Progressive plasticity during colorectal cancer metastasis.

Metastasis is the principal cause of cancer death, yet we lack an understanding of metastatic cell states, their relationship to primary tumor states, and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that while primary tumors largely adopt LGR5 + intestinal stem-like states, metastases display progressive plasticity. Loss of intestinal cell states is accompanied by reprogramming into a highly conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states, which is exacerbated by chemotherapy and associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cancer cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a stabilizer of intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming.

Bone marrow traffic to regenerating islets induced by streptozotocin injection and partial pancreatectomy in mice.

The role of bone marrow (BM)-derived cells in the process of pancreatic islet regeneration remains unclear. The purpose of this study was to determine the role of BM cells in the repair process or regeneration of pancreatic islets in mice using chimeric green fluorescent protein (GFP) expressing BM cells. BM-infused chimeric mice were made diabetic by streptozotocin (STZ) injection or 60% partial pancreatectomy. GFP-positive cells within the islets and pancreas were studied immunohistologically. STZ treatment induced a 10-fold increase in PCNA-positive cells within the islets on day 7 posttreatment. GFP-positive cells increased in number within the islets as well as in the pancreatic parenchyma immediately after STZ injection. The partial pancreatectomy induced 2- to 3-fold increases on day 7 to 28 posttreatment. GFP-positive cells increased in number in pancreatic parenchyma but not within the islets. BM traffic to the pancreas significantly increased in the 2 models inducing islet regeneration. In both models, GFP-positive cells were not positive for antibodies against insulin, glucagon, or somatostatin, but were positive for markers of macrophages or fibroblasts, suggesting their involvement in the initiation of islet regeneration.

Gait initiation in bilateral vestibular loss.

OBJECTIVE: Gait initiation is a transient procedure between orthostatic posture and steady-state locomotion and includes anticipatory anteroposterior (AP) and lateral movements. Commands for this task are located in some levels of brain stem, which modulates activity of central pattern generator in the spinal cord. The purpose of this work was to explore the role of the vestibular system in this voluntary stepping. METHODS: Six patients with chronic bilateral vestibular loss (BVL) were measured by means of a large force plate (70 cm x 120 cm ) and the displacement of the center of pressure (COP) during gait initiation was calculated. Measurement parameters comprised maximum distance (MD), velocity (MV) in the AP and lateral direction as well as for pre-, first- and second-step stages, and the angle of the COP trajectory. RESULTS: For all stages, BVL patients registered lower values for both MD and MV in the AP direction than did normal subjects. In the lateral direction, however, neither MD nor MV in BVL patients showed any difference from those of normals. The step angle of the COP trajectory was obviously reduced. CONCLUSION: These results suggest that in the AP direction, the vestibulospinal pathway can influence the locomotor related neural circuits, including the central pattern generator and supraspinal levels, by means of modifying the velocity and step length in order to stabilize the trunk. On the other hand, the control mechanism in the lateral direction may be different from that in the AP direction.

The effects of intense click sounds on velocity storage in optokinetic after-nystagmus.

Vestibular evoked myogenic potentials (VEMP) occurring after click stimulation in cervical muscles are thought to be a polysynaptic response of otolith-vestibular nerve origin. In optokinetic after-nystagmus (OKAN) the direction of after-nystagmus changes and slow-phase velocity decreases with head tilt. This phenomenon may be an otolith response to the direction of gravity. We assumed that intense clicks might have some influence on OKAN via the otolith-vestibular nerve. Twelve normal subjects who showed VEMP at 75 dB normal hearing level (nHL) clicks were examined. The OKAN was recorded under four conditions: right monaural, left monaural and binaural stimulation by 75 dB nHL clicks, and absence of click stimulation. Horizontal optokinetic stimulation was applied using stepwise increasing speeds from 30 deg/s to 90 deg/s. Two seconds before the stimulus ended, clicks were sounded. The slow-phase velocity of the recorded electro-nystagmography was manually measured. There was no effect on OKAN with unilateral stimulation but binaural stimulation suppressed it. These results suggest that a velocity storage integrator is influenced by intense clicks via the otolithic area.

Neurotological evaluation of vertical semicircular canal function in inner ear malformation. A case report.

A 9-year-old boy with inner ear malformation complained of slight deafness and unsteadiness. CT revealed a normal cochlea despite enlargement of the lateral semicircular canals. The vertical semicircular canals developed more or less normally. The caloric test showed complete canal paresis bilaterally; however, a horizontal rotational stimulus elicited a vestibulo-ocular response, which showed only rightward and downward nystagmus, and their maximal slow-phase velocities were low. In addition, the examination of the vertical semicircular canal function using the head-tilted rotation test revealed a more active response, and the maximal slow-phase velocities were higher than those of a standard horizontal rotational test. These results suggest that the function of the vertical semicircular canal was well preserved and that it may have perceived the horizontal acceleration instead of the lateral semicircular canal.

Computed tomographic findings in peritonsillar abscess and cellulitis.

The differentiation of a peritonsillar abscess from peritonsillar cellulitis, although difficult on physical examination, is required in order to determine the appropriate treatment. Peritonsillar cellulitis can be treated with antibiotics alone, while a peritonsillar abscess should be drained. Computed tomography (CT) of the neck is often performed to identify the formation of a deep abscess in the neck, but is rarely used to diagnose peritonsillar infections. We report a patient in whom CT was a useful diagnostic tool for distinguishing peritonsillar abscess from peritonsillar cellulitis.

Use of lactate dehydrogenase to evaluate the anti-viral activity against influenza A virus.

The detection of lactate dehydrogenase (LDH) can be used to evaluate efficiently anti-influenza A virus agents. LDH levels in the virus-infected Madin-Darby canine kidney cell cultures were significantly higher than in controls, were in proportion to the degree of virus infection, and corresponded to a decrease in mitochondrial dehydrogenase activity as assayed using a tetrazolium colorimetric assay (MTT method). The EC50 value and cytotoxicity of ribavirin, 3-deazaguanine, pyrazofurin, and carbodine against influenza A virus as measured by the LDH detection method was equivalent to that derived by the MTT method.

Quantitative evaluation of the interrelationship of certain endocrine glands of Hemiechinus auritus collaris (Gray) during the reproductive cycle.

The paper deals with the alterations in the size and functions of the endocrine glands in relation to the reproductive and the seasonal sexual activity of the male hedgehog. Results show that the seasonal variations in body weight, testis, adrenal and the thyroid follow the general pattern of most of the hibernating mammals. Histometric measurements of the seminiferous tubule, Leydig's cells, thyroid follicles and the thyroid follicular epithelial cells also present an interrelationship in the seasonal cyclical activity with each other. This indicates that in Hemiechinus hormones fluctuate during the summer and winter months of the year or one can say that they are regulated seasonally thereby affecting the seasonal pattern of breeding. It has also been proposed that the cyclic activity of the endocrine glands is partly correlated with the hibernation of the animal and partly with the increased metabolic activity of the body incidental to the events of the annual cycle.