The prevalence of ultrasound curricula in a sampling of U.S. physician assistant programs and recommendations for common ultrasound objectives: A national survey.

An increasing number of practicing physician assistants (PAs) are using ultrasound (US) in clinical settings. However, a lack of US learning objectives for PA students limits the optimal integration of this imaging modality in PA curricula. This study surveyed PA program directors across the United States to create a list of US learning objectives for PA students and to gauge their attitudes toward integrating US into anatomy curricula. Thirty-one of the 280 PA program directors responded to the survey. While 87% of participants reported that their institution includes ultrasound in its curriculum, 71% disagreed that the state of the use of ultrasound throughout their PA curriculum is fine and needs no modification. Based on the responses of the survey participants, this study categorized US learning objectives into high, medium, low, and no agreement for integration in PA curricula. As over half of the learning objectives (73%, 43/59) had high agreement for inclusion in curricula, this study demonstrates an opportunity for educators to include US in PA curricula.

A university-wide seed grant program accelerates interprofessional education through faculty and staff engagement.

The University of Texas Health Science Center at San Antonio launched an annual university-wide seed grant program in 2019 to foster innovation in interprofessional education (IPE) and increase IPE opportunities for learners. Program objectives included leveraging hypothesis-driven research to identify sustainable IPE activities for integration into educational programs (i.e. mandated for at least one cohort of learners), increasing scholarly dissemination of IPE efforts, and using pilot data to secure extramural funding. Over the first four funding cycles (2019-2022), US$100,509.00 was awarded to support 22 IPE projects (10 curricular, 12 co-curricular) involving 80 faculty and staff collaborators and over 2,100 student participants. To date, funded projects have yielded nine sustained IPE activities (four of which have been integrated), produced 24 scholarly presentations and three peer-reviewed publications, and contributed to the success of one extramural grant. Barriers experienced are discussed in this report alongside lessons learned and unexpected positive outcomes, including identification of future IPE champions.

Corrigendum: Paraptosis: a unique cell death mode for targeting cancer.

[This corrects the article DOI: 10.3389/fphar.2023.1159409.].

Paraptosis: a unique cell death mode for targeting cancer.

Programmed cell death (PCD) is the universal process that maintains cellular homeostasis and regulates all living systems' development, health and disease. Out of all, apoptosis is one of the major PCDs that was found to play a crucial role in many disease conditions, including cancer. The cancer cells acquire the ability to escape apoptotic cell death, thereby increasing their resistance towards current therapies. This issue has led to the need to search for alternate forms of programmed cell death mechanisms. Paraptosis is an alternative cell death pathway characterized by vacuolation and damage to the endoplasmic reticulum and mitochondria. Many natural compounds and metallic complexes have been reported to induce paraptosis in cancer cell lines. Since the morphological and biochemical features of paraptosis are much different from apoptosis and other alternate PCDs, it is crucial to understand the different modulators governing it. In this review, we have highlighted the factors that trigger paraptosis and the role of specific modulators in mediating this alternative cell death pathway. Recent findings include the role of paraptosis in inducing anti-tumour T-cell immunity and other immunogenic responses against cancer. A significant role played by paraptosis in cancer has also scaled its importance in knowing its mechanism. The study of paraptosis in xenograft mice, zebrafish model, 3D cultures, and novel paraptosis-based prognostic model for low-grade glioma patients have led to the broad aspect and its potential involvement in the field of cancer therapy. The co-occurrence of different modes of cell death with photodynamic therapy and other combinatorial treatments in the tumour microenvironment are also summarized here. Finally, the growth, challenges, and future perspectives of paraptosis research in cancer are discussed in this review. Understanding this unique PCD pathway would help to develop potential therapy and combat chemo-resistance in various cancer.

Essential anatomy for core clerkships: A clinical perspective.

Clerkships are defining experiences for medical students in which students integrate basic science knowledge with clinical information as they gain experience in diagnosing and treating patients in a variety of clinical settings. Among the basic sciences, there is broad agreement that anatomy is foundational for medical practice. Unfortunately, there are longstanding concerns that student knowledge of anatomy is below the expectations of clerkship directors and clinical faculty. Most allopathic medical schools require eight "core" clerkships: internal medicine (IM), pediatrics (PD), general surgery (GS), obstetrics and gynecology (OB), psychiatry (PS), family medicine (FM), neurology (NU), and emergency medicine (EM). A targeted needs assessment was conducted to determine the anatomy considered important for each core clerkship based on the perspective of clinicians teaching in those clerkships. A total of 525 clinical faculty were surveyed at 24 United States allopathic medical schools. Participants rated 97 anatomical structure groups across all body regions on a 1-4 Likert-type scale (1 = not important, 4 = essential). Non-parametric ANOVAs determined if differences existed between clerkships. Combining all responses, 91% of anatomical structure groups were classified as essential or more important. Clinicians in FM, EM, and GS rated anatomical structures in most body regions significantly higher than at least one other clerkship (p = 0.006). This study provides an evidence-base of anatomy content that should be considered important for each core clerkship and may assist in the development and/or revision of preclinical curricula to support the clinical training of medical students.

Cadaveric study of division of the median nerve by the persistent median artery.

PURPOSE: The purpose of this study is to characterize the division of the median nerve by the persistent median artery (PMA) and highlight the associated clinical implications. Penetration of the median nerve by the PMA is believed to cause compression of the median nerve and affect nerve conduction velocity. This paper explored whether the origin and the pattern of PMA dictate its ability to divide the median nerve. METHODS: Origin, and relationship of the PMA to the median nerve were documented in 60 cadavers donated to the Human Anatomy Program at UT Health San Antonio. Entire path of this artery was followed in the forearm and the hand. RESULTS: Twenty-five cases of a persistent median artery (PMA) were found in the upper limbs (20.83%; 25/120) of these donated cadavers. Most of the persistent median arteries originated from the ulnar artery (48%; 12/25) and the others originated either from the anterior interosseous artery (36%; 9/25) or from the common interosseous artery (16%; 4/25). Sixty percent (15/25) of the persistent median arteries penetrated and divided the median nerve in the forearm. Interestingly, all the persistent median arteries that originated from the ulnar artery (100%; 12/12) divided the median nerve in the forearm and a palmar type of PMA was found to be more likely to divide the median nerve. CONCLUSION: Clinicians performing surgeries in the forearm and hand need to be aware of this anomaly and should screen patients for the presence of this artery prior to surgical intervention.

Glucocorticoid-Induced Autophagy Protects Osteocytes Against Oxidative Stress Through Activation of MAPK/ERK Signaling.

Autophagy confers protective or detrimental effects on cells depending on the cellular context. We showed here that oxidative stress-induced cell death in osteocytic MLO-Y4 cells coincided with decreased autophagy. Decreased autophagy was also observed in osteocytes of superoxide dismutase 1- (SOD1-) deficient mice. Oxidative stress-induced osteocyte death was exacerbated by an autophagy inhibitor, chloroquine, suggesting a protective function of basal autophagy levels against oxidative stress-induced cell death. Pretreatment with dexamethasone reduced the susceptibility of osteocytes to oxidative stress-induced cell death and conferred protection against TNFα/cycloheximide-induced cell death. Inhibition of MAPK/ERK attenuated the formation of autophagosome, leading to increased osteocyte cell death. Taken together, our results suggest that autophagy, induced by moderate levels of glucocorticoids, leads to the preconditioning of osteocytes and conveys a novel cell-protective function against cell death induced by oxidative stress and other insults. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Incomplete superficial palmar arch and bilateral persistent median artery.

INTRODUCTION: The superficial palmar arch (SPA) is a major source of blood supply to much of the hand and is conventionally formed by the anastomosis of the ulnar artery with the superficial branch of the radial artery. The SPA has been classified into complete or incomplete based on the presence or absence of anastomosis between the arteries contributing to the formation of this palmar arch. CASE REPORT: Reported here is a unilateral presentation of incomplete superficial palmar arch. The ulnar artery (UA) gave off one proper palmar digital artery, which supplied the ulnar side of the little finger, and two common palmar digital arteries, which supplied the little, ring, and the middle finger. The superficial palmar branch of the radial artery gave off a proper palmar digital artery to the thumb, and two common palmar digital arteries, which supplied the thumb, index, and middle fingers. Apart from the presence of the incomplete SPA, persistent median arteries were also observed bilaterally in this cadaver. DISCUSSION: The prevalence of incomplete SPA has been reported to vary between 3.6-54.76%. To the best of our knowledge, this is the first case report describing an incomplete palmar arch and bilateral persistent median artery in a cadaver. CONCLUSION: Patients should be screened for the presence of complete or incomplete SPA before harvesting the radial artery either for myocardial revascularization or for radial artery forearm flap to prevent ischemic complications in the hand.

Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to Its Antley-Bixler Syndrome-like Phenotype.

Human NADPH-cytochrome P450 oxidoreductase (POR) gene mutations are associated with severe skeletal deformities and disordered steroidogenesis. The human POR mutation A287P presents with disordered sexual development and skeletal malformations. Difficult recombinant expression and purification of this POR mutant suggested that the protein was less stable than WT. The activities of cytochrome P450 17A1, 19A1, and 21A2, critical in steroidogenesis, were similar using our purified, full-length, unmodified A287P or WT POR, as were those of several xenobiotic-metabolizing cytochromes P450, indicating that the A287P protein is functionally competent in vitro, despite its functionally deficient phenotypic behavior in vivo Differential scanning calorimetry and limited trypsinolysis studies revealed a relatively unstable A287P compared with WT protein, leading to the hypothesis that the syndrome observed in vivo results from altered POR protein stability. The crystal structures of the soluble domains of WT and A287P reveal only subtle differences between them, but these differences are consistent with the differential scanning calorimetry results as well as the differential susceptibility of A287P and WT observed with trypsinolysis. The relative in vivo stabilities of WT and A287P proteins were also examined in an osteoblast cell line by treatment with cycloheximide, a protein synthesis inhibitor, showing that the level of A287P protein post-inhibition is lower than WT and suggesting that A287P may be degraded at a higher rate. Current studies demonstrate that, unlike previously described mutations, A287P causes POR deficiency disorder due to conformational instability leading to proteolytic susceptibility in vivo, rather than through an inherent flavin-binding defect.

Mitogen-activated Protein Kinase (MAPK) Activated by Prostaglandin E2 Phosphorylates Connexin 43 and Closes Osteocytic Hemichannels in Response to Continuous Flow Shear Stress.

Cx43 hemichannels serve as a portal for the release of prostaglandins, a critical process in mediating biological responses of mechanical loading on bone formation and remodeling. We have previously observed that fluid flow shear stress (FFSS) opens hemichannels; however, sustained FFSS results in hemichannel closure, as continuous opening of hemichannels is detrimental to cell viability and bone remodeling. However, the mechanism that regulates the closure of the hemichannels is unknown. Here, we show that activation of p44/42 ERK upon continuous FFSS leads to Cx43 phosphorylation at Ser(279)-Ser(282), sites known to be phosphorylated sites by p44/42 MAPK. Incubation of osteocytic MLO-Y4 cells with conditioned media (CM) collected after continuous FFSS increased MAPK-dependent phosphorylation of Cx43. CM treatment inhibited hemichannel opening and this inhibition was reversed when cells were pretreated with the MAPK pathway inhibitor. We found that prostaglandin E2 (PGE2) accumulates in the CM in a time-dependent manner. Treatment with PGE2 increased phospho-p44/42 ERK levels and also Cx43 phosphorylation at Ser(279)-Ser(282) sites. Depletion of PGE2 from CM, and pre-treatment with a p44/42 ERK pathway-specific inhibitor, resulted in a complete inhibition of ERK-dependent Cx43 phosphorylation and attenuated the inhibition of hemichannels by CM and PGE2. Consistently, the opening of hemichannels by FFSS was blocked by PGE2 and CM and this blockage was reversed by U0126 and the CM depleted of PGE2. A similar observation was also obtained in isolated primary osteocytes. Together, results from this study suggest that extracellular PGE2 accumulated after continuous FFSS is responsible for activation of p44/42 ERK signaling and subsequently, direct Cx43 phosphorylation by activated ERK leads to hemichannel closure.

Oxidative stress induces phosphorylation of neuronal NOS in cardiomyocytes through AMP-activated protein kinase (AMPK).

Neuronal nitric oxide synthase (nNOS) plays a critical role in regulating cardiomyocyte function. nNOS was reported to decrease superoxide production in the myocardium by inhibiting the function of xanthine oxidoreductase. However, the effect of oxidative stress on nNOS in cardiomyocytes has not been determined. We report here that brief exposure of HL-1 cardiomyocytes to hydrogen peroxide (H2O2) induces phosphorylation of nNOS at serine 1412. This increase in phosphorylation was concomitant with increased nitric oxide (NO) production. Prolonged exposure to the oxidant, however, resulted in decreased expression of the protein. H2O2 treatment for short periods also stimulated phosphorylation of AKT and AMPK. H2O2-induced phosphorylation of nNOS was reduced when AMPK activity was inhibited by compound C, suggesting that AMPK is a mediator of oxidative stress-induced phosphorylation of nNOS. However, inhibition of AKT activity by the pan AKT inhibitor, AKTi, had no effect on nNOS phosphorylation caused by H2O2. These data demonstrate the novel regulation of nNOS phosphorylation and expression by oxidative stress.

Direct regulation of osteocytic connexin 43 hemichannels through AKT kinase activated by mechanical stimulation.

Connexin (Cx) 43 hemichannels in osteocytes are thought to play a critical role in releasing bone modulators in response to mechanical loading, a process important for bone formation and remodeling. However, the underlying mechanism that regulates the opening of mechanosensitive hemichannels is largely unknown. We have recently shown that Cx43 and integrin α5 interact directly with each other, and activation of PI3K appears to be required for Cx43 hemichannel opening by mechanical stimulation. Here, we show that mechanical loading through fluid flow shear stress (FFSS) increased the level of active AKT, a downstream effector of PI3K, which is correlated with the opening of hemichannels. Both Cx43 and integrin α5 are directly phosphorylated by AKT. Inhibition of AKT activation significantly reduced FFSS-induced opening of hemichannels and disrupted the interaction between Cx43 and integrin α5. Moreover, AKT phosphorylation on Cx43 and integrin α5 enhanced their interaction. In contrast to the C terminus of wild-type Cx43, overexpression of the C-terminal mutant containing S373A, a consensus site previously shown to be phosphorylated by AKT, failed to bind with α5 and hence could not inhibit hemichannel opening. Together, our results suggest that AKT activated by FFSS directly phosphorylates Cx43 and integrin α5, and Ser-373 of Cx43 plays a predominant role in mediating the interaction between these two proteins and Cx43 hemichannel opening, a crucial step to mediate the anabolic function of mechanical loading in the bone.

Connexin 43 channels protect osteocytes against oxidative stress-induced cell death.

The increased osteocyte death by oxidative stress (OS) during aging is a major cause contributing to the impairment of bone quality and bone loss. However, the underlying molecular mechanism is largely unknown. Here, we show that H2O2 induced cell death of primary osteocytes and osteocytic MLO-Y4 cells, and also caused dose-dependent decreased expression of gap junction and hemichannel-forming connexin 43 (Cx43). The decrease of Cx43 expression was also demonstrated with the treatment of other oxidants, rotenone and menadione. Antioxidant reversed the effects of oxidants on Cx43 expression and osteocyte cell death. Cx43 protein was also much lower in the osteocytes from 20-month-old as opposed to the 5-week-old or 20-week old mice. Dye transfer assay showed that H2O2 reduced the gap junction intercellular communication (GJIC). In contrast to the effect on GJIC, there was a dose-dependent increase of hemichannel function by H2O2, which was correlated with the increased cell surface expression of Cx43. Cx43(E2) antibody, an antibody that specifically blocks Cx43 hemichannel activity but not gap junctions, completely blocked dye uptake induced by H2O2 and further exacerbated H2O2-induced osteocytic cell death. In addition, knockdown of Cx43 expression by small interfering RNA (siRNA) increased the susceptibility of the cells to OS-induced death. Together, our study provides a novel cell protective mechanism mediated by osteocytic Cx43 channels against OS.

Antibodies targeting extracellular domain of connexins for studies of hemichannels.

Hemichannels are transmembrane channels composed of either a connexin or pannexin hexamer. The docking of the extracellular domains of connexin hemichannels contributed by neighboring cells forms a gap junction channel that joins the cytoplasm of adjacent cells. Connexins are expressed ubiquitously in different organs, but some subtypes are expressed exclusively in certain tissues and tumors. Both gap junction channels and hemichannels participate in diverse physiological and pathological responses. However, the lack of specific reagents that inhibit only gap junction channels or hemichannels is a challenge that makes it different to discern the specific roles of either channel. Fortunately, the available information regarding the connexin sequence, secondary and tertiary structure, and their biochemical and physiological properties permits the development of strategies to block exclusively the hemichannel activity exclusively, with no effect on gap junction activity. This task is accomplished through the use of specifics antibodies that target the extracellular sites of desired connexin subtype. However, the underlying mechanism of how antibodies targeting extracellular connexin epitopes actually inhibit hemichannels remains unknown. Although these antibodies are being used for detecting and blocking of hemichannels in normal and tumor cells, they can also be potentially used for tissue-specific treatment and drug delivery in clinical applications. In this article, we will first review the literature concerning the structure of connexins and the unique properties of extracellular loop domains of the connexins. Furthermore, we will discuss briefly the development of connexin (Cx) 43(E2) antibody, a specific antibody which detects the second extracellular loop of Cx43 and specifically prevents the opening of Cx43 hemichannels. We will then summarize the reported studies of specific reagents used for the inhibition of connexin hemichannels including antibodies developed against extracellular loop domains. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'.

Biological role of connexin intercellular channels and hemichannels.

Gap junctions (GJ) and hemichannels (HC) formed from the protein subunits called connexins are transmembrane conduits for the exchange of small molecules and ions. Connexins and another group of HC-forming proteins, pannexins comprise the two families of transmembrane proteins ubiquitously distributed in vertebrates. Most cell types express more than one connexin or pannexin. While connexin expression and channel activity may vary as a function of physiological and pathological states of the cell and tissue, only a few studies suggest the involvement of pannexin HC in acquired pathological conditions. Importantly, genetic mutations in connexin appear to interfere with GJ and HC function which results in several diseases. Thus connexins could serve as potential drug target for therapeutic intervention. Growing evidence suggests that diseases resulting from HC dysfunction might open a new direction for development of specific HC reagents. This review provides a comprehensive overview of the current studies of GJ and HC formed by connexins and pannexins in various tissue and organ systems including heart, central nervous system, kidney, mammary glands, ovary, testis, lens, retina, inner ear, bone, cartilage, lung and liver. In addition, present knowledge of the role of GJ and HC in cell cycle progression, carcinogenesis and stem cell development is also discussed.

Gap junctions and hemichannels in signal transmission, function and development of bone.

Gap junctional intercellular communication (GJIC) mediated by connexins, in particular connexin 43 (Cx43), plays important roles in regulating signal transmission among different bone cells and thereby regulates development, differentiation, modeling and remodeling of the bone. GJIC regulates osteoblast formation, differentiation, survival and apoptosis. Osteoclast formation and resorptive ability are also reported to be modulated by GJIC. Furthermore, osteocytes utilize GJIC to coordinate bone remodeling in response to anabolic factors and mechanical loading. Apart from gap junctions, connexins also form hemichannels, which are localized on the cell surface and function independently of the gap junction channels. Both these channels mediate the transfer of molecules smaller than 1.2kDa including small ions, metabolites, ATP, prostaglandin and IP(3). The biological importance of the communication mediated by connexin-forming channels in bone development is revealed by the low bone mass and osteoblast dysfunction in the Cx43-null mice and the skeletal malformations observed in occulodentodigital dysplasia (ODDD) caused by mutations in the Cx43 gene. The current review summarizes the role of gap junctions and hemichannels in regulating signaling, function and development of bone cells. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Regulation of gap junction function and Connexin 43 expression by cytochrome P450 oxidoreductase (CYPOR).

Cytochrome P450 oxidoreductase (CYPOR) is a microsomal electron-transferring enzyme containing both FAD and FMN as co-factors, which provides the reducing equivalents to various redox partners, such as cytochromes P450 (CYPs), heme oxygenase (HO), cytochrome b(5) and squalene monooxygenase. Human patients with severe forms of CYPOR mutation show bone defects such as cranio- and humeroradial synostoses and long bone fractures, known as Antley-Bixler-like Syndrome (ABS). To elucidate the role of CYPOR in bone, we knocked-down CYPOR in multiple osteoblast cell lines using RNAi technology. In this study, knock-down of CYPOR decreased the expression of Connexin 43 (Cx43), known to play a critical role in bone formation, modeling, and remodeling. Knock-down of CYPOR also decreased Gap Junction Intercellular Communication (GJIC) and hemichannel activity. Promoter luciferase assays revealed that the decrease in expression of Cx43 in CYPOR knock-down cells was due to transcriptional repression. Primary osteoblasts isolated from bone specific Por knock-down mice calvariae confirmed the findings in the cell lines. Taken together, our study provides novel insights into the regulation of gap junction function by CYPOR and suggests that Cx43 may play an important role(s) in CYPOR-mediated bone defects seen in patients.

Glucocorticoid dose determines osteocyte cell fate.

In response to cellular insult, several pathways can be activated, including necrosis, apoptosis, and autophagy. Because glucocorticoids (GCs) have been shown to induce both osteocyte apoptosis and autophagy, we sought to determine whether osteocyte cell fate in the presence of GCs was dose dependent by performing in vivo and in vitro studies. Male Swiss-Webster mice were treated with slow-release prednisolone pellets at 1.4, 2.8, and 5.6 mg/kg/d for 28 d. An osteocyte cell line, MLO-Y4 cells, was treated with various doses of dexamethasone. We found that GC treatments dose dependently decreased activation of antioxidant-, autophagy-, and antiapoptosis-focused RT-PCR gene pathways in mouse cortical bone. The activation of antioxidant genes was correlated with autophagy gene expression after the GC treatments. The presence of osteocyte autophagy, as detected by immunostaining for LC3, increased ∼50% at the distal femur cortical bone region but not at trabecular bone region at the 1.4 and 2.8 mg/kg/d GC dose levels. The number of apoptotic osteocytes was increased at the cortical bone region by ∼40% initially observed at the 2.8 mg/kg/d dose level. In addition, the presence of the osteocyte autophagy was associated with an increased protein level of cathepsin K in vitro after the GC treatments. In summary, we found that GC treatment dose-dependently decreased antioxidant gene expression, with lower GC doses activating autophagy, whereas a higher dose increased apoptosis. These data suggest that autophagy may provide a mechanism for osteocytes to survive the stress after GC exposure and provide further insight into how GCs alter bone cell fate.

Mitochondrial remodeling following fission inhibition by 15d-PGJ2 involves molecular changes in mitochondrial fusion protein OPA1.

We showed earlier that 15 deoxy Delta(12,14) prostaglandin J2 (15d-PGJ2) inactivates Drp1 and induces mitochondrial fusion [1]. However, prolonged incubation of cells with 15d-PGJ2 resulted in remodeling of fused mitochondria into large swollen mitochondria with irregular cristae structure. While initial fusion of mitochondria by 15d-PGJ2 required the presence of both outer (Mfn1 and Mfn2) and inner (OPA1) mitochondrial membrane fusion proteins, later mitochondrial changes involved increased degradation of the fusion protein OPA1 and ubiquitination of newly synthesized OPA1 along with decreased expression of Mfn1 and Mfn2, which likely contributed to the loss of tubular rigidity, disorganization of cristae, and formation of large swollen degenerated dysfunctional mitochondria. Similar to inhibition of Drp1 by 15d-PGJ2, decreased expression of fission protein Drp1 by siRNA also resulted in the loss of fusion proteins. Prevention of 15d-PGJ2 induced mitochondrial elongation by thiol antioxidants prevented not only loss of OPA1 isoforms but also its ubiquitination. These findings provide novel insights into unforeseen complexity of molecular events that modulate mitochondrial plasticity.

MicroRNA biogenesis is required for Myc-induced B-cell lymphoma development and survival.

Many tumor cells express globally reduced levels of microRNAs (miRNA), suggesting that decreased miRNA expression in premalignant cells contributes to their tumorigenic phenotype. In support of this, Dicer, an RNase III-like enzyme that controls the maturation of miRNA, was recently shown to function as a haploinsufficient tumor suppressor in nonhematopoietic cells. Because the Myc oncoprotein, a critical inducer of B-cell lymphomas, was reported to suppress the expression of multiple miRNAs in lymphoma cells, it was presumed that a deficiency of Dicer and subsequent loss of miRNA maturation would accelerate Myc-induced lymphoma development. We report here that, surprisingly, a haploinsufficiency of Dicer in B cells failed to promote B-cell malignancy or accelerate Myc-induced B-cell lymphomagenesis in mice. Moreover, deletion of Dicer in B cells of CD19-cre(+)/Emicro-myc mice significantly inhibited lymphomagenesis, and all lymphomas that did arise in these mice lacked functional Cre expression and retained at least one functional Dicer allele. Uncharacteristically, the lymphomas that frequently developed in the CD19-cre(+)/Dicer(fl/fl)/Emicro-myc mice were of very early precursor B-cell origin, a stage of B-cell development prior to Cre expression. Therefore, loss of Dicer function was not advantageous for lymphomagenesis, but rather, Dicer ablation was strongly selected against during Myc-induced B-cell lymphoma development. Moreover, deletion of Dicer in established B-cell lymphomas resulted in apoptosis, revealing that Dicer is required for B-cell lymphoma survival. Thus, Dicer does not function as a haploinsufficient tumor suppressor in B cells and is required for B-cell lymphoma development and survival.