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Grade progression and high-grade transformation in neuroendocrine neoplasms.

Epithelial neuroendocrine neoplasms (NENs) comprise a biologically diverse group of malignancies that span a wide spectrum of differentiation, proliferative activity, and clinical behavior. Contemporary classifications distinguish well-differentiated neuroendocrine tumors (NETs) from poorly differentiated neuroendocrine carcinomas (NECs). However, growing longitudinal data indicate that a subset of NETs may undergo temporal evolution characterized by rising Ki-67, increasing morphologic atypia, and acquisition of genomic alterations classically associated with NEC, particularly TP53 and, less commonly, RB1 inactivation. These phenomena, referred to as grade progression and high-grade transformation, can result in tumors with NEC-like behavior despite retention of a NET molecular backbone, creating diagnostic and therapeutic ambiguity. In this review, we synthesize recent evidence on the molecular, morphologic, and clinical features of gastroenteropancreatic NET grade progression and transformation, highlight the role of clonal evolution and treatment-associated selection pressure, and discuss implications for imaging, biopsy strategy, molecular profiling, and therapy selection.

Humans

Gastric carcinoma classification in the WHO 6th edition (2026): Updated framework and emerging entities.

The sixth edition of the WHO Classification of Digestive System Tumours (2026) represents an important step in the continuing evolution of gastric carcinoma classification. While preserving morphology as the foundation of diagnosis, it incorporates advances in molecular pathology, genotype-phenotype correlations, tumour evolution, and predictive biomarker assessment. This review summarizes the development of the WHO classification from the third edition (2000) to the sixth edition (2026) and highlights its relationship with other major classification systems, including those of Laurén, Nakamura, and the Japanese Gastric Carcinoma Association (JGCA). Major histological categories remain largely unchanged; however, several important conceptual and diagnostic refinements have been introduced. These include recognition of crawling-type adenocarcinoma as a distinctive variant of tubular adenocarcinoma, subclassification of poorly cohesive carcinoma into signet-ring cell and non-signet-ring cell subtypes, introduction of the concept of pure signet-ring cell carcinoma, and increased emphasis on tumour evolution. The sixth edition also expands and refines the spectrum of uncommon gastric carcinoma subtypes, including gastric carcinoma with lymphoid stroma, AFP-producing carcinoma, micropapillary adenocarcinoma, gastric adenocarcinoma of fundic-gland type, and gastric sarcomatoid carcinoma. Crucially, molecular subgroups originally proposed by The Cancer Genome Atlas (TCGA) and actionable biomarkers-including HER2 (ERBB2), Claudin 18.2, mismatch repair deficiency/microsatellite instability (dMMR/MSI), and programmed death-ligand 1 (PD-L1)-have transitioned from research-based categories into essential tools for precision oncology. Rather than providing exhaustive diagnostic criteria, this review offers a conceptual framework and encourages consultation of the original WHO text for full details. These advances illustrate the transition of gastric carcinoma classification from a predominantly morphology-based system toward an integrated histomolecular framework that more closely links pathological diagnosis with tumour biology, prognostication, and therapeutic stratification.

Crawling-type adenocarcinoma

Skeletal differences between pygmy (Pan paniscus) and common chimpanzees (Pan troglodytes).

Skeletal dimensions of pygmy (Pan paniscus) and common (Pan troglodytes) chimpanzees were compared. Significant differences were found in the clavicles, scapulae, pelvises, and in the humerus/femur and femur head/length ratios. No significant differences were observed in long bone lengths or talar breadths. There is extensive overlap in body weights, so that the observed differences cannot be accounted for by body size alone. We conclude that pygmy and common chimpanzees are morphologically distinct. Implications for hominoid evolution are discussed.

Animals

[Pathogenesis of primary lymphedemas].

The role of the involvement of regional limph-node relays is already known, in the genesis of secondary lymphatic oedemas. With regard to the primary lymphatic oedemas however the role of regional lymph-nodes is considered to be limited. Following a complex investigation of an important clinical material the authors conclude that, in cases of primary lymphatic oedemas the determinat lesion is in the regional lymph nodes, and that it consists in an alteration of the filtration capacity, as well as in a reduction of the processing capabilities by the lymph nodes of the lymph flowing from the afferent lymph vessels. Simultaneously with the functional alterations lymphography revealed a series of changes, and macro- and microscopic examination also showed morphological pathologic alterations. The clinicat evolution and the prognosis of the oedema in the limb involved will depend on the extension and the evolution of these lesions.

Adolescent

Some aspects of monogenean existence.

This paper deals with some ecology and evolution problems of monogeneans--gill parasites of fishes, such as congeneric simultaneous doublets, spatial distribution of species on the gills, interspecific restrictions of biotopes etc. The author proves competitive character of site selection in monogeneans. The role of hermaphroditism in the evolution and biology of monogeneans, and morphological adaptations (mainly androgynous) directed to increasing of mating chance are discussed. The author concentrates on analyzing the cases of monoxenous distribution and speciation and also on examining the concept of symxenity and alloxenity. He attaches great importance to ecological and evolutionary investigations of Monogenoidea.

Animals

[Evolution of the pulp chamber and pseudodentin in the selachians the Brazilian coast (suborder Galeoidea). Morphological study].

The author made a morphological study of Selachii (Suborder Galeoidae) of the Brazil coast using ground sections. Dental structures undergo modifications as one studies species of different evolutionary stages. The lower Selachii have an osteodentine nucleus which suffer alterations until it disappears leaving a pulp chamber in its place. The layer of pseudodentine shows modification too. It consists of pseudodentine in lower Selachii but its modifications are such that in higher Selachii (Sphyrnidae, for instance) one may suppose it is made of orthodentine. Based on these and other published data the author concludes that the degree of evolution of the pulp chamber and pseudodentine allows the establishment, with great probability, of the phylogenitic position of the Selachii within the Galeoidea Suborder.

Animals

Teleost Hox code defines regional identities competent for the formation of dorsal and anal fins.

The dorsal and anal fins can vary widely in position and length along the anterior-posterior axis in teleost fishes. However, the molecular mechanisms underlying the diversification of these fins remain unknown. Here, we used genetic approaches in zebrafish and medaka, in which the relative positions of the dorsal and anal fins are opposite, to demonstrate the crucial role of hox genes in the patterning of the teleost posterior body, including the dorsal and anal fins. By the CRISPR-Cas9-induced frameshift mutations and positional cloning of spontaneous dorsalfinless medaka, we show that various hox mutants exhibit the absence of dorsal or anal fins, or a stepwise posterior extension of these fins, with vertebral abnormalities. Our results indicate that multiple hox genes, primarily from hoxc-related clusters, encompass the regions responsible for the dorsal and anal fin formation along the anterior-posterior axis. These results further suggest that shifts in the anterior boundaries of hox expression which vary among fish species, lead to diversification in the position and size of the dorsal and anal fins, similar to how modulations in Hox expression can alter the number of anatomically distinct vertebrae in tetrapods. Furthermore, we show that hox genes responsible for dorsal fin formation are different between zebrafish and medaka. Our results suggest that a novel mechanism has occurred during teleost evolution, in which the gene network responsible for fin formation might have switched to the regulation downstream of other hox genes, leading to the remarkable diversity in the dorsal fin position.

Animals

[Unexplained electrographic temporal discharges (author's transl)].

Unilateral or bilateral electrographic temporal discharges at 5 Hz were analyzed in relation to their morphological characteristics, their topography, and their evolution in II subjects. The clinical context, in which there was no evidence of epileptic disorder, was also analyzed. These discharges were compared to other infraclinical critical phenomena reported in the literature, and related to similar manifestations described by the Gibbs "school" as "Psychomotor variant type of discharge", or by Hughes group as "Rhythmic mid Temporal discharges".

Adolescent

The strategy of infection as a criterion for phylogenetic relationships of non-coli phages morphologically similar to phage T7.

Five phages which are morphologically similar to coliphage T7 but attack other host bacteria have been compared to T7 and to its relative, T3, by the following criteria: (a) cross-reactivity with antisera against T7 and T3, (b) DNA base sequence homologies, as determined by the C0t technique, (c) synthesis of two phage-coded enzymes: RNA polymerase and SAMase, (d) patterns of phage-directed protein synthesis, as determined by SDS-polyacrylamide gel electrophoresis of phage coat subunits. As judged by all these criteria, Pseudomonas phage PX3 is not related to T7; thus, morphological similarity was attributed to convergent evolution. The other phages, i.e. Serratia phage IV, Psuedomonas phage gh-1, Citrobacter phage ViIII and Klebsiella phage No. 11, were considered to be related to T7 on the basis of similarities in the patterns of phage-coded proteins and because, early after infection, these phages induced, as T7 does, an RNA polymerase which specifically transcribes the DNA of thehomologous phage. Phages IV and No. 11 also induced the early synthesis of SAMase (previously only known to occur upon T3 infection). With the exception of phage IV, however, DNA base sequence homologies with T7 or T3 seem to be poor or non-existent. The tested phages, again with the exception of phage IV, did not react with antiserum against T3 or T7. It is concluded that a particular pattern of phage-directed protein synthesis (as characterized by polyacrylamide gel electrophoresis and enzyme tests) may provide evidence for phylogenetic relationships between phages, even in cases where other criteria, such as genetic recombination, serological cross-reaction, and DNA base sequence homologies, fail to indicate relatedness.

Adenosylmethionine Decarboxylase

Evolution of spirographic patterns in pulmonary bilaterally denervated dogs.

One stage total bilateral pulmonary denervation produced in a group of 23 dogs an increase breathing frequency, an increase in the amplitude of respiration and a characteristic morphology of the spirographic pattern. Later in the evolution, these alterations returned to normal with the exeption of the amplitude of respiration which remained increased. This normalization was not accompanied by the reappearance of the Hering-Breuer reflux. Administration of an aerosol of acetylcholine after normalization of the spirographic pattern produced a temporary reappearance of the immediate postdenervation spirographic pattern. We postulate that in denervated lung a nervous plexus localized in the bronchi not related to the vagus might assume an important role in the regulation of respiration. One cannot exclude, however, the possibility that the reappearance of postdenervation pattern is due to stimulation of airways vagal receptors located in areas proximal to the level of the nervous section.

Acetylcholine

Ultrastructural studies on developing parotid gland of the rat at early postnatal periods.

An electron microscopic study of the exocrine and myoepithelial cells of the parotid gland of the rat between days 2 and 40 of the postpartum was undertaken. Besides confirming morphological data of the literature on the evolution of the acinar cells, the following observations are reported. 1. At early postnatal development in some acini "mucous-like" cells containing secretory granules with light and dense parts may be observed. Cells with these types of granules were not found after day 20. 2. Morphological differentiation and maturation of the myoepithelial cells were followed. A parallelism was observed between the maturation of these myoepithelial cells and of the acinar cells. Myofilaments first appear around the nucleus at day 5 and between days 20 and 30 a considerable amount of these filaments is found in the already typical myoepithelial cells. 3. Active morphogenesis seems to be occurring in all cellular compartments namely at very early postnatal periods, e.g., between days 2 to 15. 4. The distribution and amount of thin and intermediate sized microfilaments in cells of these compartments varied visibly by various orders of magnitude.

Animals

Different morphological types of myocardial cell death in man.

The evolutive histological stages, the frequency, and the eventual association of the different types of myocardial cell death have been studied in the following human material: acute infarction, sudden "coronary" death, accidental death, pheochromocytoma, transplanted hearts, "stone" heart syndrome, thrombotic thrombocytopenic purpura, and alcoholic cardiomyopathy. Three distinct main histological types of myocardial cell death are recognizable: Coagulation necrosis, the fundamental lesion in infarcts in which the myocardial cell loses its capability to contract and dies in an atonic state with overdistension due to the intraventricular pressure. No early myofibrillar damage is seen. Coagulative myocytolysis, found in all the present cases, always seen in the outer zone of an early infarct and in the surrounding normal myocardium at any stage of the repair process in most of the acute infarcts and in most cases of sudden death. The myocardial cell dies in a hypercontracted state, with early myofibrillar rhexis, and anomalous irregular cross-band formations. This tetanic death is similar to that seen in pheochromocytoma and in experimental catecholamine-induced necrosis. Colliquative myocytolysis, in which edematous vacuolization with dissolution of myofibrils is the main early finding, without hypercontraction, anomalous bands, and myofibrillar rhexis. This pattern, likely related to the low-output syndrome, was often seen in the preserved subendocardial and perivascular muscle fibers of acute infarct cases, in some transplanted hearts, and in all the alcoholic hearts. The different clear-cut morphological patterns of these three types of myocardial necrosis suggest a different pathogenesis and that different pathogenetic mechanisms may act in the same disease.

Acute Disease

Phoronida-A small clade with a big role in understanding the evolution of lophophorates.

Phoronids, together with brachiopods and bryozoans, form the animal clade Lophophorata. Modern lophophorates are quite diverse-some can biomineralize while others are soft-bodied, they could be either solitary or colonial, and they develop through various eccentric larval stages that undergo different types of metamorphoses. The diversity of this clade is further enriched by numerous extinct fossil lineages with their own distinct body plans and life histories. In this review, I discuss how data on phoronid development, genetics, and morphology can inform our understanding of lophophorate evolution. The actinotrocha larvae of phoronids is a well documented example of intercalation of the new larval body plan, which can be used to study how new life stages emerge in animals with biphasic life cycle. The genomic and embryonic data from phoronids, in concert with studies of the fossil lophophorates, allow the more precise reconstruction of the evolution of lophophorate biomineralization. Finally, the regenerative and asexual abilities of phoronids can shed new light on the evolution of coloniality in lophophorates. As evident from those examples, Phoronida occupies a central role in the discussion of the evolution of lophophorate body plans and life histories.

Animals

A spatiotemporal resolution to genetic redundancy: MIR164 diversification coordinates development and metabolism in Brassica.

Whole-genome duplication (WGD) events create genetic redundancy, posing the evolutionary challenge of how paralogs escape functional overlap to drive innovation. Here, we demonstrate that the MIR164 family in Brassica oleracea resolves this redundancy through spatiotemporal niche partitioning. Following WGD, the family expanded to eight members, which subsequently underwent divergent selection-some preserved under purifying selection, while others showed signals of positive selection. This led to expression divergence, with Bol-MIR164a1 emerging as a key universally expressed paralog. CRISPR-Cas9 mutagenesis of Bol-MIR164a1 revealed its essential role in coordinating two pivotal traits: leaf serration and leaf coloration. Mutants exhibited enhanced leaf serration due to spatial deregulation of CUC2 at organ boundaries, concurrently with yellow-green leaves and elevated flavonoid accumulation. We mechanistically linked the metabolic phenotype to direct transactivation of the anthocyanidin reductase (ANR) promoter by NAC100, alongside its upregulation of chlorophyll catabolism genes. Our findings establish a paradigm in which spatial segregation of target gene expression domains enables a single, widely expressed miRNA paralog to resolve genetic redundancy by independently orchestrating distinct regulatory programs. This provides a fundamental framework for understanding complex trait evolution in polyploids. This allows a single miRNA locus to independently orchestrate both morphological patterning and metabolic programming, providing a fundamental framework for understanding complex trait evolution in polyploid crops.

MicroRNAs

Pathology: the evolution of a specialty in American medicine.

The historical evolution of pathology as a full-time specialty in medicine is viewed as a response of pathologists to changes in the level and pattern of demand for their services. The development and decline of morphologic pathology, changes in academic pathology and the evolution of clinical pathology from a medical specialty to an industry with an extensive division of labor are all examined in this perspective. It is shown that pathology as a medical specialty is most successful within a limited range of demand, neither too low to support full-time specialization nor too high to lead to deprofessionalization through routinization of the work activities of pathologists.

Health Services Needs and Demand

[Morphological and functional variations of the muscles of invertebrates].

The problem of muscle evolution among Invertebrates has been considered, mainly in obliquely strated fibers of Annelida and in trasversally striated fibers of Insecta. In both groups the morphological variations run parallel to the functional requirements; similar modulations, in fact, have been observed in fast and slow acting muscle fibers independently from the basic pattern of Insecta and Annelida fibers. Fast acting muscles are characterized by a lesser diameter of myosin filaments and a low thin-to-thick filament ratio. On the contrary, the slow acting muscles show a greater diameter of the myosin filaments and a higher thin-to-thick filament ratio. These observations agree with the hypothesis of a common origin of almost all muscular systems.

Animals

The functional morphology of the cercopithecoid wrist and inferior radioulnar joints, and their bearing on some problems in the evolution of the Hominoidea.

The cercopithecoid wrist joint differs from the wrist joints of hominoids in several ways. The distal ulna, the distal radius, the pisiform, the triquetrum, the hamate, and the base of the fifth metacarpal are on the one hand remarkably alike among cercopithecoid genera, and on the other remarkably distinct from homologous bones in the Hominoidea. Functionally, the triquetrum and the pisiform, in conjuction with the ulnar styloid process, check the proximal carpal row during ulnar deviation, and are possibly important in stabilizing the wrist during dorsiflexion as well. The head of the ulna almost certainly betokens a range of radioulnar supination in cercopithecoids that is substantially less than is to be found in any of the hominoid genera. The articulation between the hamate bone and the base of the fifth metacarpal allows for considerable dorsiflexion in the Cercopithecoidea; this potential was not evidenct in any of the hominoids examined. Behaviorally, the cercopithecoid wrist can most profitably be viewed as an adaptation for a quadrupedal life style involving dorsiflexion of the wrist and palmigrade/digitigrade substrate contact. The hominoid wrist joint is not adapted for such a behavioral potential.

Animals