Chemoradiation induces upregulation of immunogenic cell death-related molecules together with increased expression of PD-L1 and galectin-9 in gastric cancer.

Surgery alone or combined with chemo- and/or radiation therapy remains the primary treatment for gastric cancer (GC) to date and immunotherapeutic tools such as monoclonal antibodies are only slowly being implemented. This is partly due to the fact that the immune microenvironment in GC during chemoradiation and other treatment modalities is still poorly understood. 7 gastric cancer (GC) cell lines were tested for their response to chemoradiation using 5-FU in combination with X-ray irradiation. We conducted flow cytometric analysis to determine the cells' ability to undergo immunogenic cell death (ICD) and their expression of the two immunosuppressive proteins programmed death-ligand 1 (PD-L1) and galectin-9 (Gal-9). We evaluated the overall immunogenicity of two cell lines (MKN7, MKN74) in co-culture experiments with human monocyte-derived dendritic cells (Mo-DCs). Chemoradiation induces distinct responses in different GC cell lines. We observe ICD in vitro in all tested GC cell lines in the form of calreticulin (CRT) translocation to the plasma membrane. As a resistance mechanism, these cells also upregulated Gal-9 and PD-L1. Mo-DC maturation experiments showed that GCs provoked the maturation of Mo-DCs after chemoradiation in vitro. The addition of α-PD-L1 blocking antibody further enhanced the immunogenicity of these cells while improving DC viability. Blocking Tim-3, as the main receptor for Gal-9, had no such effect. Our findings suggest that the benefits of chemoradiation can substantially depend on tumor subtype and these benefits can be offset by induced immune evasion in GC. Combination treatment using checkpoint inhibitors could potentially lead to enhanced immune responses and yield better patient outcomes.

Single-blind randomized clinical trial of transinguinal preperitoneal repair using self-expanding mesh patch vs. Lichtenstein repair for adult male patients with primary unilateral inguinal hernia.

PURPOSE: The aim of the study was to compare proportions of chronic postoperative inguinal pain (CPIP) and other surgical outcomes between transinguinal preperitoneal repair with modified Kugel patch (MK) and Lichtenstein repair (LR). METHODS: Two-hundred adult male patients with primary unilateral inguinal hernia were randomized into MK or LR groups. The primary endpoint was CPIP, pain at 6 months after surgery. Secondary outcomes included recurrence rate, incidence of postoperative complications, time until return to activities, inguinal pain and sensory disturbances assessed at 1 week, 1 month, 3, 6, and 12 months after the operation using an 11-point numerical rating scale (NRS). The study was an intention-to-treat analysis. RESULTS: In comparison of MK (n = 100) and LR (n = 100) with similar backgrounds, proportions of CPIP were similar (7.2 vs. 11.1%, p = 0.3452). Favorable outcomes for MK were duration of operation (32 vs. 40 min, p < 0.0001), NRS of foreign body sensation at 1 year (0 [0-1] vs. 0 [0-2], p = 0.0067), and NRS of numbness at 1 month (0 [0-1] vs. 0 [0-3], p = 0.0078) after the operation. CONCLUSIONS: In regard to CPIP, the short-term results of MK and LR were similar.

Terminal Ileac Ulcers Mimicked Post-transplantation Lymphoproliferative Disorder in a Heart Recipient Treated With Everolimus: A Case Report.

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized and potentially fatal complication of cardiac transplantation that commonly involves the gastrointestinal tract. Herein, we report a case of life-threatening gastrointestinal bleeding from recurrent terminal ileac ulcers mimicking PTLD in a heart recipient treated with everolimus (EVL). A 40-year-old man underwent heart transplantation for dilated cardiomyopathy 3 years prior to the current admission and was treated with tacrolimus and EVL. He was admitted to a local hospital because of fever, abdominal pain, and diarrhea. His symptoms persisted and, 3 weeks later, hematochezia occurred; thus, he was transferred to our hospital. As computed tomography and 18F-fluorodeoxyglucose positron emission tomography showed bowel-wall thickening of the terminal ileum, gastrointestinal PTLD was initially suspected. However, although colonoscopy- performed after switching EVL to mycophenolate mofetil (MMF)-showed terminal ileac ulcers, the histologic examination revealed no findings corresponding to PTLD. As EVL may delay ulcer healing, MMF was maintained for 3 months. After repeated colonoscopy showed ulcer healing, MMF was switched back to EVL for cardiac allograft vasculopathy prevention. Three weeks later, he was emergently admitted to a local hospital for life-threatening gastrointestinal bleeding from a recurrent terminal ileal ulcer, which required hemostatic forceps hemostasis. As EVL is suspected to be associated with recurrent ileal ulcers, EVL was again switched back to MMF. The ileal ulcers resolved, without recurrence in 3 months of clinical follow-up. This case demonstrates that cases of life-threatening gastrointestinal bleeding from recurrent terminal ileac ulcers can mimic PTLD in a heart recipient treated with EVL.

The analgesic effect of rescue administration of intravenous acetaminophen in cancer patients may be associated with sex and opioid dose, and the effect would appear to patients administered under 45 mg/day opioid (oral morphine equivalents).

There have been no investigations examining the analgesic effect of rescue administration of intravenous acetaminophen (IV APAP) for pain in cancer patients. Fifty cancer patients who received IV APAP for pain at Ashiya Municipal Hospital (Hyogo, Japan) between January 2014 and July 2016 were retrospectively evaluated. The degree of pain was evaluated using a 4-point verbal rating scale. Pain intensity differences ≥ 1 defined the IV APAP effective group, and the patient' characteristics were compared by a medical chart review. Variables were extracted from medical records for logistic regression analyses of factors associated with analgesic effect. The cut-off value of opioid dose (oral morphine equivalent) was determined using receiver operator characteristic (ROC) curve analysis. Thirty eight (76%) patients experienced an analgesic effect of rescue administration of IV APAP. Sex (odds ratio [OR] 5.4014; p = 0.0397) and opioid dose used for pain control (OR 0.9901; p = 0.0147) were found to be associated with the efficacy of rescue administration of IV APAP. The cut-off value of opioid dose (oral morphine equivalent), which may be difficult to match the analgesic effect of IV APAP, was calculated to be more than 45 mg/day. This study demonstrated the efficacy of a rescue administration of IV APAP for pain in cancer patients, and revealed that sex and opioid dose may be associated with the analgesic effect. Furthermore, this study also proposes a criterion for the analgesic effect.

Reversible Cerebral Vasoconstriction Syndrome After Heart Transplantation: A Case Report.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is a transient cerebrovascular disorder putatively caused by some immunosuppressive agents. CASE REPORT: We recently encountered a 47-year-old female patient diagnosed with dilated cardiomyopathy who developed RCVS after heart transplantation. A triple-drug regimen consisting of tacrolimus, mycophenolate mofetil, and a corticosteroid was started after surgery. On postoperative day (POD) 11, the patient developed a severe headache, although computed tomography of the head demonstrated no signs of hemorrhage or infarction. At first, both a painkiller and migraine drugs were regularly administered to the patient. On POD 21, however, she developed an unbearable headache with a visual field defect and mild hemiparesis of the right hand. Magnetic resonance imaging (MRI) of the brain revealed a cerebral infarction in the left occipital lobe with diffuse vasoconstriction of both the middle and posterior cerebral arteries. A diagnosis of RCVS was made and tacrolimus, a drug suspected to cause RCVS, was discontinued. In its place, two doses of basiliximab followed by everolimus, both of which are alternatives for tacrolimus, were given. The corticosteroid dose was also increased. Furthermore, to release vasoconstriction, both verapamil and diltiazem were administered. On POD 27, cerebrovascular constrictions were shown to be relieved on brain MRI and the patient's neurological symptoms subsequently almost completely diminished. CONCLUSION: RCVS should always be considered as a cause of headache in heart transplant recipients because tacrolimus, an immunosuppressive agent, may trigger RCVS. This will allow rapid intervention that is essential for avoiding irreversible neurological deficits.

Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting in Heart Transplant Recipients With Transplant Coronary Arterial Vasculopathy.

BACKGROUND: Transplant coronary arterial vasculopathy (TCAV) is a major cause of death after heart transplantation (HTx). Palliative coronary revascularization has been attempted in patients with severe TCAV; however, the outcome has not been fully elucidated. METHODS: Ninety-six patients who were treated after HTx at our institute between 1999 and 2015 were screened for TCAV. TCAV was defined as >70% stenosis on coronary angiography (CAG) or a maximal intimal thickness of >0.5 mm in the right or left coronary arteries on intracoronary ultrasonography (IVUS). In the present study, the outcomes of patients with severe TCAV who underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were investigated. RESULTS: TCAV containing donor-transmitted atherosclerosis was cumulatively found in 69 patients (71.9% of the total; mean age, 34.6 ± 13.1 years; 52 men; mean follow-up duration, 83.0 ± 60.4 months). Five (7.2%) and 64 (92.8%) of the 69 patients were diagnosed as having TCAV by use of CAG and IVUS, respectively. All 5 patients diagnosed by with the use of CAG underwent coronary revascularization between 1 and 236 months after HTx. Three patients underwent PCI with drug-eluting stents, with a primary success rate of 100%. No angiographic restenosis occurred in 2 patients at 31 and 36 months after PCI, respectively. Meanwhile, 2 patients underwent CABG. No peri-operative complications occurred, and all grafts were patent as assessed by use of CAG at 34 and 5 months after CABG. CONCLUSIONS: Coronary revascularization was feasible and effective for severe TCAV with middle-term follow-up.

EAF2 regulates DNA repair through Ku70/Ku80 in the prostate.

Androgens are known to protect prostate cancer cells from DNA damage. Recent studies showed regulation of DNA repair genes by androgen receptor signaling in prostate cancers. ELL-associated factor 2 (EAF2) is an androgen-regulated tumor suppressor and its intracellular localization can be modulated by ultraviolet light, suggesting a potential role for EAF2 in androgen regulation of DNA repair in prostate cancer cells. Here we show that knockdown of EAF2 or its homolog EAF1 sensitized prostate cancer cells to DNA damage and the sensitization did not require p53. EAF2 knockout mouse prostate was also sensitized to γ-irradiation. Furthermore, EAF2 knockdown blocked androgen repression of LNCaP or C4-2 cells from doxorubicin induction of γH2ax, a DNA damage marker. In human prostate cancer specimens, EAF2 expression was inversely correlated with the level of γH2ax. Further analysis showed that EAF2 and EAF1 are required for the recruitment and retention of Ku70/Ku80 to DNA damage sites and play a functional role in nonhomologous end-joining DNA repair. These findings provide evidence for EAF2 as a key factor mediating androgen protection of DNA damage via Ku70/Ku80 in prostate cancer cells.

Three-dimensional evaluation of subclinical extension of extramammary Paget disease: visualization of the histological border and its comparison to the clinical border.

BACKGROUND: In extramammary Paget disease (EMPD), Paget cells are sometimes detected outside the clinical border (subclinical extension). However, the spreading pattern of Paget cells in subclinical extension remains unclear. In addition, the macroscopic appearances of lesions accompanied by subclinical extension are totally unknown. OBJECTIVES: To characterize the spreading pattern of Paget cells as well as the macroscopic appearance of lesions of EMPD with subclinical extension. METHODS: Nineteen patients with primary anogenital EMPD underwent mapping biopsies and excisional surgeries; biopsy samples were then taken at the periphery of well-demarcated lesions. Samples were transparentized and subjected to whole-mount immunostaining with anticytokeratin 7 antibody to label Paget cells. The histological border was evaluated in three dimensions by two-photon microscopy. The shape and location of the histological border were compared with those of the clinical border. RESULTS: In 21 samples taken at the lesion where subclinical extension was not shown by mapping biopsy, the shape and location of the histological border were almost identical to those of the clinical border. However, two samples exhibited small foci of Paget cells outside the clinical border, showing subclinically extended satellite lesions. In the two samples taken at the lesions where subclinical extension was shown by mapping biopsy, a continuous arrangement of Paget cells extending beyond the clinical border was identified. Subclinically extended Paget cells were detected solely outside hypopigmented patches with erythema. CONCLUSIONS: In EMPD, at least two patterns of subclinical extension exist: continuous and satellite lesions. Subclinical extension might exist preferentially outside hypopigmented patches with erythema.

Diagnostic and Prognostic Value of 11C-Methionine PET for Nonenhancing Gliomas.

BACKGROUND AND PURPOSE: Noninvasive radiologic evaluation of glioma can facilitate correct diagnosis and detection of malignant transformation. Although positron-emission tomography is considered valuable in the care of patients with gliomas, (18)F-fluorodeoxyglucose and (11)C-methionine have reportedly shown ambiguous results in terms of grading and prognostication. The present study compared the diagnostic and prognostic capabilities of diffusion tensor imaging, FDG, and (11)C-methionine PET in nonenhancing gliomas. MATERIALS AND METHODS: Thirty-five consecutive newly diagnosed, histologically confirmed nonenhancing gliomas that underwent both FDG and (11)C-methionine PET were retrospectively investigated (23 grade II and 12 grade III gliomas). Apparent diffusion coefficient, fractional anisotropy, and tumor-to-normal tissue ratios of both FDG and (11)C-methionine PET were compared between grade II and III gliomas. Prognostic values of these parameters were also tested by using progression-free survival. RESULTS: Grade III gliomas showed significantly higher average tumor-to-normal tissue and maximum tumor2-to-normal tissue than grade II gliomas in (11)C-methionine (P = .013, P = .0017, respectively), but not in FDG-PET imaging. There was no significant difference in average ADC, minimum ADC, average fractional anisotropy, and maximum fractional anisotropy. (11)C-methionine PET maximum tumor-to-normal tissue ratio of 2.0 was most suitable for detecting grade III gliomas among nonenhancing gliomas (sensitivity, 83.3%; specificity, 73.9%). Among patients not receiving any adjuvant therapy, median progression-free survival was 64.2 ± 7.2 months in patients with maximum tumor-to-normal tissue ratio of <2.0 for (11)C-methionine PET and 18.6 ± 6.9 months in patients with maximum tumor-to-normal tissue ratio of >2.0 (P = .0044). CONCLUSIONS: (11)C-methionine PET holds promise for World Health Organization grading and could offer a prognostic imaging biomarker for nonenhancing gliomas.

Differentiation between primary central nervous system lymphoma and glioblastoma: a comparative study of parameters derived from dynamic susceptibility contrast-enhanced perfusion-weighted MRI.

AIM: To evaluate the diagnostic performance of parameters derived from dynamic susceptibility contrast-enhanced perfusion-weighted magnetic resonance imaging, including first-pass slope ratio (FSR), which is potentially easier to derive than the other proposed parameters in this study, for differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma. MATERIALS AND METHODS: Twenty-eight patients (10 PCNSLs and 18 glioblastomas) were analysed. Six perfusion parameters - corrected cerebral blood volume ratio (cCBVR), uncorrected CBV ratio (uCBVR), FSR, leakage coefficient (K2), percentage of signal-intensity recovery measured at the end of the first-pass (PSRend), and PSR measured using mean signal-intensity after the first-pass (PSRmean) - were derived from enhancing areas selected semi-automatically. Comparisons of cCBVR and uCBVR and of PSRend and PSRmean were conducted. The differences between PCNSL and glioblastoma were compared for the six parameters, and their diagnostic performance was evaluated by receiver operating characteristic curve analysis. RESULTS: For both tumours, cCBVR was significantly higher than uCBVR, and PSRend was significantly lower than PSRmean. PCNSL demonstrated lower cCBVR, uCBVR and FSR, and higher K2, PSRend and PSRmean compared with glioblastoma (p=0.0044 or less). On receiver operating characteristic curve analysis, the areas under the curve were 0.822 for cCBVR, 0.944 for uCBVR, 0.917 for FSR, 0.917 for K2, 0.933 for PSRend, and 0.894 for PSRmean. No significant difference was observed among the parameters, except cCBVR, which was significantly inferior to uCBVR. CONCLUSIONS: PCNSL can be differentiated from glioblastoma with high diagnostic value using any of the parameters, except cCBVR. FSR demonstrates high differential performance comparable to the other parameters.

Possible involvement of LKB1-AMPK signaling in non-homologous end joining.

LKB1/STK11 is a tumor suppressor gene responsible for Peutz-Jeghers syndrome, an inherited cancer disorder associated with genome instability. The LKB1 protein functions in the regulation of cell proliferation, polarization and differentiation. Here, we suggest a role of LKB1 in non-homologous end joining (NHEJ), a major DNA double-strand break (DSB) repair pathway. LKB1 localized to DNA ends upon the generation of micro-irradiation and I-SceI endonuclease-induced DSBs. LKB1 inactivation either by RNA interference or by kinase-dead mutation compromised NHEJ-mediated DNA repair by suppressing the accumulation of BRM, a catalytic subunit of the SWI/SNF complex, at DSB sites, which promotes the recruitment of an essential NHEJ factor, KU70. AMPK2, a major substrate of LKB1 and a histone H2B kinase, was recruited to DSBs in an LKB1-dependent manner. AMPK2 depletion and a mutation of H2B that disrupted the AMPK2 phoshorylation site impaired KU70 and BRM recruitment to DSB sites. LKB1 depletion induced the formation of chromosome breaks and radials. These results suggest that LKB1-AMPK signaling controls NHEJ and contributes to genome stability.

An in vitro demonstration of CMOS-based optoelectronic neural interface device for optogenetics.

A CMOS-based neural interface device equipped with an integrated micro light source array for optogenetics was fabricated and demonstrated. A GaInN LED array formed on sapphire substrate was successfully assembled with a multifunctional CMOS image sensor that is capable of on-chip current injection. We demonstrated a functionality of light stimulation onto ChR2-expressed cells in an in vitro experiment. A ChR2-expressed cell were successfully stimulated with the light emitted from the fabricated device.

Modified Kugel herniorrhaphy using standardized dissection technique of the preperitoneal space: long-term operative outcome in consecutive 340 patients with inguinal hernia.

PURPOSE: The aim of this study was to evaluate the outcome, with a special reference to recurrence and postoperative chronic pain, of the modified Kugel herniorrhaphy (MKH) using standardized dissection of the preperitoneal space. PATIENTS AND METHODS: Operative results were examined based on medical records and questionnaire surveys in 340 consecutive cases of MKH performed at a single institution. The operation was performed with an original 3-stage dissection of the preperitoneal space only via the internal inguinal ring. RESULTS: The mean follow-up period was 50.5 ± 24.3 months. The mean operating time was 42.2 ± 13.1 min, and by Nyhus classification, significant difference was observed between types IIIA and IIIB (39.5 ± 10.8 vs. 45.6 ± 15.6 min, P = 0.0279). Eight surgeons performed 10 or more operations, and no significant difference was found in their operating time. Thirty-one patients used additional analgesics postoperatively (9.1 %) and the length of postoperative stay was 1.2 ± 0.7 days. Seven patients (2.1 %) developed complications related to the hernia operation, but none of them required re-operation. The period required to return to normal daily activities was 3 ± 3.2 days. Questionnaire forms were returned from 77.7 % of all the patients, in which 12 patients reported chronic pain (4.7 %). Visual analog scale for patients with chronic pain scored 3.8 ± 2.4, with no patient indicating restrictions on daily life. Recurrence was observed in only one case (0.3 %). CONCLUSION: MKH using standardized dissection of the preperitoneal space is a highly reproducible procedure with acceptable rate of postoperative chronic pain and recurrence.

Cordycepin as a sensitizer to tumour necrosis factor (TNF)-α-induced apoptosis through eukaryotic translation initiation factor 2α (eIF2α)- and mammalian target of rapamycin complex 1 (mTORC1)-mediated inhibition of nuclear factor (NF)-κB.

Cordycepin (3'-deoxyadenosine) is one of the major bioactive substances produced by Cordyceps militaris, a traditional medicinal mushroom. Cordycepin possesses several biological activities, including both pro-apoptotic and anti-apoptotic properties. In the present report, we investigated an effect of cordycepin on the survival of cells exposed to tumour necrosis factor (TNF)-α. We found that subtoxic doses of cordycepin increased susceptibility of cells to TNF-α-induced apoptosis. It was associated with suppression of nuclear factor-κB (NF-κB), a major prosurvival component involved in TNF-α signalling. The adenosine transporter and A3 adenosine receptor, but not A1 and A2 adenosine receptors, mediated both anti-NF-κB and pro-apoptotic effects. We found that cordycepin had the potential to phosphorylate eukaryotic translation initiation factor 2α (eIF2α) and that activation of eIF2α mimicked the suppressive effect of cordycepin on the NF-κB pathway. Furthermore, activation of eIF2α sensitized cells to TNF-α-induced apoptosis. To identify molecular events downstream of eIF2α, the role of mammalian target of rapamycin complex 1 (mTORC1) was examined. Selective activation of 3eIF2α, as well as treatment with cordycepin, caused phosphorylation of mTORC1. Rapamycin, an inhibitor of mTORC1, significantly reversed the suppressive effects of eIF2α on NF-κB. These results suggest that cordycepin sensitizes cells to TNF-α-induced apoptosis, at least in part, via induction of the eIF2α-mTORC1 pathway and consequent suppression of NF-κB.

mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1-JNK pathway.

Mammalian target of rapamycin (mTOR) has a key role in the regulation of an array of cellular function. We found that rapamycin, an inhibitor of mTOR complex 1 (mTORC1), attenuated endoplasmic reticulum (ER) stress-induced apoptosis. Among three major branches of the unfolded protein response, rapamycin selectively suppressed the IRE1-JNK signaling without affecting PERK and ATF6 pathways. ER stress rapidly induced activation of mTORC1, which was responsible for induction of the IRE1-JNK pathway and apoptosis. Activation of mTORC1 reduced Akt phosphorylation, which was an event upstream of IRE-JNK signaling and consequent apoptosis. In vivo, administration with rapamycin significantly suppressed renal tubular injury and apoptosis in tunicamycin-treated mice. It was associated with enhanced phosphorylation of Akt and suppression of JNK activity in the kidney. These results disclosed that, under ER stress conditions, mTORC1 causes apoptosis through suppression of Akt and consequent induction of the IRE1-JNK pathway.

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3'-deoxyadenosine.

The unfolded protein response (UPR) is involved in a diverse range of pathologies triggered by endoplasmic reticulum (ER) stress. Endeavor to seek selective regulators of the UPR is a promising challenge towards therapeutic intervention in ER stress-related disorders. In the present report, we describe aberrant, differential and bidirectional regulation of the UPR by 3'-deoxyadenosine (cordycepin) towards cell survival. 3'-Deoxyadenosine blocked ER stress-induced apoptosis via inhibiting the IRE1-JNK pro-apoptotic pathway. 3'-Deoxyadenosine also inhibited apoptosis through reinforcement of the pro-survival eIF2α signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2α, and dephosphorylation of eIF2α by salubrinal mimicked the anti-apoptotic effect of 3'-deoxyadenosine. Unexpectedly, although 3'-deoxyadenosine caused activation of eIF2α, it inhibited downstream pro-apoptotic events including induction of ATF4 and expression of CHOP. Cooperation of adenosine transporter and A3 adenosine receptor, but not A1/A2 receptors, mediated the pluripotent effects of 3'-deoxyadenosine. In mice, ER stress caused activation of JNK, expression of CHOP and induction of apoptosis in renal tubules. The apoptosis was significantly attenuated by administration with 3'-deoxyadenosine, and it was correlated with blunted induction of JNK and CHOP in the kidney. These results disclosed atypical pro-survival regulation of the UPR by 3'-deoxyadenosine, which may be advantageous for the treatment of intractable, ER stress-related disorders.

Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors.

Non-homologous end joining (NHEJ) is a major repair pathway for DNA double-strand breaks (DSBs) generated by ionizing radiation (IR) and anti-cancer drugs. Therefore, inhibiting the activity of proteins involved in this pathway is a promising way of sensitizing cancer cells to both radiotherapy and chemotherapy. In this study, we developed an assay for evaluating NHEJ activity against DSBs in chromosomal DNA in human cells to identify the chromatin modification/remodeling proteins involved in NHEJ. We showed that ablating the activity of the homologous histone acetyltransferases, CBP and p300, using inhibitors or small interfering RNAs-suppressed NHEJ. Ablation of CBP or p300 impaired IR-induced DSB repair and sensitized lung cancer cells to IR and the anti-cancer drug, etoposide, which induces DSBs that are repaired by NHEJ. The CBP/p300 proteins were recruited to sites of DSBs and their ablation suppressed acetylation of lysine 18 within histone H3, and lysines 5, 8, 12, and 16 within histone H4, at the DSB sites. This then suppressed the recruitment of KU70 and KU80, both key proteins for NHEJ, to the DSB sites. Ablation of CBP/p300 also impaired the recruitment of BRM, a catalytic subunit of the SWI/SNF complex involved in chromatin remodeling at DSB sites. These results indicate that CBP and p300 function as histone H3 and H4 acetyltransferases at DSB sites in NHEJ and facilitate chromatin relaxation. Therefore, inhibition CBP and p300 activity may sensitize cancer cells to radiotherapy and chemotherapy.

[Pulmonary pleomorphic carcinoma; an investigation of thirteen cases].

Pleomorphic carcinoma is a rare pulmonary epithelial malignant tumor defined in the World Health Organization classification updated in 1999. We investigated the clinical findings and prognosis associated with this tumor since to our knowledge they have yet to be well-understood. Between 2000 and 2006, in our hospital 387 patients underwent surgical resection for primary nonsmall cell lung carcinoma (NSCLC). Of these, 13 (3.4%) were diagnosed as pleomorphic carcinoma. We compared the clinical and pathological data between the patients with pleomorphic carcinoma (n = 13) and patients with other NSCLC (n = 374). Twelve (92.3%) of our patients were men and 9 (69.2%) were symptomatic. These tumors were located predominantly in an upper lobe and were associated more often with adjacent bullae than were other NSCLC. Surgical resection in 4 of the cases was incomplete due to tumor invasion into mediastinum, aortic arch, pleurae and/or chest wall. None of the diagnoses could be confirmed preoperatively. Thus, invasion of surrounding tissue occurred frequently and early. Although there are no defined management strategies for pleomorphic carcinoma, it is important to make the diagnosis early and perform complete resection if possible.