Dynamics of depressive states among university students in Japan during the COVID-19 pandemic: an interrupted time series analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic was reported to have increased depression among university students which was associated with impairments in their campus lives. This study examined changes in depressive states among Japanese university students during the COVID-19 pandemic. METHODS: A secondary data analysis from a factorial randomized controlled trial involving smartphone-based cognitive-behavioral therapy was performed. Six cohorts (N = 1626) underwent an 8-week intervention during the spring or autumn of 2019-2021, with a 9-month follow-up. We evaluated participants' depressive states weekly using the Patient Health Questionnaire-9 (PHQ-9) during the intervention, with monthly evaluations thereafter. The follow-up periods included Japan's four states of emergency (SOEs) to control COVID-19. Hypothesizing that SOEs caused a sudden worsening of depressive states, Study 1 compared the cohorts' PHQ-9 scores, and Study 2 employed time series analysis with a mixed-effects model to estimate identified changes in PHQ-9 scores. RESULTS: Although no changes in depressive states were observed in relation to the SOEs, Study 1 identified sudden increases in PHQ-9 scores at the 28-week evaluation point, which corresponded to the beginning of the new academic year for the three autumn cohorts. In contrast, the three spring cohorts did not exhibit similar changes. Study 2 showed that, for all three autumn cohorts (n = 522), the 0.60-point change was significant (95% CI 0.42-0.78; p < .001) at 28 weeks; that is, when their timeline was interrupted. CONCLUSIONS: While the results do not indicate any notable impact of the SOEs, they highlight the influence of the new academic year on university students' mental health during COVID-19. Trial registration UMIN, CTR-000031307. Registered on February 14, 2018.

A phase I/II study of KW-2478, an Hsp90 inhibitor, in combination with bortezomib in patients with relapsed/refractory multiple myeloma.

BACKGROUND: KW-2478 is a novel non-ansamycin Hsp90 inhibitor with modest single-agent activity in relapsed/refractory myeloma but which shows synergistic antimyeloma activity with bortezomib (BTZ) in preclinical studies. This study determined the safety, preliminary clinical activity, and pharmacokinetics of KW-2478, an Hsp90 inhibitor, in combination with BTZ in patients with relapsed/refractory multiple myeloma (MM). METHODS: Phase I dose escalation determined the recommended phase II dose (RP2D) of KW-2478 plus BTZ, which was then used during phase II. RESULTS: The maximum tolerated dose was not reached during phase I and the RP2D was KW-2478 175 mg m-2 plus BTZ 1.3 mg m-2 on days 1, 4, 8, and 11 every 3 weeks. In the efficacy evaluable phase I/II population treated at the RP2D (n=79), the objective response rate was 39.2% (95% confidence interval: 28.4-50.9%), clinical benefit rate 51.9% (40.4-63.3%), median progression-free survival 6.7 (5.9-not reached (NR)) months, and median duration of response 5.5 (4.9-NR) months. In the phase I/II safety population (n=95), the most frequently observed treatment-related grade 3/4 adverse events were diarrhoea, fatigue, and neutropenia (each in 7.4% of patients), and nausea and thrombocytopenia (each in 5.3%). CONCLUSIONS: KW-2478 plus BTZ was well tolerated with no apparent overlapping toxicity in patients with relapsed/refractory MM. The antimyeloma activity of KW-2478 in combination with BTZ as scheduled in this trial appeared relatively modest; however, the good tolerability of the combination would support further exploration of alternate dosing schedules and combinations.

Recent developments of ion sources for life-science studies at the Heavy Ion Medical Accelerator in Chiba (invited).

With about 1000-h of relativistic high-energy ion beams provided by Heavy Ion Medical Accelerator in Chiba, about 70 users are performing various biology experiments every year. A rich variety of ion species from hydrogen to xenon ions with a dose rate of several Gy/min is available. Carbon, iron, silicon, helium, neon, argon, hydrogen, and oxygen ions were utilized between 2012 and 2014. Presently, three electron cyclotron resonance ion sources (ECRISs) and one Penning ion source are available. Especially, the two frequency heating techniques have improved the performance of an 18 GHz ECRIS. The results have satisfied most requirements for life-science studies. In addition, this improved performance has realized a feasible solution for similar biology experiments with a hospital-specified accelerator complex.

Three-dimensional morphology of the human embryonic brain.

The morphogenesis of the cerebral vesicles and ventricles was visualized in 3D movies using images derived from human embryo specimens between Carnegie stage 13 and 23 from the Kyoto Collection. These images were acquired with a magnetic resonance microscope equipped with a 2.35-T superconducting magnet. Three-dimensional images using the same scale demonstrated brain development and growth effectively. The non-uniform thickness of the brain tissue, which may indicate brain differentiation, was visualized with thickness-based surface color mapping. A closer view was obtained of the unique and complicated differentiation of the rhombencephalon, especially with regard to the internal view and thickening of the brain tissue. The present data contribute to a better understanding of brain and cerebral ventricle development.

Morphology and morphometry of the human embryonic brain: A three-dimensional analysis.

The three-dimensional dynamics and morphology of the human embryonic brain have not been previously analyzed using modern imaging techniques. The morphogenesis of the cerebral vesicles and ventricles was analyzed using images derived from human embryo specimens from the Kyoto Collection, which were acquired with a magnetic resonance microscope equipped with a 2.35-T superconducting magnet. A total of 101 embryos between Carnegie stages (CS) 13 and 23, without apparent morphological damage or torsion in the brain ventricles and axes, were studied. To estimate the uneven development of the cerebral vesicles, the volumes of the whole embryo and brain, prosencephalon, mesencephalon, and rhombencephalon with their respective ventricles were measured using image analyzing Amira™ software. The brain volume, excluding the ventricles (brain tissue), was 1.15 ± 0.43 mm(3) (mean ± SD) at CS13 and increased exponentially to 189.10 ± 36.91 mm(3) at CS23, a 164.4-fold increase, which is consistent with the observed morphological changes. The mean volume of the prosencephalon was 0.26 ± 0.15 mm(3) at CS13. The volume increased exponentially until CS23, when it reached 110.99 ± 27.58 mm(3). The mean volumes of the mesencephalon and rhombencephalon were 0.20 ± 0.07 mm(3) and 0.69 ± 0.23 mm(3) at CS13, respectively; the volumes reached 21.86 ± 3.30 mm(3) and 56.45 ± 7.64 mm(3) at CS23, respectively. The ratio of the cerebellum to the rhombencephalon was approximately 7.2% at CS20, and increased to 12.8% at CS23. The ratio of the volume of the cerebral vesicles to that of the whole embryo remained nearly constant between CS15 and CS23 (11.6-15.5%). The non-uniform thickness of the brain tissue during development, which may indicate the differentiation of the brain, was visualized with surface color mapping by thickness. At CS23, the basal regions of the prosencephalon and rhombencephalon were thicker than the corresponding dorsal regions. The brain was further studied by the serial digital subtraction of layers of tissue from both the external and internal surfaces to visualize the core region (COR) of the thickening brain tissue. The COR, associated with the development of nuclei, became apparent after CS16; this was particularly visible in the prosencephalon. The anatomical positions of the COR were mostly consistent with the formation of the basal ganglia, thalamus, and pyramidal tract. This was confirmed through comparisons with serial histological sections of the human embryonic brain. The approach used in this study may be suitable as a convenient alternative method for estimating the development and differentiation of the neural ganglia and tracts. These findings contribute to a better understanding of brain and cerebral ventricle development.

Standard of practice on laparoscopic gastric cancer surgery in Korea and Japan: experts' survey.

INTRODUCTION: As the laparoscopic approach has become a popular gastric cancer treatment in Korea and Japan, the need for sharing current practices of surgeons who are experienced in laparoscopic gastric cancer surgery has increased. METHODS: We sent a questionnaire on laparoscopic instruments, image documentation, preoperative evaluation, surgical indication, operative methods, and postoperative management to laparoscopic experts in Korea and Japan, and 24 (14 from Korea and 10 from Japan) responded. RESULTS: Endoscopic ultrasound and preoperative endoscopy-guided clipping are routinely employed, respectively, by 14 (58%) and 20 (83%) of the surgeons. Surgeons perform laparoscopy-assisted distal gastrectomy (LADG) based on varying indications. Five surgeons (21%) performed LADG only for cases of stage T1 cancer, 15 (63%) performed LADG on patients with less than T2 lesions, and 4 (17%) performed LADG on patients with less than T3 lesions. With regard to postoperative anastomosis, 18 surgeons (75%) preferred extracorporeal anastomosis and 6 (25%) preferred intracorporeal anastomosis. The mean postoperative hospital stay was 6.5 days in Korea and 10.1 days in Japan (P < 0.001). CONCLUSION: This survey can help to inform the current practice of laparoscopic gastric cancer surgery in Korea and Japan, where laparoscopic surgery is frequently performed.

Case of anti-glomerular basement membrane antibody-induced glomerulonephritis with cytomegalovirus-induced thrombotic microangiopathy.

Although the involvement of cytomegalovirus (CMV) infections in the development of thrombotic microangiopathy (TMA) in HIV patients and transplant recipients has been reported, it is still controversial whether CMV itself can cause TMA. We report herein a rare case with rapid improvement of TMA by ganciclovir treatment in a patient who is neither HIV-positive nor a transplant recipient, suggesting a pathogenic role for CMV in TMA.

The maneuver to release an incarcerated obturator hernia.

An obturator hernia occurs through the pelvic obturator canal, a rigid ring made up of the underside of the superior pubic ramus and the obturator fascia. Obturator hernias have been associated with a high mortality due to the difficulty in diagnosis and the population in which it occurs. We examined four patients diagnosed with incarcerated obturator hernia, and showed that the strangulated intestine was not necrotic. We flexed the diseased leg calmly and repeatedly with slight rotation toward the outside and slight adduction toward the inside at supine position. The pain vanished suddenly during this maneuver. After this maneuver, the patients were able to undergo elective surgery after a certain interval. We discuss the possible use of this maneuver to release an incarcerated obturator hernia.

A study of maintenance therapy after intravenous maxacalcitol for secondary hyperparathyroidism.

AIM: Intravenous vitamin D therapy is an established treatment for secondary hyperparathyroidism (SHPT). However, no protocols have been established for maintenance therapy with intravenous or oral vitamin D after control of intact parathyroid hormone (iPTH) within the target range. METHODS: Step I. For patients with SHPT (200 ≤ iPTH ≤ 500 pg/ml), a dose of 2.5 mg maxacalcitol (OCT) was administered intravenously three times a week with oral sevelamer hydrochloride; the dose was increased to a 10 µg maximum three times a week to control iPTH to < 150 pg/ml. Step II. When iPTH reached the target level, patients were assigned to Group A (oral alfacalcidol 1.0 µg/day) or B (oral alfacalcidol 0.25 µg/ day). Serum iPTH, calcium, and inorganic phosphorus were measured each month for 6 months. Maintenance rates for the target iPTH levels were evaluated, < 150 pg/ml at Step I and < 200 pg/ml at Step II. RESULTS: iPTH decreased to < 150 pg/ml by OCT in 24 of 35 patients (68.6%). During the 24-week observation period, iPTH was controlled for 83.3% patients in Group A vs. 36.4% for Group B (p < 0.05). No dropouts due to hypercalcemia or hyperphosphatemia occurred. CONCLUSION: OCT dose titration was effective for SHPT. A higher daily dose of oral alfacalcidol (1.0 µg) appears to be more effective than a lower dose (0.25 µg) as maintenance therapy after iPTH control.

Feasibility of fibrin glue versus endoclips to close the transgastric peritoneal access site in NOTES in a survival porcine study.

INTRODUCTION: Safe peritoneal access and gastric closure are the most important concerns in clinical applications of NOTES. Our past study demonstrated usefulness of the submucosal tunnel technique for safe peritoneal access and closure with endoclips. However, such closure is sometimes difficult and time-consuming. This study investigated the feasibility of fibrin glue for submucosal tunnel closure in a NOTES porcine model. METHODS: In 10 female pigs each weighing 40 kg, transgastric peritoneoscopy was performed through a 60 mm-long submucosal tunnel created using the endoscopic submucosal dissection technique. After transgastric peritoneoscopy for 30 min, the submucosal tunnel was closed with endoclips in five pigs and fibrin glue in five pigs. After a 7 d follow-up period, the pigs were euthanized for post-mortem examination. Outcome measures included (a) technical feasibility of closure with endoclips versus fibrin glue, (b) clinical monitoring for 7 d, (c) follow-up necropsy at 7 d, and (d) histopathologic examination of the peritoneal access site. RESULTS: Transgastric peritoneoscopy with submucosal tunnel technique was successful in all pigs. Mean time required to close the mucosal incision site with fibrin glue was 1.6 ± 0.5 versus 19 ± 18.7 min with endoclips. All pigs survived well without complications. Necropsy revealed no peritonitis. There were no differences in transgastric peritoneal access sites between endoclips and fibrin glue. Histopathologic examination of the submucosal tunnel demonstrated wound healing with transmural fibrosis. No adverse effects from fibrin glue were noted. CONCLUSION: Compared with endoclips, the application of fibrin glue is easy and simple in the closure of transgastric peritoneal access in NOTES.

Submucosal tunneling using endoscopic submucosal dissection for peritoneal access and closure in natural orifice transluminal endoscopic surgery: a porcine survival study.

BACKGROUND AND STUDY AIMS: Safe peritoneal access and gastric closure are the most important concerns in the clinical application of natural orifice transluminal endoscopic surgery (NOTES). We aimed to clarify the feasibility of a submucosal tunnel technique using endoscopic submucosal dissection (ESD) for transgastric peritoneal access and subsequent closure for NOTES. METHODS: Seven female pigs, each weighing about 40 kg were included in the study. The following procedures were performed: (i) after injection of normal saline into the submucosa, the mucosa was cut with a flex knife; (ii) the submucosal layer was dissected using an insulation-tipped electrosurgical knife to make a narrow longitudinal 50-mm submucosal tunnel; (iii) a small incision was made at the end of the tunnel and enlarged with a dilation balloon. After transgastric peritoneoscopy, the mucosal incision site was closed with clips. The following outcome measures were used: (a) evaluation of the technical feasibility of making a submucosal tunnel; (b) clinical monitoring for 7 days; (c) follow-up endoscopy and necropsy; and (d) peritoneal fluid culture. RESULTS: Natural orifice transluminal endoscopic peritoneoscopy with a submucosal tunnel was successfully carried out in all pigs. The pigs recovered well, without signs of peritonitis. Follow-up endoscopy showed healing of mucosal incision sites without open defects. Necropsy revealed no findings of peritonitis, confirming completeness of gastric closure; there was a thin scar in one pig and adhesion of the omentum in six pigs. Peritoneal fluid culture demonstrated no bacterial growth. CONCLUSIONS: The submucosal tunnel technique is feasible and effective for transgastric peritoneal access and closure.

Long-term quality of life after laparoscopy-assisted distal gastrectomy for gastric cancer.

BACKGROUND: Laparoscopy-assisted distal gastrectomy (LAG) is gaining acceptance for treating early gastric cancer. However, the long-term quality of life after LAG for gastric cancer is unknown. This study compared the long-term quality of life after LAG versus open distal gastrectomy (ODG) for early gastric cancer. METHOD: This study included 53 patients who underwent LAG and 37 patients who underwent ODG for treatment of early gastric cancer. Quality of life was evaluated on the basis of a 22-item questionnaire that addressed food tolerance and mental and physical conditions, scored on a scale of 1-3. RESULTS: The mean follow-up periods after LAG and ODG were 99.3 and 97.0 months, respectively. Although the majority of patients who had undergone LAG were consuming a normal diet and had weight loss of less than 5 kg, all 22 items and the total score of the LAG group were comparable to those of the ODG group. However, the incidence of postoperative intestinal obstruction was significantly lower in the LAG group than in the ODG group (1% vs. 13%, p < 0.05). CONCLUSIONS: LAG is equivalent to ODG with respect to long-term quality of life and is associated with a reduced incidence of postoperative intestinal obstruction.

Laparoscopic sentinel node navigation achieved by infrared ray electronic endoscopy system in patients with gastric cancer.

BACKGROUND: The sentinel node (SN) concept has attracted considerable attention recently for the treatment of patients with early gastric cancer (EGC). This study evaluated the feasibility of laparoscopic SN navigation achieved by means of an infrared ray electronic endoscopy (IREE) system with indocyanine green (ICG) injection in patients with EGC. METHODS: Laparoscopic SN navigation was performed for 16 patients with preoperatively diagnosed EGC. After identification of SNs, routine laparoscopically assisted distal gastrectomy with lymphadenectomy was performed. Lymph nodes were examined histologically for metastasis by hematoxylin and eosin staining on one section of each node. RESULTS: One or more SNs and lymphatic basins were detected in all 16 patients. The average number of SNs detected was 2.9. Lymph node metastasis was found in 2 of the 16 patients (13%). In one of these two patients, lymph node metastasis was found in SNs. In the other patient, metastasis was found in a non-SN rather than a SN, but in the same lymphatic basin. The accuracy of this detection method was 94%, and there was one false-negative case. No adverse events occurred after injection of ICG. CONCLUSION: Laparoscopic SN navigation by means of IREE combined with ICG injection is feasible for patients undergoing laparoscopic surgery for EGC.

Didox, a ribonucleotide reductase inhibitor, induces apoptosis and inhibits DNA repair in multiple myeloma cells.

Ribonucleotide reductase (RR) is the enzyme that catalyses the rate-limiting step in DNA synthesis, the production of deoxynucleotides. RR activity is markedly elevated in tumour tissue and is crucial for cell division. It is therefore an excellent target for cancer chemotherapy. This study examined the anti-myeloma activity of Didox (3,4-Dihydroxybenzohydroxamic acid), a novel RR inhibitor (RRI). Our data showed that Didox induced caspase-dependent multiple myeloma (MM) cell apoptosis. Didox, unlike other RRIs that mainly target the pyrimidine metabolism pathway, targets both purine and pyrimidine metabolism pathways in MM, as demonstrated by transcriptional profiling using the Affymetrix U133A 2.0 gene chip. Specifically, a >or=2-fold downregulation of genes in these anabolic pathways was shown as early as 12 h after exposure to Didox. Furthermore, apoptosis was accompanied by downregulation of bcl family proteins including bcl-2, bcl(xl), and XIAP. Importantly, RR M1 component transcript was also downregulated, associated with decreased protein expression. Genes involved in DNA repair mechanisms, specifically RAD 51 homologue, were also downregulated. As Didox acts on MM cells by inhibiting DNA synthesis and repair, combination studies with melphalan, an agent commonly used in MM, were performed. A strong in vitro synergism was shown, with combination indices of <0.7 as determined by the Chou-Talalay method. These studies therefore provide the preclinical rationale for evaluation of Didox, alone and in combination with DNA-damaging agents, to improve patient outcome in MM.

Inhibition of prostasin-induced ENaC activities by PN-1 and regulation of PN-1 expression by TGF-beta1 and aldosterone.

Prostasin has been shown to regulate sodium handling in the kidney. Recently, a serine protease inhibitor, protease nexin-1 (PN-1), was identified as an endogenous inhibitor for prostasin. Therefore, we hypothesized that PN-1 may regulate sodium reabsorption by reducing prostasin activity, and that expression of PN-1 was regulated by transforming growth factor-beta1 (TGF-beta1) or aldosterone, like prostasin. cRNAs for epithelial sodium channel (ENaC), prostasin, and PN-1 were expressed in Xenopus oocytes, and the amiloride-sensitive sodium currents (I(Na)) were measured. The effect of TGF-beta1 and aldosterone on the mRNA and protein abundance of PN-1 and ENaC was detected by real-time polymerase chain reaction and immunoblotting in M-1 cells. Expression of PN-1 substantially decreased prostasin-induced I(Na) by approximately 68% in oocytes. Treatment of M-1 cells with 20 ng/ml TGF-beta1 significantly increased protein expression of PN-1 by 3.8+/-0.5-fold, whereas administration of 10(-6) M aldosterone markedly decreased protein expression of PN-1 to 53.7+/-6.7%. Basolateral, but not apical, application of TGF-beta1 significantly reduced I(eq). To elucidate the involvement of PN-1 in basal ENaC activity, we silenced the expression of PN-1 by using short-interfering RNA. This increased I(eq) by 1.6+/-0.1-fold. Our study indicates that PN-1 could have a natriuretic role by inhibiting prostasin activity and suggests the possibility that aldosterone and TGF-beta reciprocally regulate the expression of PN-1 in renal epithelial cells contributing to salt retention or natriuresis, respectively by an additional mechanism. PN-1 could represent a new factor that contributes to regulation of ENaC activity in the kidney.

Gamma-aminobutyric acid (GABA) and cell proliferation: focus on cancer cells.

In addition to its role in the adult mammalian nervous system as an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) is involved in the proliferation, differentiation, and migration of several kinds of cells including cancer cells. GABA is synthesized predominantly from glutamate by glutamate decarboxylase and exerts its effects via ionotropic GABA(A) receptors and/or metabotropic GABA(B) receptors. In this review, the current state of knowledge regarding the role of the GABAergic system in peripheral nonneuronal cell proliferation is described, and recent advances in elucidation of the mechanisms leading to cell proliferation are discussed.

Usefulness of transanal endoscopic surgery for carcinoid tumor in the upper and middle rectum.

BACKGROUND: This study evaluated the indications and outcome for transanal endoscopic surgery (TES) used to manage rectal carcinoid tumor as compared with those of conventional transanal local resection (TAR). METHODS: The retrospective study subjects were 28 patients with rectal carcinoid tumor treated by TES (n = 17) or TAR (n = 11) between January 1995 and December 2001. Patient and tumor characteristics, operative results, and postoperative outcomes were compared between the two groups. RESULTS: The distance from the anal verge to the distal tumor margin in the TES group (range, 4-12 cm; median, 6.8 cm) was significantly greater than in the TAR group (range, 3-6 cm; median, 4.5 cm) (p = 0.001). The median tumor diameter was 5.5 mm (range, 3-11 mm) in the TES group and 5.0 mm (range, 3-8 mm) in the TAR group, showing no statistical difference. Microscopically, resected specimens in both groups were typical carcinoid tumors restricted to the submucosal layer. No recurrence was noted in either group. CONCLUSION: Whereas TES is useful for patients with small rectal carcinoid tumor of typical histology within the submucosal layer in the upper and middle rectum, TAR is effective for accessing the lower rectum.

Liver metastasis and ICAM-1 mRNA expression in the liver after carbon dioxide pneumoperitoneum in a murine model.

BACKGROUND: Liver metastasis of colorectal malignancies is an important prognostic factor. Several studies have demonstrated that carbon dioxide (CO2) pneumoperitoneum enhances liver metastasis in animal models. Little is known about intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF-(alpha) mRNA expression in the liver after CO2 pneumoperitoneum. METHODS: Forty-five male BALB/c mice were randomly divided into three groups after intra-splenic tumor cell (colon 26) inoculation and the following procedures were performed: CO2 pneumoperitoneum (n = 15), open laparotomy (n = 15), and anesthesia alone (n = 15). On day 7 after each procedure, the livers were excised and the number and diameter of the tumor nodules and the cancer index score were determined. Another 90 male BALB/c mice were randomly divided into three groups as described above, and they underwent each procedure (n = 30 each). After each procedure, the livers were excised on days 0, 1, 3, and ICAM-1 and TNF-alpha mRNA expression were examined by real-time RT-PCR using SYBR Green I. RESULTS: The number of tumor nodules and the cancer index score were larger in the CO2 pneumoperitoneum group than in the control group (p < 0.05). The mean diameter of the tumor nodules was not different among the three groups. The expression of ICAM-1 in the CO2 pneumoperitoneum group was higher than that in the other groups on day 1 (p < 0.05), and the TNF-alpha mRNA was higher than that in the control group on day 1 (p < 0.05). CONCLUSIONS: CO2 pneumoperitoneum enhances liver metastasis compared with anesthesia alone, and ICAM-1 expression in the liver after the pneumoperitoneum plays an important role in establishing liver metastasis in a murine model.

Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs.

Thalidomide alone or in combination with steroids has significant activity in multiple myeloma (MM). However, given its teratogenic potential, analogs have been synthesized, retaining the anti-MM activity without these side effects. We examined the anti-MM activity of two thalidomide analogs, CPS11 and CPS49. Direct cytotoxicity of the drugs on myeloma cell lines and patient myeloma cells was examined using thymidine uptake. Tumor cell apoptosis was evaluated by flow cytometry as well as Western blotting for caspase and PARP cleavage. Cellular signaling events were examined by immunoblotting for phosphorylated proteins. Both drugs inhibit proliferation of several MM cell lines sensitive and resistant to conventional therapies. They decrease secretion of IL-6, IGF, and VEGF by marrow stromal cells. Importantly, they inhibit proliferation of MM cells adherent to stromal cells. These drugs induce caspase-mediated apoptosis in MM cell lines, as well as patient MM cells. They inhibit the PI3K/Akt and JAK/STAT (signal transducers and activators of transcription) pathways in MM cells and are antiangiogenic in matrigel-based assays. CPS11 and CPS49 have potent antimyeloma activity and can overcome protective effects of the tumor microenvironment. They have potent antiangiogenic activity and direct effect on bone marrow stroma. These encouraging preclinical data provide the basis for further evaluation in the clinic.

Morphological changes in hepatic vascular endothelium after carbon dioxide pneumoperitoneum in a murine model.

BACKGROUND: Liver metastasis is an important prognostic factor in advanced colorectal cancer. Several studies have demonstrated that carbon dioxide (CO2) pneumoperitonem enhances liver metastasis in an animal model. In the present study, we used scanning electron microscopy (SEM) to investigate morphological changes in hepatic vascular endothelium after CO2 pneumoperitoneum in a murine model. METHODS: Thirty-three male BALB/c mice were randomized to undergo pneumoperitoneum (CO2, air, or helium), open laparotomy, and anesthesia alone. After each procedure, the animals' livers were excised at days 0, 1, and 3 and examined by SEM. RESULTS: In the CO2 pneumoperitoneum group, we observed rough surface and derangement of the hepatic vascular endothelial cells and intercellular clefts on day 1. In the other groups, no major morphologic changes were observed at any time. CONCLUSIONS: Hepatic vascular endothelium changes after CO2 pneumoperitoneum. Such characteristic changes may play an important role in establishing liver metastasis after CO2 pneumoperitoneum.