The cerebellum monitors errors and entrains executive networks.

Frontal midline θ (Fmθ) activity occurs in medial prefrontal cortices (mPFC), when expected and actual outcomes conflict. Cerebellar forward models could inform the mPFC about this mismatch. To verify this hypothesis we correlated the mPFC activation during a visuomotor tracking task (VM) with performance accuracy, in control and cerebellum-lesioned participants. Additionally, purely visual (V), motor (M) and a motor plus visual tasks (V + M) were performed. An Independent Component, with a mid-frontal topography scalp map and equivalent dipole location in the dorsal anterior cingulate cortex accounted for Fmθ. In control participants Fmθ power increased during VM, when the error level crossed a threshold, but not during V + M, M and V. This increase scaled with tracking error. Fmθ power failed to increase during VM in cerebellar participants, even at highest tracking errors. Thus, in control participants, activation of mPFC is induced when a continuous monitoring effort for online error detection is required. The presence of a threshold error for enhancing Fmθ, suggests the switch from an automatic to an executive tracking control, which recruits the mPFC. Given that the cerebellum stores forward models, the absence of Fmθ increases during tracking errors in cerebellar participants indicates that cerebellum is necessary for supplying the mPFC with prediction error-related information. This occurs when automatic control falters, and a deliberate correction mechanism needs to be triggered. Further studies are needed to verify if this alerting function also occurs in the context of the other cognitive and non-cognitive functions in which the cerebellum is involved.

Italian version of the cornell musculoskeletal discomfort questionnaire (CMDQ-I): Translation, cultural adaptation and validation.

BACKGROUND: Almost 25%of workers in the European Union suffer from back pain, and 23%complain of muscle pain. Sixty-two percent of workers carry out repetitive operations with their hands or arms, 46%work in painful or tired positions and 35%carry or handle loads. OBJECTIVE: This study aimed to translate, culturally adapt and validate the Italian version of the Cornell Musculoskeletal Discomfort Questionnaire (CMDQ-I). METHODS: Translation and cultural adaptation procedures followed international guidelines. Participants were recruited from among the personnel components of the Italian Air Force, who were between 18 and 65 years old. Cronbach's alpha and the intraclass correlation coefficient (ICC) were calculated to assess internal consistency and stability, respectively. The CDMQ-I was administered together with the Visual Analogic Scale (VAS), and the validity was evaluated using Pearson's correlation coefficient. RESULTS: All CDMQ-I items were either identical or similar in meaning to the original version's items. The scale was administered twice with a retest after seven to 10 days to 66 participants. Cronbach's alpha was higher than 0.761, and the ICC ranged between 0.737 and 0.952. Pearson's correlation coefficient showed positive and significant correlations (p > 0.01). CONCLUSIONS: The study produced an Italian version of the CMDQ with good reliability and validity. This scale is a useful tool to investigate the frequency and intensity of musculoskeletal disorders in various categories of workers.

Cervical re-injection of indocyanine green to improve sentinel lymph node detection in endometrial cancer.

OBJECTIVES: To evaluate the role of cervical re-injection of indocyanine green (ICG) to increase the detection rate of sentinel lymph node (SLN) in patients with endometrial cancer (EC) who underwent robotic-assisted surgical staging. METHODS: We retrospectively identified consecutive EC patients undergoing robotic-assisted staging with SLN biopsy at our Institution between June 2016 and April 2020. Patients were excluded if they had open abdominal surgical approach, neoadjuvant chemotherapy, and advanced stage [International Federation of Gynecology and Obstetrics (FIGO) stage III-IV] at diagnosis. According to our SLN protocol, in case of either unilateral or no SLN detection, we performed an ipsilateral or bilateral cervical re-injection of ICG. RESULTS: In total, 251 patients meeting inclusion criteria were included in the analysis. At first injection, bilateral detection was achieved in 184 (73.3%), unilateral detection in 57 (22.7%), and no detection in 10 (4.0%) patients. Cervical re-injection was performed in 51 of 67 patients with failed bilateral mapping. After cervical re-injection, bilateral detection rate increased to 94.5% (222/235), while unilateral and no detection were 5.1% (12/235) and 0.4% (1/235), respectively. CONCLUSIONS: Our results suggest that cervical re-injection of ICG, in case of failed bilateral mapping of SLN, brings about a significant improvement in SLN detection rates, therefore reducing the number of side-specific required lymphadenectomies.

Unlocked versus dynamic and static distal locked femoral nails in stable and unstable intertrochanteric fractures. A prospective study.

INTRODUCTION: Few clinical studies have analyzed the utility of distal interlocking screws in stable and unstable intertrochanteric fractures treated with intramedullary devices. We performed a prospective analysis comparing short unlocked versus short dynamic and short static distal locked intramedullary nails. MATERIALS AND METHODS: Nine level-II trauma centres were involved in the study. 240 patients over the age of 65 with a stable (AO/OTA 31-A1) or unstable intertrochanteric fracture (AO/OTA 31-A2) were prospectively investigated. The same type of nail was used in every patient. Patients were randomly divided into 3 groups according to the type of distal locking used. Intra-operative variables were examined and patients were followed clinically and radiographically at 1, 3, 6, 12 months postoperatively. All complications were recorded. RESULTS: A total of 212 patients completed 1 year of follow-up visits. In the Unlocking Group (UG) the operation time, blood loss, fluoroscopy time, total length of incision were significantly decreased compared to both the Dynamic Group (DG) and the Static Group (SG) (p < 0.05). Conversely, no reliable differences in intraoperative variables were noted between the Dynamic Group and the Static Group (p > 0.05). In terms of time of fracture union we found no differences among the three Groups (p > 0.05). Moreover, no cases of limb shortening >1 cm or varus collapse were detected in any group. The 3 Groups were similar in terms of HHS, SF-12 and Barthel index results at 1-year follow-up (p > 0.05). Finally, no significant differences were demonstrated across the three Groups in terms of major complications. CONCLUSIONS: This clinical study further confirms the hypothesis that short intramedullary nails do not need to be locked for stable and unstable intertrochanteric fractures.

Is distal locking with short intramedullary nails necessary in stable pertrochanteric fractures? A prospective, multicentre, randomised study.

We investigated whether a proximal femoral nail can be implanted without a distal locking screw in AO/OTA 31-A1 and 31-A2 pertrochanteric stable femur fractures. A multicentre, randomised study was conducted in six level-two trauma centres in our area (Puglia, Italy). A total of 333 patients received their allocated intervention (162 in the locking group [LG] and 171 in the unlocking group [UG]) and 266 patients were included in the final analysis at 1year. Our data showed no statistically significant difference between the two groups at 1-year follow-up for ability to walk, SF-36 questionnaire results, residual pain (visual analogue scale [VAS] score) and level of overall satisfaction. There were also no statistically significant differences between groups for mortality and length of hospital stay. Conversely, the UG was associated with shorter operation and fluoroscopy times, shorter surgical incision length, and less blood loss and residual thigh pain. Pertrochanteric stable fractures (31-A1, 31-A2) can be treated successfully with intramedullary nails without distal locking, reducing patient and clinical personnel radiation exposure and sanitary costs (surgery time and screws costs).

Total rectosigmoidectomy versus partial rectal resection in primary debulking surgery for advanced ovarian cancer.

PURPOSE: To compare in a sample of Italian patients intraoperative, perioperative complications, Quality of Life (QoL), recurrence rate and overall survival of advanced ovarian cancer (AOC) patients according to the type of surgery performed on sigma-rectum, total rectosigmoid resection (TRR) versus partial rectosigmoid resection (PRR). METHODS: From May 2004 to May 2010, consecutive patients affected by epithelial AOC (FIGO Stage III-IV) were assessed for this prospective case-control study, According to the type of colorectal surgery performed to approach rectosigmoid involvement, patients were allocated into Group A (TRR) and Group B (PRR). PRR was performed when the complete removal of disease led to a laceration <30-40% of intestinal wall circumference. RESULTS: 82 and 72 patients were included in Group A and Group B respectively. Surgical outcomes were statistically similar except hospital stay which was significantly lower in the PRR group. There was not a statistically significant difference as regarding intra-operative, perioperative and postoperative complications, even if a higher rate of major complications were recorded in TRR. An improvement in QoL's scores has been recorded in PRR's group. There was not a statistically difference concerning the optimal debulking rate (92% and 96% respectively) and 5-year Overall Survival (48% and 52% respectively). CONCLUSIONS: PRR seems to be feasible in over 40% of patients with advanced ovarian cancer and recto-sigmoid colon involvement. It is related to higher QoL and can be easily performed, without jeopardizing surgical radicality, in those cases in which conservative surgery at intestinal tract does not compromise residual tumor.

The Trop-2 signalling network in cancer growth.

Our findings show that upregulation of a wild-type Trop-2 has a key controlling role in human cancer growth, and that tumour development is quantitatively driven by Trop-2 expression levels. However, little is known about the regulation of expression of the TROP2 gene. Hence, we investigated the TROP2 transcription control network. TROP2 expression was shown to depend on a highly interconnected web of transcription factors: TP63/TP53L, ERG, GRHL1/Get-1 (grainyhead-like epithelial transactivator), HNF1A/TCF-1 (T-cell factor), SPI1/PU.1, WT (Wilms' tumour)1, GLIS2, AIRE (autoimmune regulator), FOXM1 (forkhead box M1) and FOXP3, with HNF4A as the major network hub. TROP2 upregulation was shown to subsequently drive the expression and activation of CREB1 (cyclic AMP-responsive-element binding protein), Jun, NF-κB, Rb, STAT1 and STAT3 through induction of the cyclin D1 and ERK (extracellular signal regulated kinase)/MEK (MAPK/ERK kinase) pathways. Growth-stimulatory signalling through NF-κB, cyclin D1 and ERK was shown to require an intact Trop-2 cytoplasmic tail. Network hubs and interacting partners are co-expressed with Trop-2 in primary human tumours, supporting a role of this signalling network in cancer growth.

Upregulation of Trop-2 quantitatively stimulates human cancer growth.

Trop-2 is a calcium signal transducer that is associated with transformed cell growth in experimental systems. However, its role in human cancer remains essentially unknown. In this study, we profiled Trop-2 expression in normal human tissues at the mRNA and protein levels. We then systematically compared Trop-2 mRNA and protein levels in tumours with their tissues of origin. We find that Trop-2 expression is invariably upregulated in tumours, regardless of baseline expression in normal tissues, which suggests a corresponding selective advantage. Thus, we investigated the outcome of Trop-2 upregulation on tumour growth. Overexpression of wild-type Trop-2 was shown to be necessary and sufficient to drive cancer growth in a widely invariant manner across cell type and species. Upregulation of Trop-2 was shown to quantitatively stimulate tumour growth, as proportional to expression levels in vivo, and tumour cell growth was abrogated by somatic knockdown of Trop-2 expression. On the other hand, we found no evidence of tumour-associated TROP2 mutations, nor of TROP2 induction of oncogenic transformation per se. Our data support a model where above-baseline expression of wild-type Trop-2 is a key driver of human cancer growth.

Intramuscular injections in newborns: analgesic treatment and sex-linked response.

AIM: To compare the analgesic effect of three treatments to relieve the pain produced by intramuscular injections (IMI) in term newborns, and to assess sex-linked differences in their response to pain. MATERIAL AND METHODS: We studied 62 babies. Each baby received antibiotic IMIs for clinical aims. During each IMI, one of the following analgesic treatments was utilized: oral 33% glucose (OG), sensorial saturation (SS), or topic anesthetic cream (TAC). SS is a validated analgesic method, based on the combination of three stimulations (tactile, acoustic and gustative). During the IMI, pain level was assessed with the use of the DAN scale, a validated neonatal pain scale. All babies who received three distinct analgesic procedures for three distinct IMIs were enrolled. Mean pain scores of the three analgesic treatment groups were compared. We then compared mean pain scores of females vs males in the whole cohort and within each treatment group. RESULTS: The 95% Confidence Intervals of pain scores were 5.6-6.5 for TAC, 1.4-2.3 for OG and 0.6-1.2 for SS: when treated with TAC, babies' pain scores were significantly higher than with OG or SS (p <0.0001); when treated with OG, babies' pain scores were higher than SS (p = 0.002). Females' mean pain score was significantly higher than males' mean pain score: (95% CI: 2.9-4.1 vs 2.0-3.1; p = 0.01). OG and SS produced significantly higher mean DAN scores in females than in males. Also in the TAC group females' mean DAN scores were higher than males, though this last difference was not statistically significant. CONCLUSION: This is the first study to show the effectiveness of nonpharmacologic analgesia in relieving IMI pain. It is also the first study to clearly show that the sex differences in pain perception are present since birth.

Synthesis of esters of androgens with unsaturated fatty acids for androgen requiring therapy.

Androgens' metabolism and activity are gaining a more and more important role in human physiology particularly referring to aging and to neurodegenerative diseases. Androgen treatment is often required for long-lasting disorders. In order to improve their duration and effects, androgens can be administered as esters of carboxylic acids. The novelty of our research is the use of esters of androgens with specific unsaturated fatty acids, in order to reduce possible side effects particularly related to chronic pathologies with altered lipid homeostasis such as X-linked adrenoleukodystrophy and cardiovascular disorders. Thus the esters of the main androgenic substances testosterone, dihydrotestosterone (DHT) and their metabolite 5α-androstan-3α,17ß-diol were chemically obtained by coupling with different unsaturated fatty acids. To this aim, fatty acids with various degree of unsaturation and belonging to different series were selected. Specifically, oleic acid (18:1, n-9), linoleic acid (18:2, n-6), and the n-3 fatty acids, α-linolenic acid (18:3), eicosapentaenoic acid (EPA, 20:5), and docosahexaenoic acid (DHA, 22:6) were used obtaining corresponding esters with acceptable yields and good degree of purity. All the synthesized compounds were tested for their cytotoxic activities in mouse NIH3T3 and human astrocyte cell lines. The esters demonstrated good tolerability and no in vitro cytotoxic effect in both cell cultures. After these promising preliminary results, the esters will be suitable for in vivo studies in order to ascertain their pharmacokinetic characteristics and their biological effects.

The soy phytoestrogens genistein and daidzein as neuroprotective agents against anoxia-glucopenia and reperfusion damage in rat urinary bladder.

Some bladder disorders, such as obstructive bladder and hyperactivity, may be caused partly by ischemia/reperfusion injury (I/R). The neuroprotective effects of estrogens were demonstrated in in vitro studies and a great interest in soy isoflavones (genistein and daidzein) as alternative to the synthetic estrogen receptor modulators for therapeutic use has been pointed out. The aim of this study was to investigate the effect of genistein and daidzein, on rat detrusor smooth muscle contractility and their possible neuroprotective role against I/R-like condition. Whole rat urinary bladders were subjected to in vitro anoxia-glucopenia (A-G) and reperfusion (R) in the absence or presence of drugs and response to electrical field stimulation (EFS) of intrinsic nerves evaluated. Furthermore rats were treated in vivo for 1 week with the phytoestrogens and the same in vitro protocol was applied to the ex vivo bladders. Antioxidant activity of genistein and daidzein on the A-G/R model was determined by measuring malonyldialdehyde (MDA). Moreover, hormones plasma levels were determined by radioimmunoassay. Genistein and daidzein administered either in vitro or in vivo showed significant neuroprotective effect and antioxidant activity. Testosterone and 17ß-estradiol plasma levels were not modified by daidzein, while a significant decrease of testosterone in genistein treated rats was evident. Moreover both phytoestrogens significantly decreased detrusor contractions induced by EFS in a concentration-dependent manner. For being either neuroprotective and myorelaxant, genistein and daidzein could be considered a good lead for new therapeutic agents to protect the urinary bladder from hyperactivity and nerve damage.

Can hyperbaric oxygenation therapy (HOT) modify the blood testosterone concentration?

INTRODUCTION: Testosterone has a modulating effect on inflammatory and healing processes. In this study, we evaluate whether hyperbaric oxygenation therapy (HOT) modifies the blood concentration of total testosterone (TT) in patients treated for different pathologies. MATERIALS AND METHODS: Fourteen male patients (23-72 years old) were treated with 90-min HOT sessions (range 4 to 23 sessions) as an adjuvant to the following conditions: leg fractures, osteonecrosis, diabetic foot, firearm injuries, complicated arthroprosthesis and underwater diving embolism. As controls, six healthy male volunteers (37-51 years old) were subjected to 10 HOT sessions. Testosterone plasma levels were determined immediately before the first HOT session and the day after the last session. RESULTS: At the end of treatment, 12 patients fully recovered and 2 (diabetic foot patients) showed a marked improvement. Testosterone significantly increased after hyperbaric oxygenation therapy in both patients and controls (ANOVA, p<0.004). DISCUSSION: We conclude that hyperbaric oxygenation therapy increases the blood concentration of total testosterone in patients as well as in healthy men. This finding raises new questions and indicates the need to investigate the causes of this increase and its therapeutic significance. Since testosterone modulates inflammation and healing processes, it is possible that hormonal changes are the mechanisms affected by hyperbaric oxygenation therapy.

Glucocorticoid receptor mRNA expression in peripheral blood mononuclear cells in high trained compared to low trained athletes and untrained subjects.

BACKGROUND: Physiological needs during prolonged exercise are a potent stimulus for the hypothalamic-pituitary-adrenal (HPA) axis. Hence, athletes undergoing daily endurance training sessions may have frequent and prolonged phases of endogenous hypercortisolism. Since chronic glucocorticoids treatment leads to down-regulation of glucocorticoid receptor alpha (GR-alpha) mRNA expression, endurance training could lead to modulation of GR expression. AIM: The aim of the study was to evaluate GR-alpha and GR-beta mRNA expressions in peripheral blood mononuclear cells and plasma cortisol, ACTH and cortisol binding globulin (CBG) concentrations at rest in subjects undergoing different training regimes. SUBJECTS AND METHODS: Nine high trained (HT) swimmers (training volume: 21.6+/-1.7 hours/week in 10-12 sessions) were compared with two age-matched control groups represented by 8 low trained (LT) runners (training volume: 6.4+/-2.6 h/week in 3-5 sessions) and 9 untrained subjects. Expression of GR was determined by RT-PCR of total RNA. Hormone levels were determined by radioimmunoassay methods. RESULTS: HT athletes showed 10 times less GR-alpha mRNA expression than the untrained subjects, while LT athletes exhibited values about twofold less than the untrained subjects. GR-beta mRNA expression was undetectable in all subjects. No differences were observed among the three groups in hormone levels. CONCLUSIONS: GR- alpha mRNA expression is repressed in proportion to the amount and frequency of the stressful stimuli due to training. Hence, this down-regulation may be a consequence of the frequent and prolonged exposure to cortisol acute elevations induced by training. GR-beta did not play an important role in inducing the down-regulation of GR-alpha mRNA expression observed.

[Sexual rehabilitation with intracavernous PGE1 injections and oral drug administration in diabetic patients non-responder to oral therapy alone].

Diabetes is an important risk factor in erectile dysfunction (ED), acting via several mechanisms. We assessed the efficacy of intracavernous injections (ICI) rehabilitation and oral systematic therapy in diabetic patients, as well as the response of controls to oral therapy 'on demand'. MATERIALS AND METHODS. Sixteen diabetic patients with ED were treated with vasoactive drugs orally when needed, without satisfactory erections. The patients underwent then ICI rehabilitation with PGE1 20 mcg twice weekly for 4 weeks, followed by the administration of oral drugs twice weekly for 4 weeks. Before and after rehabilitation, the patients completed a detailed anamnestic protocol to study their libido (always present); they answered questions Q3 and Q4 of the IIEF questionnaire. During ICI, a study with dynamic echocolordoppler (ECCD) was carried out. All patients had Type 2 diabetes: 10 were treated with oral antidiabetics, 4 were treated with insulin, and in the other 2 patients, treated with insulin, a sensitive neuropathy of the lower limbs was diagnosed. Fourteen patients were treated with antihypertensive drugs. RESULTS. Before rehabilitation, the mean responses to questions 3 and 4 of the IIEF (International Index of Erectile Function) questionnaire were 1.6 and 1.5 respectively; after rehabilitation, the mean responses were 2.68 and 2.5, respectively. The ECCD test showed an arterial component in 4 cases and a high end-diastolic velocity (EDV) in 14 cases. Four patients (25%), 2 of which had neuropathy, and 2 were in advanced age, did not respond to PGE1 or to oral therapy, 4 patients (25%) (2 treated with insulin and 2 by oral therapy) responded to ICI but not to oral therapy, while 8 patients (50%) showed a good response to both injectable and oral therapy, with good Q3 and Q4 scores. CONCLUSIONS. Good endothelial function appears to be essential for the maintenance of acceptable erectile function. Diabetes has a negative effect on this function, as does hypoxia and low perfusion. Based on the principle that a good erection improves endothelial function, we tried to determine if oral systematic and intracavernous rehabilitation would improve erectile function in diabetic patients. The results indicate that diabetes interferes with erectile function, compromising the effects of the vasoactive drugs. However, integrated systematic rehabilitation appears to allow a good erectile response to both intracavernous and oral therapy in a large number of cases. Therefore, we support this kind of rehabilitative protocol in the treatment of ED in diabetic patients.

Single opioid administration modifies gonadal steroids in both the CNS and plasma of male rats.

While morphine remains one of the most widely used opioids for the treatment of painful conditions, other opioids are also commonly employed. Because of the interactions between opioids and gonadal hormones, in particular opioid-induced hypogonadism, this study investigated the effects of widely used opioids on plasma testosterone and estradiol levels and brain testosterone levels in male rats. Animals were s.c. injected with two concentrations of morphine (5 or 10 mg/kg), fentanyl (0.05 or 0.1 mg/kg), tramadol (10 or 40 mg/kg), buprenorphine (0.05 or 0.1 mg/kg) or saline (0.7 ml/kg). Four or 24 h after treatment, the rats were deeply anesthetized to collect blood samples from the abdominal aorta and to perfuse the brains with saline. Plasma and brain hormone levels were measured by radioimmunoassay. In rats studied 4 h after treatment, all the opioids except tramadol 10 mg/kg decreased plasma testosterone in comparison with saline administration. At the same time, plasma estradiol levels were lower than control in the groups treated with the low doses of morphine, tramadol and buprenorphine, while estradiol remained at control levels in the other groups. Twenty-four hours after treatment, plasma testosterone levels were different (higher) than control in the animals treated with the low doses of morphine, fentanyl and buprenorphine. Estradiol was lower than control in the low dose groups, while the high doses did not produce any changes with respect to control. Four hours after treatment, brain testosterone was drastically decreased in all groups except buprenorphine, in which it remained at control levels. All groups returned to control levels at 24 h after treatment. In conclusion, opioids exert important effects on plasma and CNS sex hormone levels. The different magnitude and time-course of the effects of the different opiates on testosterone and estradiol levels are likely due to their different mechanism of action.

Effects of gonadectomy and pain on interferon-gamma production in splenocytes of male and female rats.

The role of gonadal hormones and persistent pain (formalin test) in the regulation of interferon-gamma (IFN-gamma) production in splenocytes was investigated in male and female rats. Animals were either sham-operated (Intact) or gonadectomized (GDX) and, 3 weeks later, were subcutaneously injected with formalin (50 microl, 10%) or only pricked with a syringe needle in the dorsal hind paw. Sixty minutes after treatment the animals were deeply anesthetized and the spleens were dissected under aseptic conditions. Blood was collected from the abdominal aorta for measurement of plasma steroids. IFN-gamma production was determined in vitro in the splenocytes after Con A stimulation. Splenocytes of Intact females showed higher IFN-gamma production than those of Intact males. This sex difference disappeared in GDX animals because of the lower levels in GDX females. Formalin decreased IFN-gamma in both Intact and GDX groups. In females, there was a positive correlation between IFN-gamma production in splenocytes and plasma estradiol levels. The present data demonstrate a sex difference in IFN-gamma production (due to the immunostimulating effect of estradiol in females) and an immunodepressive role of pain in both sexes.

Bisphenol-A differently affects estrogen receptors-alpha in estrous-cycling and lactating female rats.

The effect of long-term exposure to bisphenol-A (BPA) on estrogen receptor-alpha (ER) immunoreactivity was studied in the medial preoptic area, arcuate nucleus and the ventromedial nucleus of the hypothalamus of estrous cycling and lactating female rats. Pregnant/lactating or estrous cycling rats were exposed to BPA (40 mg/Kg/day) or peanut oil. Lactating females showed fewer ER-immunoreactive cells than non-lactating females in the medial preoptic area and ventromedial nucleus of the hypothalamus. BPA induced an increase in ER-immunoreactive cells in the medial preoptic nucleus irrespective of lactation. BPA only induced a decrease in ER-immunoreactive cells in the arcuate nucleus of the lactating group; oil induced an increase in ER-immunoreactive cells in the lactating with respect to non-lactating group. The results demonstrate that exposure of adult females to BPA modifies the number of ERs.

The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case.

The PAX5 gene, encoding the B-cell-specific activator protein, is a critical determinant of commitment to the B-lymphocyte pathway. This gene, mapped at 9p13, is juxtaposed to the immunoglobulin heavy chain (IgH) gene as a result of the t(9;14)(p13;q32), a rare but recurring translocation found in a subset of B-cell non-Hodgkin's lymphoma cases. In all of these, this translocation results in deregulated expression of the gene product because of the proximity of IgH. We present here the molecular characterization of a previously reported acute lymphoblastic leukemia case carrying a t(9;12)(q11;p13) translocation. Using 5' rapid amplification of cDNA ends PCR, a novel chimeric transcript was identified that contained the NH(2)-terminal region of PAX5 and most of the ETV6/TEL gene on 12p13. According to the fusion transcript, the resulting chimeric protein would retain the PAX5 paired-box domain and both the helix-loop-helix and DNA binding domains of TEL. Thus, it is reasonable to hypothesize that this protein could act as an aberrant transcription factor. This is the first report of PAX5 rearrangement in a human malignancy resulting in a chimeric transcript.