Nebulized glycyrrhizin/enoxolone drug modulates IL-17A in COVID-19 patients: a randomized clinical trial.

Introduction: Glycyrrhizin (GA) and its derivative Enoxolone (18ß), isolated from the Glycyrrhiza glabra plant, are two potential molecules for treating viral diseases. Both demonstrate to regulate immune system with antiviral and anti-inflammatory activities, with the latter mainly due to modulation of inflammatory cytokines. The aim of this clinical trial was to evaluate the safety and efficacy of a nebulized GA/18ß drug for treating COVID-19 patients. Methods: An open label, randomized, placebo-controlled clinical trial was conducted in Mexico City from January-August 2022 (Registration No. PROTAP-CLI-00). Clinical and biochemical parameters were recorded. Blood samples from patients were regularly collected to evaluate interleukins IL-4, IL-2, IL-1b, TNF-α, IL-17A, IL-6, IL-10,IFN-γ, IL-12, IL-8 and TGF-ß1, as well as IgM and IgG against SARS-CoV-2. Two doses of the drug were used - 30/2 mg (dose A) and 90/4 mg (dose B). Results and discussion: Both GA/18ß doses modulated inflammatory response by reducing mainly IL-17A expression, which in turn kept IL-1ß, IL-6, IL-8 and TNF-α interleukins unchanged, indicating significant modulation of key interleukin levels to prevent exacerbation of the immune response in COVID-19 patients. Early on, dose A increased IgM, while dose B induced expression of the antiviral IFN-γ. No severe side effects were seen with either dose, indicating nebulized GA/18ß is a safe treatment that could be used for COVID-19 and potentially other viral infections involving inflammatory response.

Ketoconazole Reverses Imatinib Resistance in Human Chronic Myelogenous Leukemia K562 Cells.

Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the oncogene BCR-ABL1, which encodes an oncoprotein with tyrosine kinase activity. Imatinib, a BCR-ABL1 tyrosine kinase inhibitor, performs exceptionally well with minimal toxicity in CML chemotherapy. According to clinical trials, however, 20-30% of CML patients develop resistance to imatinib. Although the best studied resistance mechanisms are BCR-ABL1-dependent, P-glycoprotein (P-gp, a drug efflux transporter) may also contribute significantly. This study aimed to establish an imatinib-resistant human CML cell line, evaluate the role of P-gp in drug resistance, and assess the capacity of ketoconazole to reverse resistance by inhibiting P-gp. The following parameters were determined in both cell lines: cell viability (as the IC50) after exposure to imatinib and imatinib + ketoconazole, P-gp expression (by Western blot and immunofluorescence), the intracellular accumulation of a P-gp substrate (doxorubicin) by flow cytometry, and the percentage of apoptosis (by the Annexin method). In the highly resistant CML cell line obtained, P-gp was overexpressed, and the level of intracellular doxorubicin was low, representing high P-gp activity. Imatinib plus a non-toxic concentration of ketoconazole (10 µM) overcame drug resistance, inhibited P-gp overexpression and its efflux function, increased the intracellular accumulation of doxorubicin, and favored greater apoptosis of CML cells. P-gp contributes substantially to imatinib resistance in CML cells. Ketoconazole reversed CML cell resistance to imatinib by targeting P-gp-related pathways. The repurposing of ketoconazole for CML treatment will likely help patients resistant to imatinib.

Ruxolitinib as a treatment strategy for SARS-CoV-2 pneumonia: clinical experience in a real-world setting.

INTRODUCTION: Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) infection is characterised by a viral phase and a severe pro-inflammatory phase. The inhibition of the JAK/STAT pathway limits the pro-inflammatory state in moderate to severe COVID-19. METHODOLOGY: We analysed the data obtained by an observational cohort of patients with SARS-CoV-2 pneumonia treated with ruxolitinib in 22 hospitals of Mexico. The applied dose was determined based on physician's criteria. The benefit of ruxolitinib was evaluated using the 8-points ordinal scale developed by the NIH in the ACTT1 trial. Duration of hospital stay, changes in pro-inflammatory laboratory values, mortality, and toxicity were also measured. RESULTS: A total of 287 patients were reported at 22 sites in Mexico from March to June 2020; 80.8% received ruxolitinib 5 mg BID and 19.16% received ruxolitinib 10 mg BID plus standard of care. At beginning of treatment, 223 patients were on oxygen support and 59 on invasive ventilation. The percentage of patients on invasive ventilation was 53% in the 10 mg and 13% in the 5 mg cohort. A statistically significant improvement measured as a reduction by 2 points on the 8-point ordinal scale was described (baseline 5.39 ± 0.93, final 3.67± 2.98, p = 0.0001). There were 74 deaths. Serious adverse events were presented in 6.9% of the patients. CONCLUSIONS: Ruxolitinib appears to be safe in COVID-19 patients, with clinical benefits observed in terms of decrease in the 8-point ordinal scale and pro-inflammatory state. Further studies must be done to ensure efficacy against mortality.

Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations.

Assessment of measurable residual disease (often referred to as "minimal residual disease") has emerged as a highly sensitive indicator of disease burden during and at the end of treatment and has been correlated with time-to-event outcomes in chronic lymphocytic leukemia. Undetectable-measurable residual disease status at the end of treatment demonstrated independent prognostic significance in chronic lymphocytic leukemia, correlating with favorable progression-free and overall survival with chemoimmunotherapy. Given its utility in evaluating depth of response, determining measurable residual disease status is now a focus of outcomes in chronic lymphocytic leukemia clinical trials. Increased adoption of measurable residual disease assessment calls for standards for nomenclature and outcomes data reporting. In addition, many basic questions have not been systematically addressed. Here, we present the work of an international, multidisciplinary, 174-member panel convened to identify critical questions on key issues pertaining to measurable residual disease in chronic lymphocytic leukemia, review evaluable data, develop unified answers in conjunction with local expert input, and provide recommendations for future studies. Recommendations are presented regarding methodology for measurable residual disease determination, assay requirements and in which tissue to assess measurable residual disease, timing and frequency of assessment, use of measurable residual disease in clinical practice versus clinical trials, and the future usefulness of measurable residual disease assessment. Nomenclature is also proposed. Adoption of these recommendations will work toward standardizing data acquisition and interpretation in future studies with new treatments with the ultimate objective of improving outcomes and curing chronic lymphocytic leukemia.

Real-life use of ramucirumab in gastric cancer in Spain: the RAMIS study.

Aims: To obtain real-world data on ramucirumab use and effectiveness for the treatment of advanced gastric cancer (AGC) or gastroesophageal junction adenocarcinoma (GEJ). Methods: Observational, retrospective study carried out in 20 Spanish hospitals, in patients who started ramucirumab treatment between December 2015 and December 2018. Descriptive analysis was conducted for patient characteristics, treatment patterns and effectiveness outcomes. Results: Three hundred seventeen patients were included (93.7% treated with ramucirumab-paclitaxel and 6.3% with ramucirumab); age 62.5 (11.3) years; 66.9% male. Median progression-free survival and overall survival were 3.9 months (95% CI: 3.4-4.3) and 7.4 (95% CI: 6.4-8.9) in combination regimen and 2.0 (1.1-2.8) and 4.3 (95% CI: 1.9-7.3) in monotherapy, respectively. Conclusion: The study findings were consistent with available real-world studies and randomized clinical trials.

Treatment-Related Mortality From Infectious Complications in an Acute Leukemia Clinic.

BACKGROUND: The main causes of mortality in patients with acute leukemia are the infectious complications. The author wanted to know the induction-related mortality and treatment-related mortality in the acute leukemia patients at the Instituto Nacional de Cancerologia (INCan), Mexico. Also the author is interested in finding out the micro-organism and the main site of infection to make some changes in the management of patients in these clinics. Primary objective was induction chemotherapy-related mortality and treatment-related mortality. Secondary objective was to determine the site of infection, micro-organism, type of chemotherapy related with more mortality and relapse mortality. METHODS: This was a retrospective case-series analysis of all patients who were admitted to the INCan Acute Leukemia Clinic between January 2012 and December 2015 with febrile neutropenic complications. We reviewed the case histories of all patients, including those with acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), acute biphenotypic leukemia and acute promyelocytic leukemia, regardless of disease status (newly diagnosed or relapsed) at the time of clinic attendance. Patients who died as the result of an infectious complication during the analysis window were identified, and their demographics, disease characteristics, treatment history (chemotherapy within 45 days of date of death) and details of the infectious complication resulting in death were collected. RESULTS: Of the 313 patients studied during that time period, 84 (27%) died as a result of infectious complications. Lung infections were the most common, accounting for 67% of all deaths from infectious complications. Escherichia coli producing extended-spectrum beta-lactamases was the most frequently isolated infectious organism (12 patients; 14%). The majority of deaths occurred during either induction therapy (27 patients; 32%) or treatment for a first relapse (25 patients; 30%). Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) was the chemotherapy regimen most commonly received within 45 days prior to death (17 patients; 20%). CONCLUSIONS: Our findings suggest a need for long-term management and supportive care to prevent infectious complication-associated fatalities during both initial chemotherapy and subsequent disease relapse in patients with acute leukemia. The use of prophylaxis will help patients to prevent complications.

Intergluteal Cleft Eccrine Porocarcinoma with Metastasis to Inguinal Region and Lung: Case Report and Review of the Literature.

Eccrine porocarcinoma (EPC) is an infrequent cutaneous neoplasm, and was described in 1963 by Pinkus and Mehregan. It is a rare type of skin tumor (0.005-0.01% of all skin tumors). Less than 300 cases have been described in the entire world medical literature. To our knowledge, no case of intergluteal cleft EPC has been reported in the literature in English and Spanish to date, so this would be the first reported case of such pathology. Metastatic EPC is less frequent, since only <10% of metastatic type have been reported and the rest as localized disease. The primary treatment of choice is surgical wide local excision of the tumor with histological confirmation of tumor-free margins. Prognosis is difficult to determine because of the rarity of EPC and the variations in natural history. There are no data to support the use of adjuvant chemotherapy or radiotherapy, and there are currently no agreed criteria to define patients at high risk of relapse. We present a 67-year-old man with intergluteal cleft eccrine tumor by biopsy. Metastasis to left inguinal region and lung was reported by contrasted abdominal and chest computed tomography. He started chemotherapy based on etoposide, vincristine, carboplatin. A review of pertinent literature is provided.

Ultrastructure Morphological Characterization of Different Passages of Rat Dental Follicle Stem Cells at In vitro Culture.

INTRODUCTION: Stem cells play important roles in tissue renewal and repair. Tissue-derived stem cells have been demonstrated for their applications in tissue engineering and regenerative medicine. Expansion of primary stem cells isolated from tissues to a large quantity through in vitro culture is needed for application of the stem cells. However, it is known that tissue stem cells commonly reduce or lose their stemness properties during in vitro culture. In this study, we assessed ultrastructural changes of rat dental follicle stem cells (DFSCs) during in vitro culture. It is our attempt to explain the loss of stemness properties in cultured tissue-stem cells at the ultrastructural level. METHOD: DFSCs was isolated from first molars of Sprague Dawley rat pups and cultured in medium consisting of alpha-MEM plus 20% FBS. Cells were passaged at 1 to 3 ratio at 90% confluence, and collected at passages 3, 6, 7 and 9 for assessment of ultrastructure morphology by transmission electron microscopy. RESULTS: Of the four passages (3, 6, 7, and 9) examined, dilated rough endoplasmic reticulum (RER) was abundant in Passage 3 but less so in Passages 6, 7, and 9. The dilated RER contained lipid in Passages 3, 7, and 9. The mono- and polyribosomes in Passages 3 and 6 were located between the mitochondria and the RER. Mono- and polyribosomes were abundant in Passage 7, although mainly monoribosomes were present in Passage 9. Membrane-bound glycogen granules were in vacuoles bulging off the cells in Passage 3. Some glycogen granules were grouped in the periphery of a stem cell in Passage 9. Nuclei shapes were irregular and mainly euchromatic in Passages 6, 7, and 9. The mitochondria were dark and scarce in Passage 9; irregular, small, and dark in Passage 7; and small and rounded in Passage 6, and they were spread in the cytoplasm away from the nucleus in Passage 3. Cell contacts were seen in Passages 6, 7, and 9. The ultrastructure morphology of the examined DFScs was not very different from the morphology criteria of the undifferentiated cells. Large vacuoles in Passage 3 were mainly at the periphery of the cell, with the small vacuoles in the cell center. Small vacuoles were scattered in the cell center of Passage 6 and the larger ones were observed at the cell's periphery. CONCLUSIONS: We observed the following ultrastructural changes: decreases of fine cell cytoplasmic processes, dilated cytoplasmic vacuoles, cytoplasmic pinocytotic vesicles, and nuclear heterochromatin with increasing cell passage number. Conversely, mean ratios of lipid globules, nuclear euchromatin, irregular nuclear shape, and cell contact between cells were increased with passage number. The observations may suggest an increase in committed cells among the population after long-term culture of DFSCs.

RARß2-dependent signaling represses neuronal differentiation in mouse ES cells.

Embryonic Stem (ES) cells are pluripotent cells that can be induced to differentiate into cells of all three lineages: mesoderm, endoderm, and ectoderm. In culture, ES cells can be differentiated into mature neurons by treatment with Retinoic Acid (RA) and this effect is mediated mainly through the activation of the RA nuclear receptors (RAR α, ß, and γ), and their isoforms. However, little is known about the role played by specific RAR types on ES cell differentiation. Here, we found that treatment of ES cells with AC55649, an RARß2 agonist, increased endodermal marker gene expression. On the other hand, we found that the inhibition of RARß with 5µM LE135, together with RA treatment, increased the efficiency of mouse ES cell differentiation into neurons by more than 4-fold as compared to cells treated with RA only. Finally, we performed proteomic analyses on ES cells treated with RA vs RA plus AC55649 in order to identify the signaling pathways activated by the RARß agonist. Our proteomic analyses using antibody microarrays indicated that proteins such as p38 and AKT were upregulated in cells treated with RA plus the agonist, as compared to cells treated with RA alone. Our results indicate that RARß may function as a repressor of neuronal differentiation through the activation of major cell signaling pathways, and that the pharmacological inhibition of this nuclear receptor may constitute a novel method to increase the efficiency of ES to neuronal differentiation in culture.

Observation on the ultrastructure morphology of HeLa cells treated with ethanol: Statistical analysis.

It is estimated that 5.9% of all human deaths are attributable to alcohol consumption and that the harmful use of ethanol ranks among the top five risk factors for causing disease, disability, and death worldwide. Ethanol is known to disrupt phospholipid packing and promote membrane hemifusion at lipid bilayers. With the exception of mitochondria involved in hormone synthesis, the sterol content of mitochondrial membranes is low. As membranes that are low in cholesterol have increased membrane fluidity and are the most easily disordered by ethanol, we hypothesize that mitochondria are sensitive targets for ethanol damage. HeLa cells were exposed to 50 mM ethanol and the direct effects of ethanol on cellular ultrastructure were examined utilizing transmission electron microscopy. Our ultramicroscopic analysis revealed that cells exposed to ethanol harbor fewer incidence of apoptotic morphology; however, significant alterations to mitochondria and to nuclei occurred. We observed statistical increases in the amount of irregular cells and cells with multiple nuclei, nuclei harboring indentations, and nuclei with multiple nucleolus-like bodies. Indeed, our analysis revealed that mitochondrial damage is the most extensive type of cellular damage. Rupturing of cristae was the most prominent damage followed by mitochondrial swelling. Ethanol exposure also resulted in increased amounts of mitochondrial rupturing, organelles with linked membranes, and mitochondria localizing to indentations of nuclear membranes. We theorize that these alterations could contribute to cellular defects in oxidative phosphorylation and, by extension, the inability to generate regular levels of cellular adenosine triphosphate.

[Abdominal ectopic pregnancy. A case report and literature review]. / Embarazo ectópico abdominal. Reporte de un caso y revisión de la bibliografía.

Abdominal ectopic pregnancy is an extremely rare entity, which represents 1% of all ectopic pregnancies and is associated with high maternal and fetal morbidity and mortality. The maternal mortality risk of an abdominal ectopic pregnancy is seven to eight times greater than the risk of a tubal ectopic pregnancy and is 90 times greater than the risk of intrauterine pregnancy. This is a disease of difficult diagnosis that often takes place late. We report the case of a patient with an abdominal ectopic pregnancy, which was diagnosed by abdominal ultrasound in the second trimester; the patient was suc- cessfully treated with exploratory laparotomy with complete removal of the fetus and placenta. We provide a review of the literature on the risk factors for abdominal ectopic pregnancy, diagnostic tests and therapeutic options.

Effect of the environmental pollutant hexachlorobenzene (HCB) on the neuronal differentiation of mouse embryonic stem cells.

Exposure to persistent environmental pollutants may constitute an important factor on the onset of a number of neurological disorders such as autism, Parkinson's disease, and Attention Deficit Disorder (ADD), which have also been linked to reduced GABAergic neuronal function. GABAergic neurons produce γ-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the brain. However, the lack of appropriate models has hindered the study of suspected environmental pollutants on GABAergic function. In this work, we have examined the effect of hexachlorobenzene (HCB), a persistent and bioaccumulative environmental pollutant, on the function and morphology of GABAergic neurons generated in vitro from mouse embryonic stem (ES) cells. We observed that: (1) treatment with 0.5 nM HCB did not affect cell viability, but affected the neuronal differentiation of ES cells; (2) HCB induced the production of reactive oxygen species (ROS); and (3) HCB repressed neurite outgrowth in GABAergic neurons, but this effect was reversed by the ROS scavenger N-acetylcysteine (NAC). Our study also revealed that HCB did not significantly interfere with the function of K+ ion channels in the neuronal soma, which indicates that this pollutant does not affect the maturation of the GABAergic neuronal soma. Our results suggest a mechanism by which environmental pollutants interfere with normal GABAergic neuronal function and may promote the onset of a number of neurological disorders such as autism and ADD.

[National guidelines of diagnosis and treatment of the non-Hodgkin lymphoma]. / Guías nacionales de diagnóstico y tratamiento de linfoma no Hodgkin.

Non-Hodgkin lymphoma comprises a heterogeneous group of haematological malignancies, classified according to their clinic, anatomic-pathological features and, lately, to their molecular biomarkers. Despite the therapeutic advances, nearly half of the patients will die because of this disease. The new diagnostic tools have been the cornerstone to design recent therapy targets, which must be included in the current treatment guidelines of this sort of neoplasms by means of clinical trials and evidence-based medicine. In the face of poor diagnoses devices in most of the Mexican hospitals, we recommend the present diagnose stratification, and treatment guidelines for non-Hodgkin lymphoma, based on evidence. They include the latest and most innovative therapeutic approaches, as well as specific recommendations for hospitals with limited framework and therapy resources.

All-trans-retinoid acid induces the differentiation of encapsulated mouse embryonic stem cells into GABAergic neurons.

Embryonic stem (ES) cells are pluripotent cells that can differentiate into all three main germ layers: endoderm, mesoderm, and ectoderm. Although a number of methods have been developed to differentiate ES cells into neuronal phenotypes such as sensory and motor neurons, the efficient generation of GABAergic interneurons from ES cells still presents an ongoing challenge. Because the main output of inhibitory GABAergic interneurons is the gamma-aminobutyric-acid (GABA), a neurotransmitter whose controlled homeostasis is required for normal brain function, the efficient generation in culture of functional interneurons may have future implications on the treatment of neurological disorders such as epilepsy, autism, and schizophrenia. The goal of this work was to examine the generation of GABAergic neurons from mouse ES cells by comparing an embryoid body-based methodology versus a hydrogel-based encapsulation protocol that involves the use of all-trans-retinoid acid (RA). We observed that (1) there was a 2-fold increase in neuronal differentiation in encapsulated versus non-encapsulated cells and (2) there was an increase in the specificity for interneuronal differentiation in encapsulated cells, as assessed by mRNA expression and electrophysiology approaches. Furthermore, our results indicate that most of the neurons obtained from encapsulated mouse ES cells are GABA-positive (∼87%). Thus, these results suggest that combining encapsulation of ES cells and RA treatment provide a more efficient and scalable differentiation strategy for the generation in culture of functional GABAergic interneurons. This technology may have implications for future cell replacement therapies and the treatment of CNS disorders.

Hoxa1 is required for the retinoic acid-induced differentiation of embryonic stem cells into neurons.

The ability of embryonic stem (ES) cells to differentiate into different cell fates has been extensively evaluated, and several protocols exist for the generation of various types of cells from mouse and human ES cells. We used a differentiation protocol that involves embryoid body formation and all-trans-retinoic acid (RA, 5 microM) treatment (EB/5 microM RA) to test the ability of Hoxa1 null ES cells to adopt a neuronal fate. Hoxa1(-/-) ES cells, when treated in this EB/5 microM RA protocol, failed to differentiate along a neural lineage; Hoxa1(-/-) ES cells express severalfold lower levels of many neuronal differentiation markers, including nestin, beta-tubulin III, and MAP2, and conversely, higher levels of endodermal differentiation markers (i.e., Sox17, Col4a1) than wild type (Wt) cells. Reintroduction of exogenous Hoxa1, under the control of the metallothionein I promoter, into Hoxa1(-/-) ES cells restored their capacity to generate neurons. Moreover, overexpression of Sox17, a gene that regulates endodermal differentiation, in Wt ES cells resulted in endodermal differentiation and in a complete abolition of beta-tubulin III expression. Thus, Hoxa1 activity is essential for the neuronal differentiation of ES cells in the presence of all-trans-RA, and Hoxa1 may promote neural differentiation by inhibiting Sox17 expression. Pharmacological manipulation of Hoxa1 levels may provide a method for promoting neuronal differentiation for therapeutic uses. Furthermore, because mutations in the Hoxa1 gene can cause autism spectrum disorder in humans, these data also provide important mechanistic insights into the early developmental processes that may result in this disorder.

Diepoxybutane activates the mitochondrial apoptotic pathway and mediates apoptosis in human lymphoblasts through oxidative stress.

Diepoxybutane (DEB) is the most potent metabolite of the environmental chemical 1,3-butadiene (BD), which is prevalent in petrochemical industrial areas. BD is a known mutagen and human carcinogen, and possesses multi-systems organ toxicity. We recently reported that DEB-induced cell death in TK6 lymphoblasts was due to the occurrence of apoptosis, and not necrosis. In this study, we investigated the molecular mechanisms responsible for DEB-induced apoptosis in these cells. Bax and Bak were found to be over-expressed and activated, and the mitochondrial trans-membrane potential was attenuated in cells undergoing DEB-induced apoptosis. Cytochrome c was depleted from the mitochondria of TK6 cells undergoing apoptosis, and was released into the cytosol in Jurkat T-lymphoblasts exposed to the same concentrations of DEB. Executioner caspase 3 was deduced to be activated by initiator caspase 9. DEB-induced reactive oxygen species (ROS) formation, and the ROS scavenger N-acetyl-L-cysteine effectively blocked DEB-induced apoptosis in TK6 cells. Collectively, these results demonstrate that the mitochondrial apoptotic pathway is activated to mediate DEB-induced apoptosis in human TK6 lymphoblasts. These results further demonstrate that DEB-induced apoptosis is also mediated by the DEB-induced generation of ROS. This is the first report to examine the mechanism of DEB-induced apoptosis in human lymphoblasts.

Differences in gene expression between wild type and Hoxa1 knockout embryonic stem cells after retinoic acid treatment or leukemia inhibitory factor (LIF) removal.

Homeobox (Hox) genes encode a family of transcription factors that regulate embryonic patterning and organogenesis. In embryos, alterations of the normal pattern of Hox gene expression result in homeotic transformations and malformations. Disruption of the Hoxa1 gene, the most 3' member of the Hoxa cluster and a retinoic acid (RA) direct target gene, results in abnormal ossification of the skull, hindbrain, and inner ear deficiencies, and neonatal death. We have generated Hoxa1(-/-) embryonic stem (ES) cells (named Hoxa1-15) from Hoxa1(-/-) mutant blastocysts to study the Hoxa1 signaling pathway. We have characterized in detail these Hoxa1(-/-) ES cells by performing microarray analyses, and by this technique we have identified a number of putative Hoxa-1 target genes, including genes involved in bone development (e.g. Col1a1, Postn/Osf2, and the bone sialoprotein gene or BSP), genes that are expressed in the developing brain (e.g. Nnat, Wnt3a, BDNF, RhoB, and Gbx2), and genes involved in various cellular processes (e.g. M-RAS, Sox17, Cdkn2b, LamA1, Col4a1, Foxa2, Foxq1, Klf5, and Igf2). Cell proliferation assays and Northern blot analyses of a number of ES cell markers (e.g. Rex1, Oct3/4, Fgf4, and Bmp4) suggest that the Hoxa1 protein plays a role in the inhibition of cell proliferation by RA in ES cells. Additionally, Hoxa1(-/-) ES cells express high levels of various endodermal markers, including Gata4 and Dab2, and express much less Fgf5 after leukemia inhibitory factor (LIF) withdrawal. Finally, we propose a model in which the Hoxa1 protein mediates repression of endodermal differentiation while promoting expression of ectodermal and mesodermal characteristics.

Primary lymphoma of bone.

UNLABELLED: Primary lymphoma of bone (PLB) is a rare clinical-pathological entity representing less than 1% of all lymphomas. This work was aimed to review the presentation characteristics of PLB at the Instituto Nacional de Cancerología including its management and evolution. MATERIAL AND METHODS: Thirty cases of lymphoma of bone were diagnosed between 1972 and 1999 from a database including 577 patients with lymphoma. Among them, only 8 patients (1.36% of the total lymphomas) met the criteria set out to be diagnosed as primary lymphoma of bone, stage IE. In all patients, diagnosis was histopathologically made through open biopsy, and they were classified in accordance with the former criteria of the Working Formulation (WF). This review applied the current criteria of the World Health Organization (WHO). RESULTS: Three women and five men with a mean age of 40 years (range 20-65) were identified. Mean physical performance (Karnofsky) was 80%. Six patients presented clinically evident disease of the affected region. The most frequent symptom was pain at the site of the lesion in 3 patients, being the cardinal symptom in 1 patient. Histological diagnosis was diffuse large cell lymphoma, and B immunophenotype was confirmed in 5 patients. Five patients received sequential chemotherapy and radiotherapy; 1 patient received chemotherapy; and 2 patients received exclusive radiotherapy. The chemotherapy regimes were based on anthracyclines. Five patients presented complete response and 3 patients showed progressive disease. One patient showing complete response relapse 16 years after the treatment. The mean follow-up in this series was 60 months (range 3-190 months). Tumor localization and functional condition of the patient were the best prognostic factors. Surgery was not therapeutic in any case. CONCLUSIONS: PLB still remains a rare clinical-pathological entity, and represented 1.3% of total lymphomas in this series. Sequential anthracycline-based chemotherapy and radiotherapy are the most important therapeutic choices. Functional condition of patients at diagnosis and tumor localization were the most accurate prognostic factors.