Steroid-dependent switch of OvoL/Shavenbaby controls self-renewal versus differentiation of intestinal stem cells.

Adult stem cells must continuously fine-tune their behavior to regenerate damaged organs and avoid tumors. While several signaling pathways are well known to regulate somatic stem cells, the underlying mechanisms remain largely unexplored. Here, we demonstrate a cell-intrinsic role for the OvoL family transcription factor, Shavenbaby (Svb), in balancing self-renewal and differentiation of Drosophila intestinal stem cells. We find that svb is a downstream target of Wnt and EGFR pathways, mediating their activity for stem cell survival and proliferation. This requires post-translational processing of Svb into a transcriptional activator, whose upregulation induces tumor-like stem cell hyperproliferation. In contrast, the unprocessed form of Svb acts as a repressor that imposes differentiation into enterocytes, and suppresses tumors induced by altered signaling. We show that the switch between Svb repressor and activator is triggered in response to systemic steroid hormone, which is produced by ovaries. Therefore, the Svb axis allows intrinsic integration of local signaling cues and inter-organ communication to adjust stem cell proliferation versus differentiation, suggesting a broad role of OvoL/Svb in adult and cancer stem cells.

Idiopathic Ileo-Ileo-Cecal Intussuception in a 25-Year-Old Female.

BACKGROUND Intussusception is defined as the penetration or telescoping of a segment of bowel into a more distal segment. Intussusception is a common cause of small bowel obstruction, especially in children. However, this finding is much less common in adults. Furthermore, when present in adults, intussusception is often found in association with some sort of organic mass, such as a tumor or pancreatic divisum that acts as a lead point, dragging the proximal segment into the distal one. The presence of an intussusception in an adult patient with no obvious lead point is very uncommon. CASE REPORT Here we report a case of ileo-ileo-cecal double intussusception in an adult patient that yielded no lead point on surgical exploration. The patient was a 25-year-old female who presented with symptoms of obstruction and was diagnosed with the intussusception via computed tomography scan. Surgical resection of the bowel was necessary as reduction could not be accomplished. CONCLUSIONS The finding of intussusception in an adult patient is far less common than in children, and even more rare when a lead point is not established. When surgery is required, a thorough exploration should be performed to search any signs of a potential lead point. Laparoscopy is usually preferred to laparotomy; however, in this case the degree of distention determined the surgical approach. Thus, due to severe distention, laparotomy was preferred.

Pitfalls of Diagnosing Left Lower Quadrant Pain Causes: Making the Uncommon Common Again.

BACKGROUND Left-sided acute appendicitis, although well described in the literature, is still an easily missed diagnosis. Midgut malrotation and situs inversus are 2 known leading conditions that contribute to misdiagnosis of appendicitis. CASE REPORT Here is the case of a 27-year-old male without any previous medical history, who presented with left lower quadrant tenderness and was misdiagnosed with gastroenteritis as an outpatient and sent home; the patient presented the next day to the emergency department where he was found to have acute appendicitis with situs inversus. He underwent laparoscopic appendectomy where a phlegmon was identified. Pathology came back as peri-appendiceal mucocele with no signs of malignancy. CONCLUSIONS This case report aimed to revisit the idea of left-sided acute appendicitis and discuss the management of a perforated appendiceal mucocele contained by a phlegmon.

Leishmania in a Patient with Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia.

BACKGROUND Leishmaniasis is a parasitic infection spread by the bite of infected sand flies that are usually present in the Middle East, Africa, and some parts of Asia and Europe. Leishmaniasis manifests in 3 different forms: Visceral (also known as Kala Azar), which is the most serious type; cutaneous, which is the most common type; and mucocutaneous. The symptoms of this infection range from a silent infection to fever, enlargement of the liver and spleen, weight loss, and pancytopenia. CASE REPORT In this case report, we discuss a 73-year-old man known to have chronic lymphocytic leukemia (CLL), presenting with unremitting fever and who to our surprise was found to have Kala Azar. CONCLUSIONS Early diagnosis and treatment are very important in treating visceral leishmaniasis. While the conventional treatment in immunocompromised patients is liposomal amphotericin B, our patient responded to corticosteroids.

Damage-Induced Cell Regeneration in the Midgut of Aedes albopictus Mosquitoes.

Mosquito-transmitted diseases cause over one million deaths every year. A better characterization of the vector's physiology and immunity should provide valuable knowledge for the elaboration of control strategies. Mosquitoes depend on their innate immunity to defend themselves against pathogens. These pathogens are acquired mainly through the oral route, which places the insects' gut at the front line of the battle. Indeed, the epithelium of the mosquito gut plays important roles against invading pathogens acting as a physical barrier, activating local defenses and triggering the systemic immune response. Therefore, the gut is constantly confronted to stress and often suffers cellular damage. In this study, we show that dividing cells exist in the digestive tract of adult A. albopictus and that these cells proliferate in the midgut after bacterial or chemical damage. An increased transcription of signaling molecules that regulate the EGFR and JAK/STAT pathways was also observed, suggesting a possible involvement of these pathways in the regeneration of damaged guts. This work provides evidence for the presence of regenerative cells in the mosquito guts, and paves the way towards a molecular and cellular characterization of the processes required to maintain mosquito's midgut homeostasis in both normal and infectious conditions.

Transcription factor interplay during Drosophila haematopoiesis.

Transcription factors play a key role in regulating blood cell fate choice and differentiation. In this review, we examine current knowledge of the function and mode of action of the transcription factors implicated in haematopoiesis in Drosophila. We particularly emphasize regulation by transcription factors and cofactors, such as GATA, FOG and RUNX, whose homologues in mammals also control blood cell formation and we discuss the cross talks between these transcriptional regulators at the different stages of haematopoietic cell fate decision.

An in vivo RNA interference screen identifies gene networks controlling Drosophila melanogaster blood cell homeostasis.

BACKGROUND: In metazoans, the hematopoietic system plays a key role both in normal development and in defense of the organism. In Drosophila, the cellular immune response involves three types of blood cells: plasmatocytes, crystal cells and lamellocytes. This last cell type is barely present in healthy larvae, but its production is strongly induced upon wasp parasitization or in mutant contexts affecting larval blood cell homeostasis. Notably, several zygotic mutations leading to melanotic mass (or "tumor") formation in larvae have been associated to the deregulated differentiation of lamellocytes. To gain further insights into the gene regulatory network and the mechanisms controlling larval blood cell homeostasis, we conducted a tissue-specific loss of function screen using hemocyte-specific Gal4 drivers and UAS-dsRNA transgenic lines. RESULTS: By targeting around 10% of the Drosophila genes, this in vivo RNA interference screen allowed us to recover 59 melanotic tumor suppressor genes. In line with previous studies, we show that melanotic tumor formation is associated with the precocious differentiation of stem-cell like blood progenitors in the larval hematopoietic organ (the lymph gland) and the spurious differentiation of lamellocytes. We also find that melanotic tumor formation can be elicited by defects either in the fat body, the embryo-derived hemocytes or the lymph gland. In addition, we provide a definitive confirmation that lymph gland is not the only source of lamellocytes as embryo-derived plasmatocytes can differentiate into lamellocytes either upon wasp infection or upon loss of function of the Friend of GATA cofactor U-shaped. CONCLUSIONS: In this study, we identify 55 genes whose function had not been linked to blood cell development or function before in Drosophila. Moreover our analyses reveal an unanticipated plasticity of embryo-derived plasmatocytes, thereby shedding new light on blood cell lineage relationship, and pinpoint the Friend of GATA transcription cofactor U-shaped as a key regulator of the plasmatocyte to lamellocyte transformation.

A genome-wide RNA interference screen identifies a differential role of the mediator CDK8 module subunits for GATA/ RUNX-activated transcription in Drosophila.

Transcription factors of the RUNX and GATA families play key roles in the control of cell fate choice and differentiation, notably in the hematopoietic system. During Drosophila hematopoiesis, the RUNX factor Lozenge and the GATA factor Serpent cooperate to induce crystal cell differentiation. We used Serpent/Lozenge-activated transcription as a paradigm to identify modulators of GATA/RUNX activity by a genome-wide RNA interference screen in cultured Drosophila blood cells. Among the 129 factors identified, several belong to the Mediator complex. Mediator is organized in three modules plus a regulatory "CDK8 module," composed of Med12, Med13, CycC, and Cdk8, which has long been thought to behave as a single functional entity. Interestingly, our data demonstrate that Med12 and Med13 but not CycC or Cdk8 are essential for Serpent/Lozenge-induced transactivation in cell culture. Furthermore, our in vivo analysis of crystal cell development show that, while the four CDK8 module subunits control the emergence and the proliferation of this lineage, only Med12 and Med13 regulate its differentiation. We thus propose that Med12/Med13 acts as a coactivator for Serpent/Lozenge during crystal cell differentiation independently of CycC/Cdk8. More generally, we suggest that the set of conserved factors identified herein may regulate GATA/RUNX activity in mammals.

A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO.

The t(8:21)(q22;q22) translocation is 1 of the most common chromosomal abnormalities linked to acute myeloid leukemia (AML). AML1-ETO, the product of this translocation, fuses the N-terminal portion of the RUNX transcription factor AML1 (also known as RUNX1), including its DNA-binding domain, to the almost entire transcriptional corepressor ETO (also known as MTG8 or RUNX1T1). This fusion protein acts primarily by interfering with endogenous AML1 function during myeloid differentiation, although relatively few genes are known that participate with AML1-ETO during leukemia progression. Here, we assessed the consequences of expressing this chimera in Drosophila blood cells. Reminiscent of what is observed in AML, AML1-ETO specifically inhibited the differentiation of the blood cell lineage whose development depends on the RUNX factor Lozenge (LZ) and induced increased numbers of LZ(+) progenitors. Using an in vivo RNAi-based screen for suppressors of AML1-ETO, we identified calpainB as required for AML1-ETO-induced blood cell disorders in Drosophila. Remarkably, calpain inhibition triggered AML1-ETO degradation and impaired the clonogenic potential of the human t(8;21) leukemic blood cell line Kasumi-1. Therefore Drosophila provides a promising genetically tractable model to investigate the conserved basis of leukemogenesis and to open avenues in AML therapy.