Ultraviolet Radiation-Induced Impairment of Tumor Rejection Is Enhanced in Xeroderma Pigmentosum A Gene-Deficient Mice

Xeroderma pigmentosum (XP)A gene-deficient mice display dermatologic abnormalities similar to human XP, such as enhanced ultraviolet (UV)-induced acute inflammation and high incidence of UVB-induced skin cancer. We have previously reported that UVB-induced immunosuppression of contact hypersensitivity was greatly enhanced in XPA mice. In the present study, we examined the effects of UVB radiation on tumor rejection in XPA mice. Tumor cells established from UVB-induced squamous cell carcinoma in XPA mice were injected subcutaneously. No difference in the development of tumors was observed between the non-irradiated XPA and wild-type mice. Tumors developed, grew in size, and reached the maximum at 7–10 d after the inoculation. Thereafter, all tumors decreased in size and were completely rejected by 4 wk in both strains of mice. When tumor cells were inoculated into the skin that had been irradiated with 50–150 mJ per cm2 of UVB, tumor grew in 60% (12 of 20) of the XPA mice, but only in 4% (one of 23) of wild-type mice. Phenotyping of tumor-infiltrating cells revealed that the migration of natural killer cells and CD8(+) T cells was inhibited in UVB-irradiated XPA mice. These data suggest that enhanced UVB-induced impairment of tumor rejection could be partially involved in the cancer development of XP patients

Photobiologic and Photoimmunologic Characteristics of XPA Gene-Deficient Mice

Xeroderma pigmentosum group A (XPA) gene-deficient mice cannot repair UV-induced DNA damage and easily develop skin cancers by UV irradiation. Just like human XP patients, homozygous (–/–) mice developed stronger longer-lasting acute inflammation than did wild-type mice after a single irradiation with UVB. Moreover, the model mice showed more severe UV-induced damage of keratinocytes and Langerhans cells than did the control mice. UVB-induced local and systemic immunosuppression was greatly enhanced in the (–/–) mice. Treatment with indomethacin, an inhibitor of prostaglandin (PG) synthesis, inhibited UV-induced inflammation and abrogated immunosuppression. In XPA-deficient mice, the amount of PGE2 and the expression level of COX-2 mRNA greatly increased after UVB irradiation compared with wild-type mice. These results suggest that the excess DNA photoproducts remaining in XPA-deficient cells after UV radiation induce COX-2 expression and subsequently produce a high amount of PGE2, which causes the enhancement of inflammation and immunosuppression. In XPA-deficient mice, the natural killer cell activity significantly decreased after repeated exposures to UVB. Our experimental data indicate that cancer development in XP patients involves not only mutagenesis due to the defect in DNA repair, but also the enhanced UV-immunosuppression and intensified impairment of natural killer function

Added Diagnostic Value of Cerebrospinal Fluid Carcinoembryonic Antigen in a Patient with Leptomeningeal Carcinomatosis as the Initial Manifestation of Gastric Cancer

A 77-year-old woman with no history of malignancy presented with anorexia and bilateral lower extremity weakness. Her consciousness level worsened daily, so we performed a lumbar puncture. Cerebrospinal fluid (CSF) analysis indicated meningitis, but three rounds of CSF cytology showed no malignant cells. The patient’s carcinoembryonic antigen (CEA) level was highly elevated in CSF, but normal in serum. Through gadolinium-enhanced brain/spinal magnetic resonance imaging and gastrointestinal endoscopy, she was diagnosed with leptomeningeal carcinomatosis (LC) from gastric cancer. CEA level in CSF facilitated the diagnosis of LC from gastric cancer because there were no malignant cells on CSF cytology

トウイン ニオケル ダイタイ ヘルニア シュジュツ 26ショウレイ ノ リンショウテキ ケントウ

We performed this study to investigate the differences in clinical features between incarcerated femoral hernias and non-incarcerated cases. We operated on 26 patients with a femoral hernia from April 1989 to December 1998. Twenty-four patients were female and two were male. Thir mean age at the time of operation was 68.2±15.4 years, and those older than 60 years were remarkably high. All females had a history of abortion more than twice. Eighteen of 26 (69.2%) hemoral hernias occurred on the right side, 7 on the left, and 1 on both sides. Those with an incarcerated hernia were 46.2% (12/26). Almost all patients without incarceration had only femoral tumors or swelling. On the contrary, a large number of the patients with an incarcerated hernia complained of abdominal or femoral pain, suggesting a hernial strangulation. Significant increases in white blood cell counts were recognized in the incarcerated cases compared to those without incarceration (9158.3± 2155.3 vs 6602.9±1049.5/mm3, respectively;P=0.0001). Additionally, the postoperative hospitalization periods of the patients with incarcerations were remarkably prolonged compared to those without an incarceration. According to the contents of the hernia in the 12 patients with incarcerations, we detected the small bowel in 9 and the grater omentum in 3. Six of 9 patients with an incarcerated small bowel had necrotic complications of strangulated small bowel. However, there was no clinical difference compared to the other 6 patients without a necrotic small bowel. In conculusion, we should recognize the possibility of femoral hernias in the treatment of patients complaining of a tumor or pain in the femoral triangle

Clinical study of strangulation obstruction of the small bowel

Early diagnosis of strangulation obstruction is very important for surgeons because delayed diagnosis often leads to severe complications. Thirty patients underwent an operation because of small bowel obstruction between April, 1993 and December, 1999. In the present study, we examined the differences in clinical findings between simple obstruction and strangulation obstruction. In addition, we examined the manifestation of systemic inflammatory response syndrome (SIRS) and whether it is useful for early diagnosis of strangulation obstruction, and whether it is correlated with the severity of ischemia due to strangulation. Tenderness was examined in all patients and signs such as abdominal irritation were detected more often in patients with strangulation obstruction than in the patients with simple obstruction. According to SIRS, the large number of the patients with strangulation obstruction showed SIRS before operation and the manifestation of SIRS correlated well with the length of the necrosis in the strangulated small bowel. We recognized the importance of anamnesis and clinical findings in examinations of small bowel obstruction, furthermore, it was suggested that SIRS should be the warning sign for strangulation obstruction

Association of transcription-coupled repair but not global genome repair with ultraviolet-B-induced Langerhans cell depletion and local immunosuppression.

Exposure to ultraviolet-B radiation impairs cellular immune responses. This immunosuppression seems to be associated with Langerhans cell migration. DNA damage appears to play a key role because enhanced nucleotide excision repair, a pathway essential for elimination of ultraviolet-B-induced DNA lesions, strongly counteracts immunosuppression. To determine the effect of DNA repair on ultraviolet-B-induced local immunosuppression and Langerhans cell disappearance, three mouse strains carrying different defects in nucleotide excision repair were compared. XPC mice, which were defective in global genome repair, were as sensitive to ultraviolet-B-induced local suppression of contact hypersensitivity to picryl chloride as their wild-type littermates. CSB mice, defective in transcription-coupled repair, were far more sensitive for immunosuppression as were XPA mice, defective in both transcription-coupled repair and global genome repair. Only a moderate depletion of Langerhans cells was observed in XPC mice and wild-type littermates. Ultraviolet-B-induced Langerhans cell depletion was enhanced in CSB and XPA mice. Hence, the major conclusion is that local immunosuppression is only affected when transcription-coupled DNA repair is impaired. Furthermore, a defect in transcription-coupled repair was linked to enhanced ultraviolet-B-induced Langerhans cell depletion. In combination with earlier experiments, it can be concluded that Langerhans cell disappearance is related to ultraviolet-B-induced local but not to systemic immunosuppression

Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization

The mobilization of hematopoietic stem cells does not require osteoclasts, which may even have an inhibitory effect

UVSSA and USP7, a new couple in transcription-coupled DNA repair

Transcription-coupled nucleotide excision repair (TC-NER) specifically removes transcription-blocking lesions from our genome. Defects in this pathway are associated with two human disorders: Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS). Despite a similar cellular defect in the UV DNA damage response, patients with these syndromes exhibit strikingly distinct symptoms; CS patients display severe developmental, neurological, and premature aging features, whereas the phenotype of UVSS patients is mostly restricted to UV hypersensitivity. The exact molecular mechanism behind these clinical differences is still unknown; however, they might be explained by additional functions of CS proteins beyond TC-NER. A short overview of the current hypotheses addressing possible molecular mechanisms and the proteins involved are presented in this review. In addition, we will focus on two new players involved in TC-NER which were recently identified: UV-stimulated scaffold protein A (UVSSA) and ubiquitin-specific protease 7 (USP7). UVSSA has been found to be the causative gene for UVSS and, together with USP7, is implicated in regulating TC-NER activity. We will discuss the function of UVSSA and USP7 and how the discovery of these proteins contributes to a better understanding of the molecular mechanisms underlying the clinical differences between UVSS and the more severe CS