Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer.

BACKGROUND AND PURPOSE: Pancreatic cancer is a solid tumour that is often fatal. Hence, there is an urgent need to identify new drug targets for this disease. Highly proliferating cancer cells have an increased demand for nutrients and, therefore, need to up-regulate selective amino acid transporters. Here, we investigated which amino acid transporters are up-regulated in pancreatic cancer and whether any of these transporters has potential as a drug target for this fatal disease. EXPERIMENTAL APPROACH: The expression of amino acid transporters in pancreatic cancer was analysed using publicly available microarray datasets, and the findings with the transporter SLC6A14 were validated by mRNA and protein analysis. The potential of SLC6A14 as a drug target was evaluated using a pharmacological blocker in vitro and in vivo. KEY RESULTS: SLC6A14 was up-regulated several fold in patient-derived xenografts, primary tumour tissues and pancreatic cancer cells lines compared to normal pancreatic tissue or normal pancreatic epithelial cells. The magnitude of the up-regulation of SLC6A14 was the highest among the amino acid transporters examined. A pharmacological blocker of SLC6A14, α-methyltryptophan, induced amino acid starvation in pancreatic cancer cells and reduced the growth and proliferation of these cells, both in vitro and in vivo. CONCLUSION AND IMPLICATIONS: The salient features of this study are that SLC6A14 is markedly up-regulated in pancreatic cancer and that pharmacological blockade of this transporter interferes with amino acid nutrition and reduces growth and proliferation of pancreatic cancer cells. These findings identify SLC6A14 as a novel druggable target for pancreatic cancer.

Functional dissociation between Kana and Kanji: agraphia following a thalamic hemorrhage.

We report the case of a 61-year-old woman with a left thalamic hemorrhage causing agraphia of Kanji (morphograms). Single-photon emission computed tomography (SPECT) showed a decrease in the blood flow in the left thalamus from the superior temporal convolution to the parietal lobe, as well as in the frontal lobe while computed tomography showed no remarkable lesions in the cortex. The agraphia in this case may be due to the thalamic lesion itself, but the SPECT findings strongly suggest that a secondary cortical lesion may be involved in producing the higher cognitive disorder.

Primary pericardial mesothelioma: a case report.

The imaging features of primary pericardial mesothelioma have rarely been described. Herein we present a case report of its diagnostic-pathologic features. Chest computed tomography (CT) revealed an irregularly enhanced mass occupying the entire pericardial space and surrounding the superior vena cava. At autopsy, the tumor was found to fill the pericardial space completely, and to extend to the superior vena cava through the superior pericardial sinus. The CT features of the tumor were correlated well with those revealed at autopsy, and provided satisfactory information regarding the presence and the extension of the tumor.

Rupture of a hepatic metastasis from renal cell carcinoma.

We describe a rare case of spontaneous rupture of a hepatic metastasis from renal cell carcinoma that was treated successfully by hepatic arterial embolization. A 65-year-old woman, who had been undergoing immunotherapy for inoperably disseminated renal carcinoma and lung metastases, presented with severe abdominal pain in a state of hypovolemic shock. Computed tomography revealed a highly attenuated mass lesion in the right lobe of the liver and massive intraperitoneal hemorrhage. Subsequent hepatic angiography showed extravasation from the feeding right hepatic artery. Transcatheter embolization of the right hepatic artery was subsequently performed, and the patient made an uneventful recovery. Although hepatic rupture due to metastatic cancer is extremely rare, transcatheter arterial embolization (TAE) is an appropriate and useful treatment for massive hemorrhage caused by spontaneous rupture of liver metastasis.

Retroperitoneal bronchogenic cyst: CT and MR imaging.

Retroperitoneal bronchogenic cysts are extremely rare congenital anomalies that represent malformations of the embryonic foregut and are morphologically expressed as maldevelopments of the respiratory system. Because of the low prevalence of these tumors, their imaging features have seldom been described. We present the computed tomographic and magnetic resonance imaging findings of a case of retroperitoneal bronchogenic cyst.

Transcatheter arterial embolization for postpartum massive hemorrhage: a case report.

A 29-year-old woman suffered uncontrollable massive hemorrhage from a deep vaginal laceration following spontaneous vaginal delivery. Pelvic angiography revealed extravasation from a branch of the right pudendal artery. Transcatheter arterial embolization was successfully performed and quickly achieved hemostasis. When postpartum hemorrhage cannot be controlled with conservative treatment, transcatheter arterial embolization should be considered in order to avoid major surgery in an unstable patient and to maintain reproductive potential.

Study on the concentration of circulating primordial germ cells (cPGCs) in early chick embryos.

Experiments were conducted to elucidate the factor that influences the concentration of circulating primordial germ cells (cPGCs) in two-day old chick embryos. The concentration of cPGCs was observed to be highest at stage 14 (66.9 +/- 23.2 microliters) and decreased thereafter. However, considerable egg to egg variations in cPGC concentration, especially at stages 13, 14, 15, and 16 were observed. After conducting experiments to elucidate the source of egg to egg variation in cPGC concentration among embryos, it was revealed that there are hens that lay eggs which contain either constantly high (more than 80 PGCs/microliter) or constantly low (less than 30 PGCs/microliter) concentration of cPGCs. The results obtained from the present experiments showed that one of the major source of egg to egg variation in the concentration of cPGCs was due to the individual differences among females that produced the eggs.

Strangulation of small bowel due to Meckel diverticulum: CT findings.

We report an unusual case of small bowel strangulation due to long Meckel diverticulum. CT demonstration of the bundle-like segment contiguous with the distended fluid-filled loops of bowel contributed to the prompt preoperative diagnosis.

Mesenteric schwannoma.

Schwannoma is a benign neurogenic tumor arising from the sheath of peripheral nerves. It occurs very rarely in the mesentery, where it is difficult to diagnose. Herein we describe a case in which contrast-enhanced CT and gadolinium-DTPA-enhanced MR showed a locally enhanced well-defined tumor with a cystic component just anterior to the duodenum. These findings corresponded well to the resected specimen.

"Neuritic conglomerates" in the cerebral cortex of a patient with Creutzfeld-Jakob disease.

In the cerebral cortex of a patient with Creutzfeld-Jakob disease (CJD), we found peculiar glomeruloid or skein-like structures which have not previously been described. The patient was a 67-year-old man, whose clinical features and neuropathological findings were consistent with CJD. The glomeruloid or skein-like structures were distributed in the deep layers of the cortex and consisted of intricately entangled masses of thick argyrophilic fibers. These structures were immunostained with anti-neurofilament antibodies and were considered to have originated from neuronal cytoplasmic processes, most likely axons. The pathogenesis and pathological significance of these structures, which were tentatively termed "neuritic conglomerates," remains unclear. However they probably represent an overgrowth of the distal portion of axons and indicate the plasticity of the injured neurons.

Treatment of pathologic emotionality with thyrotropin-releasing hormone.

Thyrotropin-releasing hormone (TRH) has been reported to be effective in some neuropsychiatric diseases. We examined the effect of TRH on the syndrome of pathologic laughing or crying in four patients with multiple cerebral infarction and one with olivo-ponto-cerebellar atrophy (OPCA). We found a marked therapeutic effect of the peptide on pathologic laughing with a slight improvement in ataxia in a patient with OPCA. A marked diminution in frequency of their pathologic crying with TRH was achieved in two patients with multiple cerebral infarction. The two other patients did not respond to TRH. Levodopa was administered to these patients to compare with TRH in therapeutic efficacy on the symptom and was effective in only one of four patients. The concentration of homovanillic acid in cerebrospinal fluid had diminished in two of the four patients. The results suggest that the tripeptide is effective in the control of this syndrome. We discuss the underlying mechanism(s) of the syndrome and the mode(s) of action of TRH.

[Three patients with hypopituitarism accompanied by primary empty sella presenting mental symptoms].

We report here three patients with hypopituitarism accompanied by primary empty sella, whose first manifestations were various mental symptoms. Endocrine studies revealed that two patients showed panhypopituitarism and the other had isolated adrenocorticotropin (ACTH) deficiency. Although several different types of pituitary dysfunctions have been described in a mild form, empty sella is usually asymptomatic. Their first manifestations were mental symptoms; consciousness disturbance, psychomotor agitation, visual hallucination and delusion. Isolated ACTH deficiency is an uncommon disease which etiology is still undetermined. A case with isolated ACTH deficiency associated with an empty sella has been reported before. It is suggested that empty sella might have a role in pathogenesis of isolated ACTH deficiency. The empty sella was confirmed by metrizamide cisternography and magnetic resonance imaging (MRI). These imaging studies are good tools to disclose empty sella. Replacement with cortisone and levothyroxine resulted in an improvement in the mental symptoms in two patients with panhypopituitarism. No alteration was observed following cortisone administration in the patient with isolated ACTH deficiency. Delusion and visual hallucination in this patient poorly responded to treatment with neuroleptics.

[A case of tuberculous encephalopathy with multiple intracranial tuberculomas].

A case of 56-year-old man with tuberculous encephalopathy following pulmonary tuberculosis was reported. Computed tomography (CT) revealed low density virtually confined to the white matter of the cerebral hemisphere. Contrast enhanced CT demonstrated intracranial multiple spotted lesions, all of which were homogeneously enhanced, supporting multiple intracranial tuberculomas. Magnetic resonance miss spelling imaging (MRI) suggested brain edema and demyelination of the white matter. Clinically this case was characterised by evidence of diffuse cerebral involvement in the form of convulsions, abnormal behavior and consciousness impairment without significant signs of meningitis. Antituberculous chemotherapy improved both clinical symptoms and intracranial lesions on CT and MRI. These findings strongly suggested the diagnosis of tuberculous encephalopathy with multiple tuberculomas. No adult case of tuberculous encephalopathy with multiple intracranial tuberculomas has been previously reported.

Unilateral spatial neglect due to hemorrhage in the thalamic region.

In a series of 33 cases of thalamic hemorrhage, unilateral spatial neglect (USN) was found in 11 patients all of whom had right-sided lesions. An analysis of results suggests that the posteromedial portion of the thalamus plays an important role in the pathogenesis of USN and that extensive lesions beyond the thalamus involving nearby structures may be necessary to cause persistent USN.

Expansion hyoidplasty. 1983 First-Place Resident Research Award: clinical category.

An inspiratory, circumferential, passive collapse of the hypopharyngeal lumen is the mechanism of airway obstruction in some patients with "idiopathic" obstructive sleep apnea syndrome. While permanent tracheotomy has resolved the obstruction and reversed the associated cardiopulmonary sequelae, it is not without complications. The expansion hyoidplasty was conceived as an alternative. The hyoid bone is trisected just medial to each lesser cornu, then held in an expanded position by a permanent brace. The greater cornua with attached middle constrictor and hyoglossus are moved laterally, while the body of the hyoid with attached geniohyoid and genioglossus shifts the base of tongue anteriorly. The procedure is potentially reversible. Twenty dogs were studied before and after hyoid expansion, 10 for superior hypopharyngeal pressure-volume measurements and 10 for the closing-pressure study. Pressure-volume studies demonstrated a consistent expansion of the superior hypopharynx. Deglutition and laryngeal competence wee not grossly affected. Reexamination of four animals in the closing-pressure group 1 year postoperatively demonstrated stability of the hyoid expansion and no evidence of serious parahyoid tissue complications.

[Transcortical sensory aphasia produced by lesions of the anterior basal ganglia area].

We reported three cases of an aphasic syndrome caused by unusual lesion distribution. Our patients, language disorders could be summarized as transcortical sensory aphasia and showed following symptoms; (1) fluent paraphasic verbal output, (2) anomia which was not facilitated by cueing, (3) impaired comprehension of spoken language, (4) preserved capacity of repetition, (5) preserved ability of reading aloud with impaired comprehension of the written material and (6) agraphia. In addition, all had no associated physical neurological signs such as hemiparesis or hemianopsia. All were right handed. All three cases showed the similar lesion distribution by computed tomographic scanning of the brain. All had low density areas in the anterior portion of the left basal ganglia including the head of the caudate nucleus, the anterior portion of the putamen, the anterior portion of the anterior limb of the internal capsule and the nearby white matter. Case 2 also had the small right hemisphere lesion in the white matter near the anterior portion of the lateral ventricle. Transcortical sensory aphasia with this lesion distribution has not been reported. We attributed the causative damage to lesions of the white matter and not to lesions of the basal ganglia per se. It was also speculated that fluent aphasia can be produced by the anteriorly situated white matter lesion if issuing fibers from the Broca's area were spared. Finally a possible anatomoclinical correlation for "transcortical alexia" (preserved oral reading and impaired reading comprehension) was attempted. The symptom is probably a reflection of the fact that the posterior speech area including the angular gyrus was left intact.

[On the hemispheric asymmetry of unilateral spatial neglect].

Many investigators were interested in unilateral spatial neglect (USN) and studied it in various respects. Especially the between-hemispheric difference of USN has been broadly argued. It can be considered as a well accepted fact that there is a difference of frequency of USN between left and right brain-damaged patients, however, there is no consistent opinion whether there are differences of severity and quality. To settle this dispute, 239 right-handed unilateral brain-damaged subjects were investigated on USN. 125 subjects suffered from left hemisphere lesions and 114 from right hemisphere lesions. Two tests; copy of drawings and finger imitation; were performed. On copying of drawings, each patient was required to copy line drawings of cubes, complex two-dimensional geometrical figures and simple two-dimensional geometrical figures. Those who failed to complete either the left- or right-hand side of any one of these drawings were classified as showing USN. Then failures of USN were divided into two different patterns; unilateral omission and unilateral distorsion. Again imitation of various finger patterns was tested with the hand homolateral to lesions. These items were presented by two methods. The subjects saw the dorsal side of the examiner's hand in the first, and palmar side in the second. On the copying of drawings, right brain-damaged subjects had about twice higher incidence of total USN than left brain-damaged subjects. As for omission alone, the incidence with the right hemispheric group was three times as high as the incidence with the left hemispheric group.(ABSTRACT TRUNCATED AT 250 WORDS)

Transglottic carcinoma.

The cases of 152 patients with transglottic carcinoma were reviewed. There were 31% T2, 39% T3, and 30% T4 lesions. Twenty-six percent of patients had neck node metastases at initial presentation, and 19% with no neck dissection or radical irradiation to the neck subsequently developed neck metastases. Patients treated with voice conservation surgery +/- neck dissection +/- radiation (VCS +/- ND +/- R) had small transglottic carcinomas, whereas total laryngectomy +/- neck dissection +/- radiation (TL +/- ND +/- R) was used for patients with larger lesions. The reason for radiation alone (RA) was the patient's poor general condition or refusal of surgery. The total failure rate (primary, neck, and distant metastases) was 39%. Patients treated with TL +/- ND +/- R had fewer primary and stomal failures (12%) than those treated by VCS +/- ND +/- R (23%) and RA (33%), but ultimate failure after salvage treatment was the same (12%-13%). Sixty percent of patients treated with VCS and 67% with RA had their voices preserved. The major complication rate (overall, 16%) was highest in the group treated with VCS +/- ND +/- R. Five-year observed and adjusted survival for the entire group was 47% and 55%, respectively. The lower survival in the RA group was attributable to a high death rate from intercurrent disease. The incidence of second tumors was 14%. Unfavorable prognostic factors were older age, pretreatment tracheostomy, advanced stage and the presence of tumor in surgical specimen, and lymph nodes.

Expansion hyoidplasty: a potential surgical procedure designed for selected patients with obstructive sleep apnea syndrome. Experimental canine results.

Some patients with "idiopathic" obstructive sleep apnea syndrome have an inspiratory, circumferential, passive collapse of the hypopharyngeal lumen as the mechanism of airway obstruction. Permanent tracheotomy has offered documented dramatic resolution of the airway obstruction with reversal of the associated cardiopulmonary sequelae. Tracheotomy is not, however, without psychological and physical complications detracting from its use. In hope of developing a surgical alternative, the expansion hyoidplasty was conceived. The hyoid bone is transected just medial to each lesser cornu. The trisected hyoid bone is then held in an expanded position by a permanent stainless steel brace. The greater cornua with attached middle constrictor and hyoglossus are moved laterally, while the body of the hyoid with attached geniohyoid and genioglossus shift the base of tongue anteriorly. The procedure is potentially reversible. Twenty dogs were studied pre and posthyoid expansion. Superior hypopharyngeal pressure-volume and closing pressures were obtained on 10 dogs. The pressure-volume studies demonstrate a consistent expansion of the superior hypopharynx. The average drop in pressure varied from 2.9 to 12.4 cm H2O in different animals. All posthyoid expansion dogs showed an average increase in closing pressure ranging from -4.4 to -28.3 cm H2O. Deglutition and laryngeal competence were not grossly effected. These results support the continued experimentation towards implementation of the expansion hyoidplasty in humans.