Pharmacological activation of NQO1 increases NAD⁺ levels and attenuates cisplatin-mediated acute kidney injury in mice.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD(+) is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD(+) levels by means of NAD(P)H: quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (ß-lapachone) in wild-type and NQO1(-/-) mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD(+)/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and ß-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by ß-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of ß-lapachone in wild-type mice were completely abrogated in NQO1(-/-) mice. Moreover, ß-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD(+) levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury.

Mechanoreceptors in Remnant Posterior Cruciate Ligament and Achilles Tendon Allografts After Remnant-Preserving Posterior Cruciate Ligament Reconstruction: Hematoxylin-Eosin and Immunohistochemical Assessments.

BACKGROUND: Mechanoreceptor is a subtype of somatosensory receptor. It conveys extracellular stimuli through intracellular signal conduction via mechanically gated ion channel. It conveys not only kinetic stimuli but also pressure, stretching, touch, and even sound wave. Few studies have determined whether mechanoreceptors are present in Achilles tendon allografts used during remnant-preserving posterior cruciate ligament (PCL) reconstruction (PCLR). PURPOSE/HYPOTHESIS: The purpose was to investigate whether mechanoreceptors are present in remnant tissues of the PCL and allograft tissues after PCLR. It was hypothesized that mechanoreceptors may be present in the remnant PCL tissue of the patients who underwent remnant PCLR technique. STUDY DESIGN: Controlled laboratory study. METHODS: Tissue samples were obtained from 14 participants who had undergone PCLR by means of Achilles tendon allografts (PCLR group) and from 4 healthy controls (control group). Among the PCLR group, 12 patients had undergone a remnant PCLR technique and the remaining 2 patients had undergone a nonremnant PCLR technique. In the PCLR group, we obtained samples during second-look arthroscopy or total knee arthroplasty after PCLR. In the control group, 4 biopsy specimens of normal PCL tissues were obtained from patients who had undergone other arthroscopic procedures. To check the presence of mechanoreceptors, immunohistochemical studies were performed on all biopsy specimens to identify neuronal and neurocytic markers by using monoclonal antibodies against glial fibrillary acidic protein, neuron-specific enolase, neurofilament, and S-100 protein. Only 1 of these markers needed to be positive to prove the presence of mechanoreceptors. RESULTS: Neural tissue analogs, confirmed to be mechanoreceptors with monoclonal antibodies by the Ultraview DAB detection kit, were found in all specimens obtained from the control group. Mechanoreceptors were not found in the allograft specimens. However, remnant PCL tissues were found to have mechanoreceptors in 11 of 12 samples (91.7%). CONCLUSION: The results demonstrate that Achilles tendon allografts lack mechanoreceptors. This study can be used as histological evidence to support the advantage of remnant-preserving techniques for PCLR because they preserve proprioception. CLINICAL RELEVANCE: To preserve proprioception, which leads to better functional outcome, using the remnant technique is a better procedure for PCL reconstruction.

[A case of actinomycosis of gallbladder presenting as acute cholecystitis].

Actinomycosis is a chronic suppurative and granulomatous disease, characterized by the formation of abscess, draining sinuses, abundant granulation, and dense fibrous tissue. Actinomycosis of the gallbladder is extremely rare. We report a case of an 56-years old man who abruptly presented with right upper quadrant abdominal pain. Abdominal CT showed that the gallbladder had 2 cm sized stone and an edematous thick wall. Our preoperative diagnosis was acute calculous cholecystitis. After the management of acute cholecystitis, laparoscopic cholecystectomy was performed but converted to open surgery due to severe adhesion to liver and greater omentum. Partial cholecystectomy was performed. Histologic section of the gallbladder showed sulfur granule with gram-positive branching bacilli compatible with actinomyces. After cholecystectomy, the patient received intravenous penicillin G for 2 weeks, followed by oral penicillin for 3 months.

Recombinant human epidermal growth factor accelerates recovery of mouse small intestinal mucosa after radiation damage.

PURPOSE: To determine whether systemically administered recombinant human epidermal growth factor (rhEGF) accelerates the recovery of mouse small intestinal mucosa after irradiation. METHODS AND MATERIALS: A mouse mucosal damage model was established by administering radiation to male BALB/c mice with a single dose of 15 Gy applied to the abdomen. After irradiation, rhEGF was administered subcutaneously at various doses (0.04, 0.2, 1.0, and 5.0 mg/kg/day) eight times at 2- to 3-day intervals. The evaluation methods included histologic changes of small intestinal mucosa, change in body weight, frequency of diarrhea, and survival rate. RESULTS: The recovery of small intestinal mucosa after irradiation was significantly improved in the mice treated with a high dose of rhEGF. In the mice that underwent irradiation without rhEGF treatment, intestinal mucosal ulceration, mucosal layer damage, and severe inflammation occurred. The regeneration of villi was noticeable in mice treated with more than 0.2 mg/kg rhEGF, and the villi recovered fully in mice given more than 1 mg/kg rhEGF. The frequency of diarrhea persisting for more than 3 days was significantly greater in the radiation control group than in the rhEGF-treated groups. CONCLUSIONS: Systemic administration of rhEGF accelerates recovery from mucosal damage induced by irradiation. We suggest that rhEGF treatment shows promise for the reduction of small intestinal damage after irradiation.

Combination treatment with arsenic trioxide and sulindac enhances apoptotic cell death in lung cancer cells via activation of oxidative stress and mitogen-activated protein kinases.

Arsenic trioxide (As2O3) has been introduced to the treatment of acute promyelocytic leukemia (APL), and has also been shown to induce apoptosis in a variety of solid tumor cell lines, including non-small cell lung cancer. However, the prohibitively high concentration required for the induction of apoptotic cell death in many solid tumor cells is unacceptable for clinical utilization due to the excessive toxicity associated with this dose. Sulindac is known to enhance the cellular responsiveness of tumors toward chemotherapeutic drugs. Herein, we demonstrated that combination treatment with As2O3 and sulindac resulted in a synergistic augmentation of cytotoxicity in H157 lung cancer cells, which was revealed by apoptotic induction as demonstrated by an increase in the sub-G0/G1 fraction. In addition, combination treatment with As2O3 and sulindac increased reactive oxygen species (ROS) and oxidative stress, as evidenced by the heme oxygenase-1 (HO-1) expression and mitogen-activated protein kinase (MAPK) phosphorylation. MAPK inhibitors blocked the induction of HO-1 by combination treatment. Inhibitors of p38 and JNK partially inhibited the augmented cell death whereas the ERK inhibitor showed poor inhibition. Combination treatment with As2O3 and sulindac induced oxidative DNA damage in a time-dependent fashion, which was evaluated by H2AX phosphorylation along with HO-1 induction.

[Primary duodenal choriocarcinoma presenting as massive intestinal bleeding and metastasis to brain].

Duodenal choriocarcinoma, either primary or metastatic, is very rare. Early diagnosis and prompt initiation of chemotherapy improve the prognosis of this neoplasm. We herein present, together with the referred literatures, a case of a 47-year-old female patient who visited to our hospital with upper intestinal bleeding. She was diagnosed as duodenal choriocarcinoma by operation. Brain metastasis was found soon after the operation and combination chemotherapy was done.

Superficial Fibromatosis Mimicking Glomus Tumor of the Second Toe.

Various types of tumor can occur in the subungual space, including glomus tumors, subungual exostosis, hemangioma, epidermal cysts, and malignant tumors. While fibromatosis can occur at various sites throughout the body, it is very rarely seen in the toe. Here, we are the first to report a case of superficial fibromatosis mimicking a glomus tumor in the subungual space of the second toe. The presentation of this condition shows the possibility of encountering uncommon superficial fibromatosis in the distal phalanx of the toe, and suggests that superficial fibromatosis should be included in the differential diagnosis of a glomus tumor in the toe.

Acute cholecystitis associated with Clonorchis sinensis infection.

Clonorchis sinensis is one of the most common causes of trematodiasis that is caused by the ingestion of raw fish contaminated with infective cysts. The adult flukes are predominantly present in the intrahepatic bile ducts, but occasionally they may be found in the pancreatic duct and extrahepatic bile ducts. The clinical manifestations depend on the number of flukes, the period of infestation, and complications such as pericholangitic abscess, cholangitis, bile duct stones, and cholangiocarcinoma. However, primary acute cholecystitis associated with C. sinensis infection is extremely rare. Herein, we report on a case of primary acute cholecystitis associated with C. sinensis infection.

The role of autophagy induced by pemetrexed in lung adenocarcinoma cells.

Autophagy is known as an important regulatory mediator for cell survival or death and its important role in cancer. Pemetrexed (PTX) has been used in chemotherapy for lung cancer. However, the underlying molecular mechanisms have not been fully clarified. To investigate the role of autophagy induced by PTX in A549 cells, we performed MTT assay, acridine orange staining, western blotting, Annexin V/PI by using the 3-MA autophagy inhibitor. PTX induced autophagy after 48 h treatment in A549 cells. Furthermore, PTX showed acidic vesicular organelles (AVOs) and expressed LC3-II in A549 cells. The induction of autophagy by PTX was inhibited by 3-MA which was confirmed by reduced AVOs. When the autophagy was inhibited, Annexin V was increased. In addition, PARP cleavage was increased as shown by western blotting. Taken together, PTX induced autophagy in A549 cells and these cellular events possibly cause the apoptotic and/or necrotic cell death of A549 cells.

Intramuscular ganglion of the quadriceps femoris.

Ganglion cysts are common lesions that are most often found around the joints of the hands and feet. Ganglia around the distal femur usually occur within the synovial membrane or tendon sheath, but rarely within muscles. Several cases of intramuscular ganglions in the hand and wrist have been reported, but a ganglion cyst in the quadriceps muscle has rarely been addressed in studies. In this report, we present a 17-year-old patient with a painful movable mass in the intramuscular area of the quadriceps femoris that was diagnosed by ultrasound and treated by excision and biopsy.