Decoding the role of miRNAs in multiple myeloma pathogenesis: A focus on signaling pathways.

Multiple myeloma (MM) is a cancer of plasma cells that has been extensively studied in recent years, with researchers increasingly focusing on the role of microRNAs (miRNAs) in regulating gene expression in MM. Several non-coding RNAs have been demonstrated to regulate MM pathogenesis signaling pathways. These pathways might regulate MM development, apoptosis, progression, and therapeutic outcomes. They are Wnt/ß-catenin, PI3K/Akt/mTOR, P53 and KRAS. This review highlights the impending role of miRNAs in MM signaling and their relationship with MM therapeutic interventions.

Interstitial cells of Cajal, the Maestro in health and disease.

Interstitial cells of Cajal (ICC) are important players in the symphony of gut motility. They have a very significant physiological role orchestrating the normal peristaltic activity of the digestive system. They are the pacemaker cells in gastrointestinal (GI) muscles. Absence, reduction in number or altered integrity of the ICC network may have a dramatic effect on GI system motility. More understanding of ICC physiology will foster advances in physiology of gut motility which will help in a future breakthrough in the pharmacological interventions to restore normal motor function of GI tract. This mini review describes what is known about the physiologic function and role of ICCs in GI system motility and in a variety of GI system motility disorders.

Functional activity of the rectum: A conduit organ or a storage organ or both?

AIM: To investigate whether the degree of rectal distension could define the rectum functions as a conduit or reservoir. METHODS: Response of the rectal and anal pressure to 2 types of rectal balloon distension, rapid voluminous and slow gradual distention, was recorded in 21 healthy volunteers (12 men, 9 women, age 41.7 +/- 10.6 years). The test was repeated with sphincteric squeeze on urgent sensation. RESULTS: Rapid voluminous rectal distension resulted in a significant rectal pressure increase (P < 0.001), an anal pressure decline (P < 0.05) and balloon expulsion. The subjects felt urgent sensation but did not feel the 1st rectal sensation. On urgent sensation, anal squeeze caused a significant rectal pressure decrease (P < 0.001) and urgency disappearance. Slow incremental rectal filling drew a rectometrogram with a "tone" limb representing a gradual rectal pressure increase during rectal filling, and an "evacuation limb" representing a sharp pressure increase during balloon expulsion. The curve recorded both the 1st rectal sensation and the urgent sensation. CONCLUSION: The rectum has apparently two functions: transportation (conduit) and storage, both depending on the degree of rectal filling. If the fecal material received by the rectum is small, it is stored in the rectum until a big volume is reached that can affect a degree of rectal distension sufficient to initiate the defecation reflex. Large volume rectal distension evokes directly the rectoanal inhibitory reflex with a resulting defecation.

The effect of esophageal and gastric distension on the crural diaphragm.

BACKGROUND: The mechanism of prevention of gastric reflux into the esophagus is not exactly known. The lower esophagus has a barrier function provided by the lower esophageal sphincter. We investigated the hypothesis that the crural diaphragm shares in the barrier function not only mechanically but also actively through a crural-esophageal-gastric reflex action. METHODS: The study was performed during repair of abdominal ventral and incisional hernias in 20 subjects (11 men, 9 women; age 38.6+/-4.8 years). The electromyographic response of the crural diaphragm to individual balloon distension of esophagus and stomach was recorded by means of a needle electrode inserted into the crural diaphragm and connected to an electromyographic apparatus. The recordings were repeated after separate crural, esophageal, and gastric anesthetization. RESULTS: The crural diaphragm exhibited basal motor unit action potentials, which decreased on esophageal distension (P<0.001) after a mean latency of 17.3+/-2.8 SD ms. The crural diaphragm response to esophageal distension did not occur after the crural diaphragm or esophagus was anesthetized. Gastric distension effected an increase of crural diaphragm electromyographic activity with a mean latency of 18.4+/-4.6 ms; this effect could not be achieved after the crural diaphragm or stomach was anesthetized. CONCLUSIONS: The crural diaphragm has a resting tone that relaxes after esophageal distension and contracts after gastric distension. This sphincter-like action of the crural diaphragm appears to be a reflex and is mediated through the esophagocrural inhibitory and gastrocrural excitatory reflexes. The crural diaphragm seems to share actively in the gastroesophageal competence mechanism.

Role of the rectosigmoidal junction in fecal continence: concept of the primary continent mechanism.

HYPOTHESIS: At mass contraction of the descending colon, the colonic contents stop at the sigmoid colon (SC) and do not pass directly to the rectum. We investigated the hypothesis that a continent mechanism seems to exist at the rectosigmoidal junction (RSJ), preventing the direct passage of stools from the descending colon to the rectum. METHODS: The SC in 16 healthy volunteers (mean +/- SD age, 38.6 +/- 10.2 years; 9 men and 7 women) was distended with an isotonic sodium chloride solution-filled balloon, and the pressure response of the RSJ and the rectum was recorded at rapid and gradual filling of the balloon. The test was repeated after the SC and RSJ were anesthetized separately. RESULTS: Rapid SC balloon distension with a mean +/- SD of 52.1 +/- 3.6 mL of isotonic sodium chloride solution effected an RSJ pressure increase to a mean +/- SD of 67.8 +/- 18.4 cm H(2)O (P<.01) with no rectal pressure response (P>.05). Slow SC filling produced a progressive increase in RSJ pressure but no rectal pressure change. At a mean +/- SD SC distending volume of 86.3 +/- 4.1 mL, the RSJ pressure decreased to 9.6 +/- 2.8 (P<.01), and the balloon was dispelled to the rectum; rectal pressure increased (P<.001), and the balloon was expelled to the exterior. The RSJ pressure did not respond to distension of the anesthetized SC. CONCLUSIONS: Contraction of the RSJ at rapid SC distension with big volumes implies a reflex relationship that we call the RSJ guarding reflex. This reflex seems to prevent the descending colon contents from passing directly to the rectum. It is considered the first continent reflex and may serve as an investigative tool in the study of fecal incontinence.

Electric activity of the colon in subjects with constipation due to total colonic inertia: an electrophysiologic study.

BACKGROUND: Idiopathic constipation may result from colonic inertia, which affects the whole colon or is localized to an area of the colon. The colon exhibits electric activity in the form of slow waves or pacesetter potentials (PPs) and action potentials (APs), which are coupled with elevated colonic pressure. The APs are claimed to be responsible for colonic motor activity. HYPOTHESIS: Colonic electric activity is disordered in patients with constipation due to colonic inertia. METHODS: Electric activity was studied in 11 patients with colonic inertia and constipation (mean +/- SD age, 42.8 +/- 6.6 years; 7 women) who underwent total colectomy. Eight volunteers who had no gastrointestinal complaints (mean +/- SD age, 40.6 +/- 5.8 years; 5 women) acted as controls. Control subjects underwent laparotomy for hernia repair (n = 7 patients) and for removal of a mesenteric cyst (n = 1 patient). During the operation, 2 monopolar silver-silver chloride electrodes were applied to the cecum and the ascending, transverse, descending, and sigmoid colon. RESULTS: Electric waves (PPs and APs) were recorded from all parts of the colon in control subjects. The waves were monophasic, negatively deflected, and had regular rhythm. The wave variables from the 2 electrodes of each segment of the colon were identical and reproducible. They progressively increased aborally. In the colonic inertia group, 5 patients had recorded waves from the cecum and ascending colon but no waves from the rest of the colon. The wave variables were significantly lower than those of the controls (P =.02). In the remaining 6 patients, no waves were registered from the whole colon. CONCLUSIONS: Regular electric waves were recorded from the colons of control subjects. The aboral increase of their frequency, amplitude, and conduction velocity suggests that colonic motile activity increases analward, reaching its maximum in the sigmoid colon to expel its solid contents. We postulate that constipation in patients with colonic inertia is attributable to weak or absent electric activity, the cause of which is unknown. A disorder of the interstitial cells of Cajal, which generate electric activity, is suggested to have a role in inducing diminished or absent colonic motor activity, a point that should be investigated.