas

Lineage plasticity has been proposed as a major source of intratumoral heterogeneity and therapeutic resistance. Here, by employing an inducible genetic engineered mouse model, we illustrate that lineage plasticity enables advanced Pancreatic Ductal Adenocarcinoma (PDAC) tumors to develop spontaneous relapse following elimination of the central oncogenic driver - Yap. Transcriptomic and immunohistochemistry analysis of a large panel of PDAC tumors reveals that within high-grade tumors, small niches of PDAC cells gradually evolve to re-activate pluripotent transcription factors (PTFs), which lessen their dependency on Yap. Comprehensive Cut&Tag analysis demonstrate that although acquisition of PTF expression is coupled with the process of epithelial-to-mesenchymal transition (EMT), PTFs form a core transcriptional regulatory circuitry (CRC) with Jun to overcome Yap dependency, which is distinct from the classic TGFb-induced EMT-TF network. A chemical-genetic screen and follow-up functional studies establish Brd4 as an epigenetic gatekeeper for the PTF-Jun CRC, and strong synergy between BET and Yap inhibitors in blocking PDAC growth.

Reccurent painful ophthalmoplegic neuropathy

Reccurent painful ophthalmoplegic neuropathy (the Tolosa–Hunt syndrome) occurs due to a nonspecific granulomatous infl ammation of the walls of the cavernous sinus and the intracavernous segment of the internal carotid artery. It consists of one or more oculomotor nerves dysfunction associated with peri- and retroorbital pain; spontaneous remissions and relapses are typical. Oculomotor nerve disorders may coincide with the onset of pain or follow it within a period of up to 2 weeks. Demonstration of granulomatosis in the walls of the cavernous sinus and the intracavernous segment of the internal carotid artery, superior orbital fissure or orbit by MRI or biopsy confi rms the diagnosis of Tolosa–Hunt syndrome (THS). Corticosteroid therapy leads to rapid (within 72 hours) pain relief and recovery of oculomotor nerve function. Here, we report a case of reccurent THS in 47-year-old men. Neuroimaging schowed a nonspecific inflammation in the superior orbital fissure-cavernous sinus region on left side and contrast-enhanced thickening dura mater.

Traumatic Supratrochlear Artery Pseudoaneurysm With Spontaneous Resolution

Background: Traumatic pseudoaneurysm of the supratrochlear artery is a rare lesion. It manifests, as a painless mass, in the frontal region following trauma. The unusual incidence and confusing presentation require the clinicians to thoroughly understand its presentation and diagnosis. Diagnosis is typically made on history and physical examination, but it can be confirmed by duplex ultrasound. Definitive treatment is surgical resection of the aneurysm after proximal and distal ligation of the vessel. However, in some cases, follow-up is recommended because there is a possibility of spontaneous relapse. Case Presentation: We present a case of traumatic pseudoaneurysm of the supratrochlear artery, which developed a few weeks after blunt trauma to the forehead. The radiologist reported a pseudoaneurysm originating with a narrow stalk of the supratrochlear artery. In the patient’s followup after three months, the patient’s mass became very small, and in the follow-up after five months, the mass completely disappeared. Conclusion: Pulsatile and or soft-tissue masses that are continuous with an artery with a history of trauma should be considered pseudoaneurysm. Color Doppler sonography is a convenient and noninvasive modality in diagnosis. If the pseudoaneurysm of the supratrochlear artery is small and contains thrombosis, waiting and seeing might be an effective option.

Gynecological complications in long-term survivors after allogeneic hematopoietic cell transplantation-a single-center real-life cross-sectional study.

Background and objectivesHematopoietic stem cell transplantation (HCT) is a treatment for hematopoietic diseases. However, most cured female patients may suffer from premature ovarian insufficiency (POI) after HCT, which is mainly caused by the pre-HCT conditioning regimen. Hence, this study aims to explore the impact of HCT treatment on reproductive and ovarian functions in female survivors.MethodsA total of 55 female participants under the age of 40, who underwent HCT and met the inclusion criteria were enrolled. Data related to blood disease, menstruation, and fertility in the 3 years following HCT were collected.ResultsThe involved patients received transplantation at different age stages, ranging from 8 to 37. All patients, except those with aplastic anemia (AA; 5/55), received a myeloablative conditioning regimen, usually modified total body irradiation/cyclophosphamide (TBI/Cy; 25/55) or modified Busulfan/cyclophosphamide (Bu/Cy; 23/55). Among women (42/55) who menstruated before HCT, 16.67% (7/42) had a spontaneous menstrual relapse and 83.3% (35/42) had amenorrhea after HCT. 72.7% (40/55) could be regarded as having POI. This proportion included 100% (25/25) of women aged 21–40 at the time of HCT, 62.5% (15/24) of those aged 11–20, and 0% (0/6) of those ≤10 years old. Patients with AML were more likely to have POI (95.7%). Patients aged ≤10 years (0%) or 11–20 years (16.7%) at the time of HCT were less likely to have moderate to severe menopause than those 21–40 years old (44%).ConclusionThe prevalence of POI following HCT was high and POI was associated with age, conditioning regimen, and type of blood disease.

Therapeutic Effect of Subunit Vaccine AEC/BC02 on Mycobacterium tuberculosis Post-Chemotherapy Relapse Using a Latent Infection Murine Model.

Tuberculosis (TB), caused by the human pathogen Mycobacterium tuberculosis (Mtb), is an infectious disease that presents a major threat to human health. Bacillus Calmette-Guérin (BCG), the only licensed TB vaccine, is ineffective against latent TB infection, necessitating the development of further TB drugs or therapeutic vaccines. Herein, we evaluated the therapeutic effect of a novel subunit vaccine AEC/BC02 after chemotherapy in a spontaneous Mtb relapse model. Immunotherapy followed 4 weeks of treatment with isoniazid and rifapentine, and bacterial loads in organs, pathological changes, and adaptive immune characteristics were investigated. The results showed slowly increased bacterial loads in the spleen and lungs of mice inoculated with AEC/BC02 with significantly lower loads than those of the control groups. Pathological scores for the liver, spleen, and lungs decreased accordingly. Moreover, AEC/BC02 induced antigen-specific IFN-γ-secreting or IL-2-secreting cellular immune responses, which decreased with the number of immunizations and times. Obvious Ag85b- and EC-specific IgG were observed in mice following the treatment with AEC/BC02, indicating a significant Th1-biased response. Taken together, these data suggest that AEC/BC02 immunotherapy post-chemotherapy may shorten future TB treatment.

Seizure outcome trajectories in a well-defined cohort of newly diagnosed juvenile myoclonic epilepsy patients.

To investigate the temporal course of medication response and associated prognostic factors in a cohort of juvenile myoclonic epilepsy (JME) patients over a long-term follow-up. Data from 113JME patients diagnosed according to recently proposed class II criteria were retrospectively reviewed. Early sustained remission was defined as 4-year seizure remission starting within 2years from the first antiseizure medication (ASM) intake, as opposed to delayed sustained remission. Spontaneous relapse rate (ie, not related to ASM withdrawal) was also investigated, along with factors associated with seizure relapse. Four-year seizure remission was obtained by 76/113 (67.3%) subjects. Early sustained remission was achieved by 45/76 (59.2%) patients. Absence seizures were significantly associated with no-remission at multivariable multinomial logistic regression analysis. Catamenial seizures and earlier age at epilepsy onset significantly predicted delayed sustained remission. Spontaneous seizure relapse after 4-year remission occurred in 15.7% of patients with early sustained remission and in 35.5% of those with delayed sustained remission (p=0.045). The most common concomitant factors for a spontaneous relapse were irregular lifestyle habits and pregnancy-related switch from valproate to another ASM. Patients with a history of catamenial seizures were more likely to experience a spontaneous generalized tonic-clonic seizure relapse after 4-year remission at univariable analysis. Our data support the prognostic relevance of early medication response in JME patients. Furthermore, the prognostic significance of catamenial seizures and the impact of valproate switch on seizure relapse after a prolonged remission account for the challenging therapeutic management of women with childbearing potential.

SARS-CoV-2 vaccination in multiple sclerosis: A clearer picture for the time point during CD20 depleting therapy.

The ongoing coronavirus disease 2019 (COVID-19), one of the deadliest pandemics in history, is associated with significant considerations for people living with multiple sclerosis (plwMS). The interest is motivated by knowing that viral infections are triggers for disease exacerbation [1]. In this chronic inflammatory demyelinating disorder of the central nervous system (CNS), relapses associated with infectious stimuli lead to more prolonged and severe clinical worsening than spontaneous relapses [2].

S95. DIFFERENCES IN LIFETIME PATTERNS OF PSYCHOSTIMULANTS AND THEIR IMPACT ON THE PROPORTION OF PATIENTS WITH FIRST-EPISODE PSYCHOSIS ATTRIBUTABLE TO PSYCHOSTIMULANTS USE ACROSS EUROPE

BackgroundSubstance use may be a risk factor for the onset of schizophrenia. Almost 50 % of people with first episode psychosis (FEP) have a history of cannabis or alcohol use. Smaller but significant proportions of this population have a history of psychostimulants (PS) use. Cross-sectional studies have shown a link between recreational and regular use of PS and psychotic symptoms, particularly among individuals with PS dependence, that usually revert after drug withdrawal. Nevertheless, some PS users suffer not just spontaneous relapse of the symptoms but also persistent psychosis in the absence of the drug.European data are not available for a large sample of the prevalence of consumption and its relation to the severity of symptoms in FEP. For this purpose, we described the differences in patterns of use of PS current and lifetime between FEP and healthy controls (HC) and their impact on the severity of the clinical symptomatology.MethodsThis analysis is based on data from the case-control study work package of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI), which took part between 2010 and 2015 across six countries.901 FEP patients (M age=30.76, SD= 10.51; 38.1% females) and 1235 HC (M=36.15, SD=13.30; 53% females) were included in the present case-control study. Data related to amphetamine use were obtained through CEQEU-GEI. To assess psychopathology the OPerational CRITeria (OPCRIT) system was used.Group comparisons were made using t-test or Chi square, and ANCOVA or logistic regression controlling for age, sex and cannabis use when appropriate.ResultsFEP subjects displayed a trend for higher use of PS in the last year (B=-0.18, p= 0.055: 81 (9%) FEP and 56 (4.5%)) and a significant higher lifetime use (Chi2= 37.33, p<0.001: 196 (21.8%) FEP and 149 (12.1%) HC) than HC, but the frequency of PS use did not differ between groups.Lifetime FEP PS-users showed higher scores, thus is, more severe symptoms in the Mania (t= -3.69, p< 0.001) and the general (t= -3.47, p= 0.001) factors compared to FEP non-PS-users. Current FEP PS-users showed higher scores in the Mania factor (t= -2.52, p= 0.012) than FEP non-PS-users. However, these results were not significant when the comparisons were adjusted for age, sex and cannabis use. FEP PS-users displayed lower scores than the non-users in the negative factor both in the last year (t= 2.10, p= 0.038 and: F1,866= 4.27, p= 0.039 when adjusted for age, sex and cannabis use) and lifetime (t= 1.99, p= 0.046 and F1,869= 1.37, p= 0.243 when adjusted for age, sex and cannabis use).DiscussionAs previous studies, we confirmed the higher rates of PS use in FEP than HC in a European study with a big sample. PS use was related to severity of clinical symptomatology. PS-users presented more severe general symptoms and, specifically, in the mania factor. Otherwise, FEP non-PS-user showed higher scores in the negative factor which might be related to the usual course of the psychosis without exposure to PS use.

Abstract IA27: Context-dependent role of KRAS in GI malignancies

Abstract Oncogenic Kras (Kras*) plays a key role in tumor maintenance and therapeutic resistance in several cancer types, although the precise biologic functions and mechanisms are not completely understood. We had previously shown in pancreatic ductal adenocarcinoma that some tumors underwent spontaneous relapse and were devoid of Kras* expression and downstream canonical MAPK signaling, instead acquiring amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras*-independent tumor maintenance. In a second previous study, we developed a faithful colorectal cancer (CRC) mouse model and showed that Kras* drove invasion and maintenance in CRC. Here, utilizing this CRC mouse model, we demonstrate that KRAS* promotes a pronounced immune-suppressive profile distinguished by a predominance of myeloid-derived suppressor cells (MDSCs). We performed integrated transcriptomic and genomic analyses that identified IRF2 (Interferon Regulatory Factor 2) as a key KRAS* effector mediating immune suppression. IRF2 suppresses MDSC migration and infiltration in KRAS*-expressing CRC tumors by targeting the CXCL3/CXCR2 axis. We also observed that de novo resistance of KRAS*-expressing tumors to anti-PD1 therapy could be overcome by enforced IRF2 expression or by treatment with SX-682, a small-molecule CXCR2 antagonist. In addition, CRC patient tumors with higher IRF2 expression showed increased response to anti-PD1 therapy. This KRAS*-mediated immune-suppressive mechanism provides a framework for CRC patient selection and combination therapies to enhance the effectiveness of immune checkpoint blockade therapy in advanced disease. Citation Format: Wen-Ting Liao, Michael J. Overman, Adam Boutin, Prasenjit Dey, Di Zhao, Guocan Wang, Jiexi Li, Zhengdao Lan, Jun Li, Xiaoying Shang, Ming Tang, Shan Jiang, Xingdi Ma, Peiwen Chen, Riham Katkhuda, Krittiya Korphaisarn, Deepavali Chakravarti, Qing Chang, Jianhua Zhang, Dipen M. Maru, Dean Y. Maeda, John A. Zebala, Scott Kopetz, Y. Alan Wang, Ronald A. DePinho. Context-dependent role of KRAS in GI malignancies [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA27.

Inefficient neural system stabilization: a theory of spontaneous resolutions and recurrent relapses in psychosis

A striking feature of psychosis is its heterogeneity. Presentations of psychosis vary from transient symptoms with no functional consequence in the general population to a tenacious illness at the other extreme, with a wide range of variable trajectories in between. Even among patients with schizophrenia, who are diagnosed on the basis of persistent deterioration, marked variation is seen in response to treatment, frequency of relapses and degree of eventual recovery. Existing theoretical accounts of psychosis focus almost exclusively on how symptoms are initially formed, with much less emphasis on explaining their variable course. In this review, I present an account that links several existing notions of the biology of psychosis with the variant clinical trajectories. My aim is to incorporate perspectives of systems neuroscience in a staging framework to explain the individual variations in illness course that follow the onset of psychosis.

Spontaneous relapse in patients with inactive chronic hepatitis B virus infection.

Background:Chronic hepatitis B virus infection (HBV) may reactivate during the course of the disease and is called spontaneous relapse. The purpose of this study was to evaluate the incidence of relapse of hepatitis in subjects with inactive HBV carriers.Methods:This follow-up study was performed on 785 patients with inactive HBV carriers that were followed-up at six month intervals. The presence of serum HBsAg and anti-HBe, without HBeAg, HBV DNA levels <2000 IU/ml with normal alanine aminotransferase (ALT) levels was defined as inactive carriers. Patients who developed ALT ≥80 IU/L with HBV DNA levels ≥2000 IU/ml were considered as spontaneous relapse.Results:Seven hundred- eighty five cases (441 males, 344 females) of chronic HBV infected individuals were followed-up. The mean age at the entrance of the study was 30.5±11.8 years. The mean follow-up duration was 5.9±5 years. Relapse was seen in 35 (4.5%) cases, in 27 out of 441 (6.1%) males and in 8 out of 344 (2.3%) females and in 4.2% subjects ≥30 years versus in 4.7% cases of under 30 years (p>0.05). The development of relapse in males was higher than females (hazard ratio 2.53, 95% CI 1.2-5.6, p=0.021), but age ≥30 or <30 years did not have effect (hazard ratio1.21, 95% CI 0.62-2.36, p=0.58).Conclusions:The results show that spontaneous relapse of hepatitis may develop during the course of chronic HBV infection. We suggest that all patients with chronic hepatitis B, regardless of their age, be examined for the possibility of relapse.

4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection.

BackgroundChagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice.Methodology/Principal findingsBoth acute and chronic animal models infected with wild type or transgenic T. cruzi strains were evaluated. There was no evidence of toxicity in the 28-day dosing study of uninfected animals, as judged by the monitoring of multiple serum and histological parameters. In two acute models of Chagas disease, 9 and 12 drastically reduced parasitemia, increased survival of mice, and prevented liver and heart injury. None of the compounds produced long term sterile cure. In the less severe acute model using the transgenic CL-Brenner strain of T.cruzi, parasitemia relapsed upon drug withdrawal. In the chronic model, parasitemia fell to a background level and, as evidenced by the bioluminescence detection of T. cruzi expressing the red-shifted luciferase marker, mice remained negative for 4 weeks after drug withdrawal. Two immunosuppression cycles with cyclophosphamide were required to re-activate the parasites. Although no sterile cure was achieved, the suppression of parasitemia in acutely infected mice resulted in drastically reduced inflammation in the heart.Conclusions/SignificanceThe positive outcomes achieved in the absence of sterile cure suggest that the target product profile in anti-Chagasic drug discovery should be revised in favor of safe re-administration of the medication during the lifespan of a Chagas disease patient. A medication that reduces parasite burden may halt or slow progression of cardiomyopathy and therefore improve both life expectancy and quality of life.

A case of acute spinal subdural hematoma with subarachnoid hemorrhage: Rapid spontaneous remission, relapse, and complete resolution

Abstract Acute spinal subdural hematoma (SSDH) is a rare entity that is usually managed as a surgical emergency; however, we present a case of acute SSDH that resolved rapidly and spontaneously. A 59-year-old man, who was taking antiplatelet and antihypertensive medication, experienced sudden back neck pain, followed by complete paraplegia. The symptoms resolved within minutes and then recurred before resolving completely within several hours. Magnetic resonance imaging (MRI) performed 6 h from onset revealed an intradural spinal hematoma. Lumbar puncture yielded bloody cerebrospinal fluid, confirming the presence of a subarachnoid hemorrhage. Conservative therapy was selected, leading to complete recovery without any sequelae. Follow-up MRI scans obtained 12 days from onset finally confirmed that the spinal hematoma was in the subdural space. In addition to rostrocaudal spreading of bloody components in the subdural space, rupture of the hematoma into the subarachnoid space must have released pressure, compressing the spinal cord. In this case report, we also describe the serial MRI studies and note the limitations of the resolution of spinal MRI in the acute phase.

Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia

Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.

Inflammatory Bowel Disease Affects the Outcome of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection

A significant fraction of patients with recurrent Clostridium difficile infections (CDI) have inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) can break the cycle of CDI recurrence and can be performed without evaluation of the colon. We evaluated the efficacy of colonoscopic FMT in patients with and without IBD, and whether we could identify IBD in patients during this procedure. We collected clinical meta-data and colonoscopy results from 272 consecutive patients that underwent FMT for recurrent CDI at the University of Minnesota from 2008 through 2015. Patients had at least 2 spontaneous relapses of CDI following their initial episode and did not clear the infection after 1 extended antibiotic regimen. We collected random mucosal biopsies from patients' right colons to identify lymphocytic or collagenous colitis during the FMT procedure. Failure or success in clearing CDI was determined within or at 2 months after the FMT. Of patients undergoing FMT, 15% had established IBD and 2.6% were found to have IBD during the FMT procedure. A single colonoscopic FMT cleared CDI from 74.4% of patients with IBD and 92.1% of patients without IBD (P= .0018). Patients had similar responses to FMT regardless of immunosuppressive therapy. More than one-quarter of patients with IBD (25.6%) had a clinically significant flare of IBD after FMT. Lymphocytic colitis was documented in 7.4% of patients with endoscopically normal colon mucosa; only 3 of these patients (20%) required additional treatment for colitis after clearance of CDI. Based on an analysis of 272 patients, FMT is somewhat less effective in clearing recurrent CDI from patients with IBD, compared with patients without IBD, regardless of immunosuppressive therapy. More than 25% of patients with IBD have a disease flare following FMT. Lymphocytic colitis did not affect the outcome of FMT, but a small fraction of these patients required pharmacologic treatment after the procedure.

A Functional Model of Fast Action Selection Guided by Emotional Stimuli

Key brain networks underlying cognition and emotion are modulated by major neurotransmitter systems through reward/punishment circuits. Notably, the basal ganglia are thought to funnel emotional information towards motor outcomes. However, the mechanisms that would allow emotional stimuli to guide action selection have yet to be identified. Computational models may contribute to this goal. Here, by using a computer simulation of the guidedpropagation deterministic model, we show that emotional channels can quickly and selectively modulate actionoriented channels, by instantly retrieving all the emotional stimuli paired in the past with a current cue. In agreement with animal based data, the transient modulation signals that implement emotional anticipation appear to be more useful when targeting either newly formed or remote memory traces. The timing and evolution of these signals both suggest a new interpretation of the dopaminergic neuron activity in the basal ganglia during conditioning, usually regarded as coding for a ‘reward prediction error’ in the frame of reinforcement learning. After additional computer trainings involving ‘emotions’ of extreme values, the diversity of actions selected under the influence of a conditioned cue is shown to decrease through either compulsive or avoidance behaviors. Indeed, in the proposed functional model, similar modulation mechanisms account for the development of either drug addiction or posttraumatic stress disorder. Furthermore, spontaneous relapse into these dysfunctions is attributed here to local modulating deficits. The latter can partly be overcome by selectively shifting one of the few control parameters of the model, akin to neuromodulators.

Abstract A94: Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer

Abstract Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and underlying mechanisms of, KrasG12D–independent PDAC recurrence. We utilized MRI imaging to monitor regression of advanced pancreatic tumors measuring at least 8 mm in diameter at time of doxycycline withdrawal. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression, downstream canonical MAPK signaling but instead acquired amplification and overexpression of the transcriptional co-activator Yap1. Enforced Yap1 expression can substitute for oncogenic Kras-driven tumor maintenance and associated tumor cell proliferation without activation of canonical Kras signaling surrogates. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models indicates that the oncogenic Kras-independent relapse tumors generated in response to KrasG12D extinction closely resemble the quasimesenchymal-subtype of human PDAC and rely on alternative oncogenic mechanisms including Yap1 for their growth. Citation Format: Avnish Kapoor, Wantong Yao, Haoqiang Ying, Sujun Hua, Alison Liewen, Anguraj Sadanandam, Ramsey Al-Khalil, Andrea Viale, Piergiorgio Pettazzoni, Nora Sanchez, Alexei Protopopov, Jianhua Zhang, Timothy Heffernan, Randy L. Johnson, Lynda Chin, Y. Alan Wang, Giulio Draetta, Ronald A. DePinho. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A94.

Serum IL-17A in Behçet's disease.

IntroductionBehçet's disease is a chronic multisystem disease with spontaneous remissions and relapses. Several studies show that autoimmune mechanisms play an important role in the development of Behçet's disease. Activation of T cells and neutrophils is important in the pathogenesis of the disease. Interleukin 17 (IL-17) is a new cytokine that induces several types of cells to secrete proinflammatory cytokines in many inflammatory and autoimmune diseases.AimThis study evaluated the serum levels of IL-17A in active and stable Behçet's disease patients.Material and methodsSeventy-six patients who had active clinic findings of Behçet's disease were enrolled in our study. Seventy age- and sex-matched controls were also enrolled. Serum IL-17 levels were studied in peripheral venous blood samples.ResultsNo significant differences were found between active Behçet's disease patients and controls in terms of serum IL-17A (p > 0.05).ConclusionsThese results suggest that IL-17A serum levels do not play an important role in active Behçet's disease.

Factors precipitating acute ulcerative colitis.

Ulcerative colitis is characterized by mucosal inflammation of a variable length of the colon starting from the rectum. The precise etiopathogenesis is unknown but it occurs in genetically susceptible individuals who manifest an abnormal immunological response against gut commensal bacteria. The disease course is-characterized by multiple spontaneous relapses and remissions. Two pathogens namely CMV and C. difficile have been associated with disease exacerbation in specific clinical situations. Whereas C. difficile may produce worsening of the disease in those exposed to broad spectrum antibiotics, CMV reactivation is seen only in patients with moderate to severe steroid refractory disease. The importance of these two super-infections can be gauged by the fact that both the ACG and the ECCO recommend testing for these two pathogens in appropriate clinical situations. The applicability of these guidelines in the Indian scenario has yet to be determined in view of the bacterial and parasitic infections endemic in tropical countries. The guidelines for diagnosis and management of these two super-infections in the presence of ulcerative colitis are discussed in this review.