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PubMed1987

Human mononuclear cell in vitro activation in microgravity and post-spaceflight.

The results of postflight and inflight human in vitro lymphocyte experiments have been reviewed. The cumulative data indicate that mitogen-stimulated T-cell proliferation is blunted following short-duration missions. Since similar responses may also be obtained following exposure to non-spaceflight stressors (hypoxia and academic stress), it is unclear if microgravity per se aggravates this response. Our studies indicate that stress-induced impaired PHA- and PWM-stimulated activation can be detected within the first 24 hours in culture at the level of protein synthesis. While the mechanism for neuroendocrine-mediated blunted mitogen stimulated T cell proliferation has not been elucidated, it is not aggravated by autologous plasma and does not require changes in mononuclear cell subpopulations. While prior studies indicate lymphocyte activation is influenced by altering G forces on in vitro cultures, impaired cellular interactions or suboptimal microenvironments related to reduced cell densities in microgravity may contribute to the greatly impaired mitogen stimulated proliferation responses observed on Spacelab flights. It will be necessary to perform lymphocyte functional assays on crewmembers during spaceflight to determine to contribution of microgravity per se on altered human immune competence.

Female↗

PubMed1994

Evidence against the "oxygen-in-the-track" hypothesis as an explanation for the radiobiological low oxygen enhancement ratio at high linear energy transfer radiation.

Oxygen sensitizes cells toward the effect of ionizing radiation. This sensitization, quantified by the oxygen enhancement ratio (OER), decreases with increasing ionization density or linear energy transfer (LET) of the radiation applied. One explanation for the decreased OER at high LET offers the "oxygen-in-the-track" hypothesis. It claims that oxygen is produced in the track of densely ionizing particles providing an oxic microenvironment around the relevant cellular target molecules, even if cells are exposed under anoxic atmospheric conditions. Experimental evidence is presented against this hypothesis. It is based on the different kinetic pattern of DNA double-strand-break rejoining observed in yeast cells exposed under oxic or anoxic conditions to 3.5 MeV alpha-particles.

DNA↗

PubMed1988

An immunohistochemical and fine-structural analysis of peptidergic hypothalamic neurosecretory axon regeneration into the leptomeninges of the rat.

Regeneration of severed hypothalamic peptidergic neurosecretory axons into the ventral pia-arachnoid was observed in rats at the light microscopic and fine-structural levels. A temporal increase occurred in the number of neurophysin-positive axons regenerating into the leptomeninges for distances up to 3.3 mm by 40 days post-lesioning. A consistent pattern of parallel, meshed and clustered axons, occurring either singly or in bundles, was present within the connective tissue, while plexus and bundles were observed in association with leptomeningeal blood vessels. Axons were characterized by preterminal and terminal dilatations. Neurosecretory granulated vesicles occurred throughout axons. The presence of microvesicles at contact points with basal lamina suggests the possibility of hormone release. Most axons were arranged as fascicles associated closely with basal lamina-bounded support cells whose thin lamellar processes wrapped single axons or fascicles of axons. We conclude, therefore, that cellular and intercellular leptomeningeal microenvironments support and sustain the growth and regeneration of transected neurosecretory axons.

Animals↗

PubMed1988

Contact-dependent inhibition of growth of normal diploid human fibroblasts by plasma membrane glycoproteins.

Homeostasis in vivo is maintained by a highly complex network of positive and negative signals. At the cellular level, this regulatory microenvironment can be divided, in a simplified fashion, into two major compartments: the humoral compartment, including compounds such as hormones, growth factors and nutrients, and the contact-environment compartment, including cell-cell and cell-matrix interactions. At least in cultures of diploid, non-transformed cells, cell-cell and cell-matrix interactions have been shown to be of major importance for the regulation of growth as well as of differentiation. Although until now the glycoprotein involved in the contact-dependent inhibition of growth has not been fully characterized, our studies give evidence for the involvement of a plasma membrane glycoprotein with an apparent molecular weight of approximately 80 kDa in the growth regulation of diploid human fibroblasts. The important characteristic of this glycoprotein is: the biologically active determinant resides in terminal, beta-glycosidically linked galactose residues on N-glycosidically linked glycans. From our studies, a receptor has to be postulated which, in addition to the galactose residues, has additional structural requirements for the specific binding of this glycoprotein, since other glycoproteins carrying terminal, beta-glycosidically linked galactose-residues are without biological activity. The postulated receptor is suggested to be defective in tumor cells, since these cells are no longer able to respond to cell-cell contacts with stopped proliferation, although they are able to inhibit growth of non-transformed cells. The inability of a tumor cell to recognize and to bind to the specific glycoprotein would result in a release from growth inhibition, leading to clonal growth of these cells. Further detailed studies on the structure and the regulation of the glycoprotein, as well as an attempt to isolate the postulated receptor, should lead to a better understanding of the complex pattern of growth regulation of normal cells.

Animals↗

PubMed1982

Immunoperoxidase staining for involucrin: a potential diagnostic aid in cervicovaginal pathology.

Involucrin, a protein subunit of keratinocyte cross-linked envelopes, is a distinctive marker for suprabasal differentiation in stratified squamous epithelium. Immunoperoxidase staining for involucrin was used to evaluate paraffin sections of tissue obtained by colposcopically directed biopsies of infectious, metaplastic, and dysplastic lesions of the cervix and vagina. Areas of normal squamous epithelium, papillary and flat condyloma acuminatum, and mature and immature squamous metaplasia showed positive staining in 99 per cent of samples lacking significant inflammation and in 60 per cent of those with moderate or severe inflammation. In contrast, only 19 per cent of the squamous cell dysplasias, even those without much inflammation, showed positive staining, and no area with moderate or severe inflammation showed positive staining. These findings indicate that expression of involucrin is modulated by cellular pathologic features and microenvironment. We suggest that immunoperoxidase staining for involucrin may be useful in distinguishing mild dysplasia from immature metaplasia and flat condyloma in some biopsy specimens in which routine histologic examination yields an indeterminate diagnosis.

Carcinoma, Squamous Cell↗

PubMed1997

Premature thymic involution, observed at the ultrastructural level, in two lineages of human-SOD-1 transgenic mice.

The human Cu/Zn superoxide dismutase (hSOD-1) gene, catalyses the dismutation of O2 to H2O2 and O2. It is located on chromosome 21 in q22.1 and is overexpressed in Down's syndrome (DS) patients. These patients present various abnormalities including mental retardation, congenital heart disease, immunological deficits and premature aging. In order to explore the potential role of SOD-1 overexpression in DS, we have generated two lineages of transgenic mice for the hSOD-1 gene and studied, at the ultrastructural level, the effect of hSOD-1 overexpression on the thymic microenvironment. Modification of the cellular architecture and morphology associated with a lipidic invasion, signs of a premature involution of the thymus, were observed in both lineages. A rupture of the filamentous network in the extracellular and probably also in the intracellular matrix was first observed. These results correlate the thymic alterations visualized in light microscopy, on the thymus from DS patients, and raise the question of the relationship between the SOD-1 overexpression and the different morphological alterations associated with the premature thymic involution observed in SOD-1 transgenic mice. They suggest that thymic and immunological impairments present in DS patients may be related to the SOD-1 gene dosage effect.

Aging↗

PubMed2000

In vitro inhibition of murine hematopoietic progenitors and stromal cells by vinorelbine.

Hematopoietic progenitor colony assays were used to establish the effects of the vinca alkaloid vinorelbine (VRB) on murine bone marrow. The in vitro growth of colony-forming units-granulocyte/macrophage (CFU-GM), burst forming units-erythroid (BFU-E) and colony-forming units-mix (CFU-mix) was dose-dependently inhibited by VRB. The highest dose assayed (0.02 microg/ml) suppressed all of the different progenitor cells by 100%. A comparison of the dose-response curves showed that CFU-GM, BFU-E, and CFU-mix exhibited similar-patterns of sensitivity to the cytotoxic action of VRB. Long-term bone marrow cultures have provided a valuable in vitro model for studying the role of the microenvironment of bone marrow. Cellularity of stromal layers was reduced with increasing doses of VRB. The appearance of these layers was altered minimally with the lowest dose used; a gradual loss of cellularity was seen in cultures exposed to 0.05 and 0.075 microg/ml; and a marked loss at the dose of 0.1 microg/ml. Our results show that VRB has an important effect on hematopoietic progenitors at the highest dose tested, while the stromal cells were not affected at a similar dose (0.025 microg/ml), suggesting that the stroma is more resistant to this drug.

Animals↗

PubMed1993

Cellular regulatory mechanisms that may underlie the effects of corticosteroids on bone.

The overall effects of corticosteroids on the skeleton are dependent on many factors including dose, duration of exposure to the steroid, steroid type and species. Some effects are indirect and are brought about by changes in, for example, parathyroid hormone secretion and intestinal calcium absorption, while others may result from cellular responses within the microenvironment of bone itself. Explants of trabecular bone are commonly used to study glucocorticoid effects in vitro, though it is often difficult to be certain that in vitro results directly reflect in vivo activity. Corticosteroids are dual inhibitors of cyclo-oxygenase and lipo-oxygenase, and may exert effects via inhibition of eicosanoid synthesis. They can also inhibit synthesis of cytokines, such as interleukin-1, which stimulate bone resorption and remodelling, by monocytes and macrophages. The production of cytokines and growth factors by bone cells themselves and the expression of their receptors may also be influenced by corticosteroids. Examples of corticosteroid-induced inhibition of synthesis include tumour necrosis factor and interleukin-6, and such effects may be important in explaining therapeutic actions of corticosteroids (e.g. in myeloma). Although it is not yet clear why different glucocorticoids have different effects, a number of factors determine the overall effect of a steroid. These include steroid metabolism and tissue distribution, selective effects on cytokine production, and tissue differences in gene transcription.

Arthritis, Rheumatoid↗

PubMedDate not supplied

Control of the thymic microenvironment by growth hormone/insulin-like growth factor-I-mediated circuits.

The thymus gland is a central lymphoid organ in which bone marrow-derived T cell precursors undergo maturation, eventually leading to the migration of positively selected thymocytes to the T-dependent areas of peripheral lymphoid organs. This process occurs under the influence of the thymic microenvironment, by means of secretory polypeptides and cell-cell contacts. The thymic microenvironment is a tridimensional cellular network composed of epithelial cells (its major component), macrophages, dendritic cells, fibroblasts and extracellular matrix elements. The epithelial reticulum is a heterogeneous tissue, in which a particular lymphoepithelial structure has been isolated in vitro: the thymic nurse cell complex, which possibly creates particular microenvironmental conditions for thymocyte differentiation. Additionally, thymic nurse cells are useful tools to study mechanisms involved in intrathymic T cell migration, including neuroendocrine influences. Previous data showed that thymic hormonal function can be modulated by hormones and neuropeptides, including growth hormone. Interestingly, GH acts pleiotropically on the thymic epithelium increasing cell growth and expression of extracellular matrix ligands and receptors, the latter resulting in an enhancement of thymocyte adhesion to the epithelial cells and thymocyte release from thymic nurse cells. The role of GH on thymus development is further stressed by the findings obtained with GH-deficient dwarf mice. Besides the precocious decline in serum thymulin found in these animals, a progressive thymic hypoplasia occurs, with decreased numbers of CD4+CD8+thymocytes, both defects being largely restored by long-term GH treatment. The effects of GH in the thymus are apparently mediated by IGF-1. Enhancement of thymulin secretion induced by GH, as well as the stimulation of thymocyte adhesion to thymic epithelial cells can be prevented in vitro by treatment with antibodies for IGF-I or IGF-I receptor. Moreover, in both systems IGF-I alone can yield similar effects. Also, the enhanced concanavalin-A mitogenic response and IL-6 production by thymocytes observed in GH-treated mice can be detected in animals treated with IGF-I. Lastly, mouse substrains selected for high or low IGF-I circulating levels exhibited differential thymus developmental patterns correlating with IGF-I levels. A further conceptual aspect concerning the GH-IGF-I-mediated control of thymus physiology is the recent demonstration of an intrathymic production of these molecules, leading to the hypothesis that, in addition to the classical endocrine pathway, GH-IGF-I-mediated paracrine and autocrine pathways may also be implicated in the control of thymus physiology. In any case, such control is exerted pleiotropically, with modulation in the expression of several genes in different cell types of the organ. In this respect, it is exciting to imagine a role of GH-IGF-I loops in shaping the intrathymically generated T cell repertoire.

Cell Differentiation↗

PubMed1996

Persistence of nontypeable Haemophilus influenzae in adenoid macrophages: a putative colonization mechanism.

That nontypeable H. influenzae (NTHI) can reside intracellularly in human adenoid tissue has been suggested by use of in situ hybridization of a fluorescein labelled 16S rRNA-targeted oligonucleotide probe (FISH). Adenoid tissues from 43 children operated on in a clinically infection-free interval were investigated. FISH revealed H. influenzae in macrophage-like cells, located subepithelially in the crypts in all 43 adenoids. Furthermore, H. influenzae was detected in 22/22 adenoids using immunohistochemistry with the monoclonal antibody MAHI-3 recognizing a conserved H. influenzae LPS inner-core region. FISH and staining with monoclonal antibodies against immunophenotypic markers were performed simultaneously in order to characterize the cellular interrelations in this microenvironment. The findings of widespread presence of H. influenzae in cells of which some strongly expressed the CD14 marker of the monocyte/macrophage lineage may correspond to an important aspect of the colonization mechanisms whereby NTHI persists in the nasopharynx of children.

Adenoids↗

PubMed1991

Analysis of immunosuppressive properties of iris and ciliary body cells and their secretory products.

The anterior chamber of the eye is an immunosuppressive microenvironment as shown experimentally by immune privilege, anterior chamber-associated immune deviation, and inability to display local delayed-type hypersensitivity responses. It recently was reported that both the aqueous humor and the cells of the iris and ciliary body (I-CB) have immune inhibitory properties in vitro, suggesting that these components of the anterior segment might contribute to the unique properties of this microenvironment. To explore the cellular sources of immunosuppressive factors in the anterior chamber, cultures of I-CB cells were established from normal eyes of BALB/c mice. Supernatants were harvested from these cultures and assayed in vitro for their ability to inhibit T-lymphocyte activation. It was found that I-CB cell-derived supernatants profoundly suppressed alloantigen-driven T-cell proliferation (mixed lymphocyte response) and interleukin-2 production by a T-cell hybridoma that responds to stimulator cells bearing I-Ad. The inhibitory activity of I-CB supernatants did not appear to be related to prostaglandins; supernatants of I-CB cells cultured with indomethacin retained their suppressive properties, as did supernatants to which neutralizing antiprostaglandin E2 antibodies had been added. Moreover, suppression by I-CB supernatants was not relieved by antibodies specific for transforming growth factor-beta, even though this cytokine is known to be present in normal aqueous humor. Thus, the identity of the suppressive factor(s) in cultured I-CB cell supernatants remains elusive. Finally, by separating I-CB cell suspensions into bone marrow-derived (T-200-positive) and those not derived from bone marrow (parenchymal) subpopulations with a fluorescence-activated cell sorter, it was determined that the inhibitory activity of I-CB cell suspensions was produced by parenchymal, rather than hematogenous, cells. It is proposed and discussed that inhibitory factors and cytokines secreted by parenchymal I-CB cells contribute to the immunosuppressive qualities of the anterior chamber.

Animals↗

PubMed1988

Polyovular follicles associated with human in vitro fertilization.

Polyovular follicles were found in 61 (24%) of 251 laparoscopies performed for in vitro fertilization. Of 898 follicles that contained at least one oocyte, 76 (8%) were polyovular. When the oocytes from polyovular follicles were assessed by morphologic criteria, it was found that 46 of the follicles contained oocytes that were discordant in maturity. Thus, oocytes can develop at different rates even though they are exposed to the same follicular fluid. It is possible that the microenvironment provided by the cellular investments of oocytes may correlate more precisely with oocyte maturity.

Female↗

PubMed1978

Dissecting the hematopoietic microenvironment. III. Evidence for a positive short range stimulus for cellular proliferation.

Experiments were carried out with the intent of defining the nature of the microenvironmental defect which severely limits erythropoiesis in the spleen of the S1/S1d mouse. Chimeric spleens, half S1/S1d and half congenic +/+, supported erythropoiesis in the +/+ region but not in the S1/S1d region, regardless of which genotype was the irradiated, marrow-injected host animal. Implants of normal marrow stroma within the spleens of irradiated S1/S1d mice also supported normal proportions of erythrocytic and granulocytic hematopoiesis. Implants of normal spleen stroma, particularly the capsular portion, into unirradiated s1/s1d mice stimulated erythropoiesis originating from S1/S1d stem cells within and in the immediate vicinity of the implant. The evidence suggests a short range, stromal erythropoietic stimulatory factor which is lacking in the S1/S1d.

Anemia, Macrocytic↗

PubMed1994

Wound infections.

Wound infections continue to be an important entity in terms of use of time and medical resources. Currently, the following risk factors are known to strongly predispose to wound infection: pre-existing medical illness, prolonged operative time, wound contamination, and contaminated or dirty wounds. Tissue level factors, including the local microenvironment, white cells, and cellular products that mediate inflammation, are important, and their manipulation holds promise for future therapies. For now, the judicious use of antibiotic prophylaxis and organized systems of wound surveillance are the most effective means to reduce the wound infection rate to its pathophysiologically attainable minimum.

Anti-Bacterial Agents↗

PubMed1993

Selective cellular acidification and toxicity of weak organic acids in an acidic microenvironment.

The mean extracellular pH (pHe) within solid tumours has been found to be lower than in normal tissues. Agents which cause intracellular acidification at low pHe might have selective toxicity towards cells in tumours. Weak acids (or their anions) with pKa values in the range of 4-6 have a higher proportion of molecules in the uncharged form at low pHe and can diffuse more rapidly into cells. The effects of organic acids including succinate, monomethyl succinate and malonate to acidify cells have been evaluated under conditions of different pHe in the acidic range. These weak acids caused intracellular acidification of murine EMT-6 and human MGH-U1 cells in a concentration and pHe dependent fashion. At concentrations of 10 mM and above, these acids also caused in vitro cytotoxicity to these cells at low pHe (< 6.5). The rate and extent of cellular acidification caused by these weak acids, and their cytotoxicity at low pHe, were enhanced by exposure to amiloride and 5-(N-ethyl-N-isopropyl)amiloride (EIPA), agents which inhibit Na+/H+ exchange, and hence the regulation of intracellular pH. Acid dependent cytotoxicity was also investigated in a murine solid tumour using the endpoints of growth delay and colony formation in vitro following treatment in vivo. Agents were tested alone or with 15 Gy X-rays to select a population of hypoxic (and presumably acidic) cells. Achievable serum concentrations of succinate were about 1 mM and no antitumour activity of succinate was detected when used in this way. It is concluded that weak acids are selectively taken up into cells, and can cause selective cellular acidification and toxicity, at low pHe in culture. Weak acids that are normal cellular metabolites are not toxic in vivo, but weak acids carrying cytotoxic groups offer the potential for selective uptake and toxicity under the conditions of low pHe that exist in many solid tumours.

Amiloride↗

PubMed1999

SCID-hu mice for the study of human cancer metastasis.

Cancer metastasis involves dynamic and multistep in vivo processes. While generation of metastatic clones requires genetic alterations in cancer cells, subsequent selection of the clones is heavily influenced by interactions with the surrounding tissue microenvironment. To reproduce the complex cellular interactions that occur in human patients is, however, difficult, and has not been achieved using currently available in vitro systems or conventional animal models. The SCID-hu mouse is generated by surgical implantation of human fetal tissues into mutant mice of the severe combined immunodeficient (SCID) phenotype. The unique feature of this model is that the implanted human tissues maintain their normal architecture and function. Therefore implanted human tissues will provide relevant microenvironments for the growth and metastasis of human cancer cells. The SCID-hu mouse model, which was specifically designed for the study of human cancer biology, enables experimental investigation of cellular events involved in cancer metastasis on the basis of interactions between human cancer cells and the human tissue microenvironment. It has been demonstrated that various types of human cancer cell lines generate tumors in implanted human bone marrow and lung, organs frequently involved in metastasis in patients, upon intravenous inoculation. Tumorigenic activity in SCID-hu mice faithfully reflects the clinical features of the original cancer. Tumor formation and selection of high tumorigenic variants occur in a species-specific manner. Furthermore, it was shown that metastatic tumor formation is regulated by both cancer cells and conditions in the host organs. Conditioning of animals by either whole-body irradiation or interleukin 1alpha treatment prior to cancer cell inoculation induced metastatic tumor formation by certain small cell lung cancer (SCLC) cell lines specifically in human bone marrow. A novel gene has been identified by comparing gene expression profiles between high and low tumorigenic SCLC cells in human lung. This gene is preferentially expressed in low metastatic lines, and transfection of the gene into highly metastatic cells results in suppression of metastasis. Recent studies have shown that the gene product is involved in the apoptosis induction pathway. Collectively, our results indicate that the SCID-hu mouse will serve as a unique platform technology with which to investigate cellular events involved in human cancer metastasis, as well as to identify genes playing important roles in the growth and metastasis of human cancer, in the context of interactions between human cancer cells and human tissue environments.

Animals↗

PubMed2026

Stage-Independent Real-Time Subtype Classification and Comprehensive Biopsy Profiling of Urothelial Carcinomas by the Lund Taxonomy System.

Bladder cancer is a heterogeneous malignancy with diverse clinical outcomes, and conventional pathological assessment alone is insufficient to capture its underlying biology. Gene expression profiling can stratify tumors into molecular subtypes with prognostic and predictive potential, but the reliability of transcriptomic classification and its clinical utility remains to be established. The translational/observational UROSCANSEQ study (ISRCTN15459149) prospectively evaluates RNA-based Lund Taxonomy (LundTax) molecular subtype classification in a clinical setting. Among 784 consecutive biopsies collected between 2018 and 2022, RNA sequencing was successful for 90% of all biopsies, encompassing 662 bladder cancer patients with a stage distribution of 48% Ta, 27% T1, 24% ≥T2, and 1% CIS. We demonstrate that the LundTax subtype classification algorithm, applied to individual samples, accurately identifies cancer cell phenotypes with characteristic gene and protein expression patterns in a manner robust to RNA quality, data preprocessing strategies, and batch effects, supporting its clinical feasibility across both non-muscle-invasive and muscle-invasive disease. We further extend the LundTax framework by incorporating single-sample molecular risk scores reflecting tumor grade, proliferation, and progression risk, as well as tumor microenvironment signatures. Both risk scores and overall immune and stromal content in biopsies were significantly associated with an increased risk of clinical progression in noninvasive disease. In a separate analysis of the relative cellular composition of the tumor microenvironment, however, only the fraction of natural killer cells remained significant. Together, the expanded LundTax system provides a comprehensive molecular portrait of individual tumor biopsies. By explicitly separating cancer cell-intrinsic phenotypes, prognostic indexes, and microenvironmental signals, the framework minimizes biological confounding and establishes a strong foundation for future studies evaluating clinical outcomes and treatment responses.

Humans↗

PubMed1991

Molecular mechanisms of tubulointerstitial hypertrophy and hyperplasia.

Adult kidneys, which are principally composed of tubulointerstitium, do not normally regenerate or expand their working pool of functional cells at a very high rate. Loss of kidney tissue, however, can lead to some compensatory renal enlargement. The catalytic forces initiating such exchanges have not been fully articulated by current experimental endeavors. Increasing evidence, nevertheless, does suggest that factors other than simple changes in renal hemodynamics may be involved in this process. Different cellular elements in the tubulointerstitial microenvironment probably modulate changes in tubular enlargement or size through a complex cytokine network. Autocrine and paracrine stimulation of enlargement by different local growth factors also seem to play a pivotal role. After binding to cellular receptors, these factors activate signal transduction pathways resulting in expression of immediate early genes, which by themselves can synchronize the expression of subsequent genes through the medium of transacting factors. The renal enlargement response can also be modified by endocrine hormones that can activate such genes directly and/or stimulate other adjunctive processes, like receptor expression for the regional binding of growth factors. Furthermore, renal enlargement is under negative feedback of inhibitory factors like TGF beta. It is possible, for example, that special genes exist which are only expressed to arrest enlargement. It has been further suggested that activation of the Na+/H+ antiporter is a common denominator in renal enlargement. Recent findings, however, indicate that the activation of this antiporter is not always necessary, and might rather be a parallel event rather than a key phenomena in tubular enlargement. G0/G1 transition of tubular cells seems to involve similar factors in tubular hypertrophy and hyperplasia. The factors which are responsible for the final determination of the enlargement pattern (hypertrophy vs. proliferation) are unknown. The separation between hypertrophy and hyperplasia, although suggested by striking differences in cellular regulation, may be somewhat artificial, since responses leading to tubular enlargement also exist in circumstances where hyperplasia and hypertrophy are combined events. Recently it has been proposed that growth factors stimulate gluconeogenesis in proximal tubular cells producing hyperplasia, whereas factors inhibiting gluconeogenesis might induce hypertrophy. Whether the common pathway message of this intriguing hypothesis is correct still requires further validation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗