Efficacy of cooling therapy and α-lipoic acid derivative against chemotherapy-induced alopecia in an animal model.

Chemotherapy-induced alopecia is frequently induced by various regimens of chemotherapy and has a significant impact on mental health and quality of life. However, the effect of available current treatment for chemotherapy-induced alopecia is not sufficient. This study aimed to clarify the therapeutic effects and mechanism of skin cooling and the antioxidant α-lipoic acid derivative on chemotherapy-induced alopecia. We developed a chemotherapy-induced alopecia model of cyclophosphamide (120 µg/g) using Institute of Cancer Research mice. We used cooling therapy and α-lipoic acid derivative application as the treatments. We compared the alopecia score, hair bulb diameter, insulin-like growth factor-1 level, vascular permeability, and apoptosis between the control and treatment groups. The alopecia score significantly improved in each treatment group compared with that in the cyclophosphamide group. Hair bulb diameter significantly improved in the cyclophosphamide + cooling group compared with that in the cyclophosphamide group. The insulin-like growth factor-1 level and vascular permeability level was significantly retained and suppressed, respectively, in each treatment group compared with that in the cyclophosphamide group. The number of apoptotic cells in the vascular endothelium significantly decreased in the cyclophosphamide + α-lipoic acid derivative group compared with that in the cyclophosphamide group. In conclusion, cooling therapy and α-lipoic acid derivative facilitated recovery from chemotherapy-induced alopecia caused by cyclophosphamide through decreasing vascular permeability.

Success rate of acquiring informed consent and barriers to participation in a randomized controlled trial of laparoscopic versus open surgery for non-curative stage IV colon cancer in Japan (JCOG1107).

BACKGROUND: Successful achievement of randomized controlled trials (RCTs) is dependent on the acquisition of informed consent (IC) from patients. The aim of this study was to prospectively calculate the proportion of participation in a surgical RCT and to identify the reasons for failed acquisition of IC. METHODS: A 50-insitution RCT was conducted to evaluate oncological outcomes of open and laparoscopic surgery for stage IV colon cancer (JCOG1107: UMIN-CTR 000000105). The success rate of obtaining IC was evaluated in eight periods between January 2013 and January 2021. In addition, reasons for failed acquisition of IC were identified from questionnaires. RESULTS: In total, 391 patients were informed of their eligibility for the trial, and 168 (42%) were randomly assigned to either the laparoscopic surgery group (n = 84) or open surgery group (n = 84). The success rate of IC acquisition ranged from 33 to 58% in three periods. The most common reasons for failed IC acquisition were the patients' preference for one approach of surgery based on recommendations from referring doctors and family members, and anxiety/unhappiness about randomization. CONCLUSIONS: The success rate of acquiring IC from patients for an RCT of laparoscopic versus open surgery for stage IV colon cancer was lower than the expected rate planned in the protocol. To obtain the planned rate, investigators should make efforts to inform patients and their families about the medical contributions a surgical RCT can make and recognize that the period in equipoise may be limited.

Appropriate mesh size in the totally extraperitoneal repair of groin hernias based on the intraoperative measurement of the myopectineal orifice.

BACKGROUND: Insufficient coverage of the area of a possible groin hernia is an important risk factor in hernia recurrence. To prevent recurrence, it is important to use the appropriate mesh size based on the size of the myopectineal orifice (MPO), which is the weak area of the abdominal wall where inguinal hernias occur. We aimed to estimate the appropriate mesh size for groin hernias by investigating MPO size. METHODS: Four hundred and six patients underwent groin hernia repair using a totally extraperitoneal (TEP) approach at the Zeze Hospital between July 2009 and December 2017. We investigated patients' backgrounds, MPO components dimensions, and hernia recurrence, and evaluated the appropriate mesh size. RESULTS: The 359 male and 47 female patients had an average age of 63 ± 15 years. In 171, 147, and 88 cases, hernias were localized to the right, left, and bilaterally, respectively. The number of lateral, medial, femoral, and combined hernias was 317, 124, 11, and 42, respectively. The 95th percentile for the horizontal and vertical lengths in cases of hernia orifice ≥ 3 cm were 9.6 cm and 7.0 cm, respectively, while it was 9.2 cm and 6.4 cm in cases of hernia orifice < 3 cm. We added 2 cm and 3 cm to the 95th percentile for the length and width of the MPO, resulting in 13.2 × 10.4 cm and 15.6 × 13.0 cm in cases with hernia orifice < 3 cm and ≥ 3 cm, respectively. Relapse after TEP occurred in 1 patient (0.2%). CONCLUSION: The appropriate mesh size for TEP repair, derived from intraoperative MPO measurements, was estimated as 13.2 × 10.4 cm and 15.6 × 13.0 cm when the hernia orifice was < 3 cm and ≥ 3 cm, respectively. Using appropriate mesh sizes based on MPO measurement may reduce groin hernia recurrence after TEP.

Role of increased vascular permeability in chemotherapy-induced alopecia: In vivo imaging of the hair follicular microenvironment in mice.

Chemotherapy-induced alopecia is one of the most difficult adverse events of cancer treatment for patients. However, it is still unknown why anticancer drugs cause hair loss. We aimed to clarify the mechanism of chemotherapy-induced alopecia in mice using an in vivo imaging technique with a two-photon microscope, which enables observation of the deep reaction in the living body in real time. In this study, ICR mice were injected intraperitoneally with cyclophosphamide (120 µg/g). Changes in the hair bulb morphology, subcutaneous vessel permeability, and vessel density were evaluated by two-photon microscopy and conventional methods. In order to determine whether there is a causal relationship between vascular permeability and hair loss, we combined cyclophosphamide (50 µg/g) with subcutaneous histamine. Using two­photon microscopy and conventional examination, we confirmed that the hair bulbs became smaller, blood vessels around the hair follicle decreased, and vascular permeability increased at 24 hours after cyclophosphamide injection [corrected]. Apoptosis occurred in vascular endothelial cells around the hair follicle. Additionally, hair loss was exacerbated by temporarily enhancing vascular permeability with histamine. In conclusion, cyclophosphamide caused a decrease in vascular density and an increase in vascular permeability, therefore increased vascular permeability might be one of the causes of chemotherapy-induced alopecia.

Intraperitoneal Phototherapy Suppresses Inflammatory Reactions in a Surgical Model of Peritonitis.

BACKGROUND: Standard treatment for diffuse peritonitis due to colorectal perforation may be insufficient to suppress inflammatory reaction in sepsis. Thus, developing new treatments is important. This study aimed to examine whether intraperitoneal irradiation by artificial sunlight suppresses inflammatory reaction in a lipopolysaccharide (LPS)-induced peritonitis model after surgical treatments. MATERIALS AND METHODS: Mice were divided into naive, nontreatment (NT), and phototherapy (PT) groups. In the latter two groups, LPS was intraperitoneally administered to induce peritonitis and removed by intraperitoneal lavage after laparotomy. The PT group was irradiated with artificial sunlight intraperitoneally. We evaluated the local and systemic inflammatory reactions. Murine macrophages were irradiated with artificial sunlight after stimulation by LPS, and cell viability and expression of tumor necrotizing factor-α (TNF-α) were evaluated. RESULTS: As a local inflammatory reaction, the whole cell count, the expression of interleukin-6 and TNF-α in the intra-abdominal fluid, and the peritoneal thickness were significantly lower in the PT group than in the NT group. As a systematic inflammatory reaction, the expression of serum TNF-α, granulocyte macrophage colony-stimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1α, and MIP-1ß were significantly lower in the PT group than in the NT group. Irradiation by artificial sunlight suppressed the expression of TNF-α in murine macrophages without affecting cell viability. CONCLUSIONS: Intraperitoneal irradiation by artificial sunlight could suppress local and systemic inflammatory reactions in the LPS-induced peritonitis murine model. These effects may be associated with macrophage immune responses.

The utility of DHL-HisZnNa, a novel antioxidant, against anticancer agent-induced alopecia in breast cancer patients: a multicenter phase II clinical trial.

PURPOSE: Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of anticancer drugs; however, there are currently no mechanisms to completely prevent CIA. In this study, we performed a clinical trial to examine whether sodium N-(dihydrolipoyl)-l-histidinate zinc complex (DHL-HisZnNa), an alpha-lipoic acid derivative, prevents CIA in patients with breast cancer. METHODS: Between July 2014 and May 2015, we performed a multi-center, single arm, clinical trial involving 103 breast cancer patients who received adjuvant chemotherapy at three medical institutions in Japan. During chemotherapy, a lotion containing 1% DHL-HisZnNa was applied daily to the patients' scalps. The primary endpoint was the incidence of grade 2 alopecia; the secondary endpoints were the duration of grade 2 alopecia, alopecia-related symptoms, and drug-related adverse events. Alopecia was evaluated by three independent reviewers using head photographs taken from four angles. RESULTS: Safety analysis was performed for 101 patients who started the protocol therapy. After excluding one patient who experienced disease progression during treatment, 100 patients who received at least two courses of chemotherapy underwent efficacy analysis. All original 101 patients developed grade 2 alopecia, the median durations of which were 119 days (112-133 days) and 203 days (196-212 days) in the groups treated with four and eight courses of chemotherapy, respectively. Mild or moderate adverse events potentially related to DHL-HisZnNa were observed in 11 patients. Alopecia-related symptoms were observed in 53 patients (52%). CONCLUSIONS: The application of 1% DHL-HisZnNa to the scalp did not prevent CIA. However, this drug may promote recovery from CIA. TRIAL REGISTRATION NUMBER: UMIN000014840.

Nuclear receptor gene alteration in human induced pluripotent stem cells with hepatic differentiation propensity.

AIM: Human induced pluripotent stem (hiPS) cells are an alternative cell source of regenerative medicine for liver disease. Because variations in hepatic differentiation efficacy among hiPS cells exist, it is important to select a hiPS cell line with hepatic differentiation propensity. In addition, nuclear receptors (NR) regulate essential biological processes including differentiation and development. In this study, we identified the hiPS cell line with hepatic differentiation propensity and examined expression levels of 48 NR during this process. METHODS: We screened 28 hiPS cell lines, which are established from various tissues of healthy persons with various reprogramming methods, using a three-step differentiation method, and examined expression levels of 48 NR by quantitative real-time polymerase chain reaction during the differentiation process in the selected cells. RESULTS: hiPS-RIKEN-2B and hiPS-RIKEN-2F cells have hepatic differentiation propensity. Differentiation propensity towards endoderm was affected by donor origin but not by reprogramming methods or cell type of origins. Expression levels of NR were closely associated with those of hepatic differentiation markers. Furthermore, expression patterns of NR were categorized as five patterns. In particular, seven NR such as chicken ovalbumin upstream promoter transcription factor 1, retinoic acid receptor α, peroxisome proliferator-activated receptor-γ, progesterone receptor, photoreceptor cell-specific nuclear receptor, tailless homolog orphan receptor and glucocorticoid receptor were identified as the genes of which expression gradually goes up with differentiation. CONCLUSION: These findings will be useful for not only elucidating mechanisms of hepatic differentiation of hiPS cells but also cell-based therapy for liver diseases.

Crosstalk between mitotic reassembly and repair of the nuclear envelope.

In eukaryotic cells, the nuclear envelope (NE) is a membrane partition between the nucleus and the cytoplasm to compartmentalize nuclear contents. It plays an important role in facilitating nuclear functions including transcription, DNA replication and repair. In mammalian cells, the NE breaks down and then reforms during cell division, and in interphase it is restored shortly after the NE rupture induced by mechanical force. In this way, the partitioning effect is regulated through dynamic processes throughout the cell cycle. A failure in rebuilding the NE structure triggers the mixing of nuclear and cytoplasmic contents, leading to catastrophic consequences for the nuclear functions. Whereas the precise details of molecular mechanisms for NE reformation during cell division and NE restoration in interphase are still being investigated, here, we mostly focus on mammalian cells to describe key aspects that have been identified and to discuss the crosstalk between them.

Bolus injection of newly synthesized vitamin E derivative ETS-GS for the treatment of acute severe ulcerative colitis in a mouse model. New vitamin E derivative for acute severe UC.

PURPOSE: Vitamin E with its antioxidant action has therapeutic effects on ulcerative colitis (UC), but use of vitamin E is limited because of its insolubility in water. We developed ETS-GS (γ-L-glutamyl-S-[2-[[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltri-decyl)-2 H-1-benzopyran-6-yl]oxy]carbonyl]-3-oxo-3-[(2-sulfoethyl)amino]propyl]-L-cysteinylglycine sodium salt), a newly synthesized soluble vitamin E derivative with strong antioxidant action. We evaluated the therapeutic effects of bolus injection of ETS-GS on acute severe UC in a mouse model. METHODS: An animal model of acute severe UC was induced by feeding mice 5 % dextran sulfate sodium (DSS) for 5 days, followed by 1 % DSS on days 5-8, the experimental period. ETS-GS or saline was administered by subcutaneous bolus injection during the experimental period. We examined disease activity index (DAI) score, histological score, colon length, colon weight, and serum cytokines in the mice. RESULTS: The following results at day 8 in the DSS + ETS-GS group were significantly lower than those in the DSS + Saline group: DAI score, 2.6 ± 0.6 vs. 3.1 ± 0.5; histological score, 2.1 ± 1.0 vs. 3.1 ± 0.8; serum interleukin (IL)-6, 15 ± 9.4 vs. 39 ± 23 pg/ml; and keratinocyte-derived chemokine (KC), 122 ± 61 vs. 228 ± 66 pg/ml (P < 0.05). Colon length, colon weight, and serum IL-10 in the DSS + ETS-GS group were significantly higher than those in the DSS + Saline group (88 ± 12 vs. 75 ± 5.7 mm, 0.48 ± 0.09 vs. 0.38 ± 0.05 g, and 55 ± 18 vs. 31 ± 10 pg/ml, respectively; P < 0.05). CONCLUSIONS: Bolus injection of ETS-GS may be one therapeutic modality for acute severe UC. Its effects are associated with suppression of serum IL-6 and serum KC and promotion of serum IL-10.

Transrectal peritoneal access with the submucosal tunnel technique in NOTES: a porcine survival study.

BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) procedures have been performed via transgastric, transvaginal, or transcolonic approaches. However, the transcolonic approach has potential disadvantages including intraperitoneal infection. To avoid such disadvantages, we applied the submucosal tunnel technique to transrectal peritoneal access in this study. Study aims are to clarify the technical feasibility of a submucosal tunnel method for transrectal abdominal access and to assess the healing process of the submucosal tunnel histopathologically. METHODS: The study comprised six female pigs. The following procedures were performed: (1) The mucosa was cut after injection of sodium hyaluronate into the submucosa at the upper rectum. (2) Submucosal tunneling was performed by endoscopic submucosal dissection technique. (3) A small incision was made at the end of the tunnel. (4) After transrectal peritoneoscopy, the mucosal incision site was closed with endoclips. RESULTS: Transrectal peritoneoscopy was successfully performed in all pigs. Necropsy revealed no findings of peritonitis. Histopathologic examination showed good healing of the submucosal tunnel. The wound healing process of the submucosal tunnel on postoperative day 7 was mainly in the inflammatory phase at the mucosal incision site, the proliferative phase at the submucosal tract, and the proliferative/remodeling phase at the seromuscular incision site. CONCLUSIONS: The submucosal tunnel technique appears to be useful and safe for transrectal peritoneal access because healing at the seromuscular incision site proceeded rapidly.

Laparoscopic versus open resection for stage II/III rectal cancer in obese patients: A multicenter propensity score-based analysis of short- and long-term outcomes.

Aim: Whether a laparoscopic procedure can contribute to the improvement of clinical outcomes in obese patients with stage II/III rectal cancer compared to an open procedure remains unclear. Objective: This study evaluated the technical and oncological safety of laparoscopic surgery versus open surgery in obese patients (body mass index [BMI] ≥25 kg/m2) with rectal cancer. Patients and Methods: Data were collected from patients with pathological stage II/III rectal cancer and analyzed. Operations were performed via laparoscopic or open surgery from 2009 to 2013. A comparative analysis was performed after applying propensity score matching to the two cohorts (laparoscopic group and open group). The primary endpoint was 3-y relapse-free survival (RFS). Results: Overall, 524 eligible cases were collected from 51 institutions. Equal numbers of propensity score-matched patients were included in the laparoscopic (n = 193) group and open (n = 193) group. Although the rate of D3 lymph node dissection did not differ between the laparoscopic group (87.0%) and the open group (88.6%), the median number of harvested lymph nodes was significantly lower in the laparoscopic group versus open group (17.5 vs 21, P = 0.0047). The median postoperative hospital stay was also significantly shorter in the laparoscopic group (14 d) vs the open group (17 d) (P = 0.0014). Three-y RFS was not significantly different between the two groups (hazard ratio 1.2454, 95% confidence interval 0.9201-1.6884, P = 0.4689). Conclusion: The short- and long-term results of this large cohort study (UMIN ID: UMIN000033529) indicated that laparoscopic surgery in obese rectal cancer patients has advantageous short-term outcomes and no disadvantageous long-term outcomes.

A multicenter survey of effects and challenges of an 8K ultra-high-definition endoscopy system compared to existing endoscopy systems for endoscopic surgery.

INTRODUCTION: 8K ultra-high-definition (UHD) images enabling clearer recognition of anatomical structures could contribute to further development of surgical techniques and advanced applications in endoscopic surgery fields. This study aimed to clarify effects and challenges of endoscopic surgery with 8K UHD endoscopy compared to existing endoscopy systems. METHODS: In this multicenter, cross-sectional, questionnaire survey, data were collected from surgical participants who newly used and observed 8K UHD endoscopy in patients undergoing surgery from February 2020 to February 2021. Survey items included sense of presence, reality, depth perception, visibility of tissue, eyestrain, and degree of satisfaction for operators and observers, and weight, operability, focus adjustment, physical fatigue, eyestrain, and satisfaction for camera assistants. Participants rated each 8K UHD endoscopic surgery on a one-to-five scale (definitively inferior, relatively inferior, equivalent, relatively superior, definitively superior) compared to the existing endoscopy system of each facility. RESULTS: Overall, questionnaire responses from 139 participants assessing 8K UHD endoscopic surgery were collected from surgeries performed in 46 patients. Respective ratings of operators and observers included sense of presence: "superior or relatively superior", 97.8% and 91.5%; reality: "superior or relatively superior", 76.1% and 72.3%; and visibility of tissue: "superior or relatively superior", 93.5% and 87.2%. Weight was rated as "inferior or relatively inferior" by 73.9% of camera assistants and focus adjustment as "inferior" by 60.9% of them. CONCLUSIONS: 8K UHD endoscopic surgery enabled identification of surgical anatomies more clearly, provided a sense of presence and reality, and might improve educational effect. Technological development is expected to reduce the burden of camera assistants.

Impact of laparoscopic surgery on short-term and long-term outcomes in elderly obese patients with colon cancer.

Background: Laparoscopic surgery is reported to be useful in obese or elderly patients with colon cancer, who are at increased risk of postoperative complications because of comorbidities and physical decline. However, its usefulness is less clear in patients who are both elderly and obese and may be at high risk of complications. Methods: Data for obese patients (body mass index ≥25) who underwent laparoscopic or open surgery for stage II or III colon cancer between January 2009 and December 2013 were collected by the Japan Society of Laparoscopic Colorectal Surgery. Surgical outcomes, postoperative complications, and relapse-free survival (RFS) were compared between patients who underwent open surgery and those who underwent laparoscopic surgery according to whether they were elderly (≥70 y) or nonelderly (<70 y). Results: Data of 1549 patients (elderly, n = 598; nonelderly, n = 951) satisfied the selection criteria for analysis. Length of stay was shorter and surgical wound infection was less common in elderly obese patients who underwent laparoscopic surgery than in those underwent open surgery. There were no significant between-group differences in overall complications, anastomotic leakage, ileus/small bowel obstruction, or RFS. There were also no significant differences in RFS after laparoscopic surgery according to patient age. Conclusion: Laparoscopic surgery is safe in elderly obese patients with colon cancer and does not worsen their prognosis. There was no significant difference in the effectiveness of laparoscopic surgery between obese patients who were elderly and those who were nonelderly.

Characterizing scale dependence of effective diffusion driven by fluid flows.

We study the scale dependence of effective diffusion of fluid tracers, specifically, its dependence on the Péclet number, a dimensionless parameter of the ratio between advection and molecular diffusion. Here, we address the case that length and time scales on which the effective diffusion can be described are not separated from those of advection and molecular diffusion. For this, we propose an alternate method for characterizing the effective diffusivity without relying on the scale separation. For a given spatial domain inside which the effective diffusion can emerge, a time constant related to the diffusion is identified by considering the spatiotemporal evolution of a test advection-diffusion equation, where its initial condition is set at a pulse function. Then, the value of effective diffusivity is identified by minimizing the L_{∞} distance between solutions of the above test equation and the diffusion one with mean drift. With this method, for time-independent gyre and time-periodic shear flows, we numerically show the scale dependence of the effective diffusivity and its discrepancy from the classical limits that were derived on the assumption of the scale separation. The kinematic origins of the discrepancy are revealed as the development of the molecular diffusion across flow cells of the gyre and as the suppression of the drift motion due to a temporal oscillation in the shear.

Laparoscopic distal gastrectomy for advanced gastric cancer with situs inversus totalis: a case report.

BACKGROUND: Situs inversus totalis (SIT) is a relatively rare condition, in which the thoracic and abdominal organs are reversed or mirrored from their normal positions. Here, we reported a case of a patient with SIT and advanced gastric cancer with lymph node metastasis who underwent laparoscopic distal gastrectomy (LDG). CASE PRESENTATION: A 67-year-old man with SIT was clinically diagnosed with T3N2M0 advanced gastric cancer located in the middle gastric body. Three-dimensional reconstruction of computed tomography angiogram revealed that the common hepatic artery originated from the superior mesenteric artery. The patient underwent LDG with D2 lymph node dissection and Roux-en-Y reconstruction. The postoperative course was uneventful. CONCLUSION: This case report showed that LDG could be safely performed on a patient even under complex conditions, such as advanced gastric cancer with lymph node metastasis with SIT and vascular anomalies.

Nucleoplasmic lamin C rapidly accumulates at sites of nuclear envelope rupture with BAF and cGAS.

In mammalian cell nuclei, the nuclear lamina (NL) underlies the nuclear envelope (NE) to maintain nuclear structure. The nuclear lamins, the major structural components of the NL, are involved in the protection against NE rupture induced by mechanical stress. However, the specific role of the lamins in repair of NE ruptures has not been fully determined. Our analyses using immunofluorescence and live-cell imaging revealed that the nucleoplasmic pool of lamin C rapidly accumulated at sites of NE rupture induced by laser microirradiation in mouse embryonic fibroblasts. The accumulation of lamin C at the rupture sites required both the immunoglobulin-like fold domain that binds to barrier-to-autointegration factor (BAF) and a nuclear localization signal. The accumulation of nuclear BAF and cytoplasmic cyclic GMP-AMP synthase (cGAS) at the rupture sites was in part dependent on lamin A/C. These results suggest that nucleoplasmic lamin C, BAF, and cGAS concertedly accumulate at sites of NE rupture for rapid repair.

Intussusception in the ascending colon caused by cecal chronic diverticulitis: a case report.

Although intussusception in adults generally results from malignant tumors and polyps, intussusception caused by chronic diverticulitis is extremely rare. We present the case of a 59-year-old man treated with steroids and biopharmaceuticals at the Department of Dermatology for psoriasis vulgaris. Cecal diverticulitis frequently recurred, for which he was treated during follow-up. This time, endoscopy showed a circumferential stenosis in the ascending colon, and computed tomography showed the appearance of a target sign in the right colon. As a result, the patient was preoperatively diagnosed as having intussusception of the ascending colon triggered by diverticulitis of the cecum and underwent laparoscopic right colectomy. Pathological findings of the specimen revealed multiple diverticulitis of the cecum. Therefore, we thought that the intussusception was caused by chronic inflammation of the diverticula and surrounding fibrosis. Among intussusception in adults, chronic diverticulitis should be considered as a target of surgical treatment on rare occasions.

Anisotropy-driven quantum criticality in an intermediate valence system.

Intermetallic compounds containing f-electron elements have been prototypical materials for investigating strong electron correlations and quantum criticality (QC). Their heavy fermion ground state evoked by the magnetic f-electrons is susceptible to the onset of quantum phases, such as magnetism or superconductivity, due to the enhanced effective mass (m*) and a corresponding decrease of the Fermi temperature. However, the presence of f-electron valence fluctuations to a non-magnetic state is regarded an anathema to QC, as it usually generates a paramagnetic Fermi-liquid state with quasiparticles of moderate m*. Such systems are typically isotropic, with a characteristic energy scale T0 of the order of hundreds of kelvins that require large magnetic fields or pressures to promote a valence or magnetic instability. Here we show the discovery of a quantum critical behaviour and a Lifshitz transition under low magnetic field in an intermediate valence compound α-YbAlB4. The QC origin is attributed to the anisotropic hybridization between the conduction and localized f-electrons. These findings suggest a new route to bypass the large valence energy scale in developing the QC.

Reactive oxygen species and NADPH oxidase 4 induced by transforming growth factor ß1 are the therapeutic targets of polyenylphosphatidylcholine in the suppression of human hepatic stellate cell activation.

OBJECTIVE AND DESIGN: To clarify the molecular mechanism of polyenylphosphatidylcholine (PPC), we examined the involvement of reactive oxygen species (ROS) and NADPH oxidase 4 (Nox4) in human hepatic stellate cells (HSCs). MATERIAL: Using human LX-2 HSC cells, we examined the effects of PPC on expression of α-smooth muscle actin (α-SMA) and collagen 1, generation of ROS, Nox4 expression, p38 activation and cell proliferation, induced by transforming growth factor ß1 (TGFß1). RESULTS: PPC suppressed ROS which are induced by TGFß1, phosphorylation of p38MAPK, and expression levels of α-SMA and collagen 1 in a dose-dependent manner. Higher concentrations of PPC also suppressed Nox4 levels. CONCLUSION: These results suggest that ROS and Nox4 induced by TGFß1 are the therapeutic targets of PPC in the suppression of human hepatic stellate cell activation.