Kamebakaurin Suppresses Antigen-Induced Mast Cell Activation by Inhibition of FcεRI Signaling Pathway.

INTRODUCTION: Kamebakaurin is an active constituent of both Rabdosia japonica and Rabdosia excisa, which are utilized in Chinese traditional medicine for improving symptoms in patients with allergies. We investigated the molecular mechanisms of the anti-allergic effects of kamebakaurin using BMMCs. METHODS: The degranulation ratio, histamine release, and the interleukin (IL)-4, leukotriene B4 (LTB4), and cysteinyl leukotriene productions on antigen-triggered BMMC were investigated. Additionally, the effects of kamebakaurin on signal transduction proteins were examined by Western blot and binding to the Syk and Lyn kinase domain was calculated. The effects of kamebakaurin on antigen-induced hyperpermeability were investigated using mouse model. RESULTS: At 10 µm, kamebakaurin partially inhibited degranulation, histamine release, and IL-4 production. At 30 µm, kamebakaurin partially reduced LTB4 and cysteinyl leukotriene productions and suppressed degranulation, histamine release, and IL-4 production. Phosphorylation of both Syk Y519/520 and its downstream protein, Gab2, was reduced by kamebakaurin, and complete inhibition was observed with 30 µm kamebakaurin. In contrast, phosphorylation of Erk was only partially inhibited, even in the presence of 30 µm kamebakaurin. Syk Y519/520 is known to be auto-phosphorylated via intramolecular ATP present in its own ATP-binding site, and this auto-phosphorylation triggers degranulation, histamine release, and IL-4 production. Docking simulation study indicated kamebakaurin blocked ATP binding to the ATP-binding site in Syk. Therefore, inhibition of Syk auto-phosphorylation by kamebakaurin binding to the Syk ATP-binding site appeared to cause a reduction of histamine release and IL-4 production. Kamebakaurin inhibited antigen-induced vascular hyperpermeability in a dose-dependent fashion but did not reduce histamine-induced vascular hyperpermeability. CONCLUSION: Kamebakaurin ameliorates allergic symptoms via inhibition of Syk phosphorylation; thus, kamebakaurin could be a lead compound for the new anti-allergic drug.

Preliminary report on ultrashort perioperative partial-breast irradiation with multicatheter interstitial brachytherapy for early-stage breast cancer.

PURPOSE: Perioperative partial-breast irradiation (PBI) with multicatheter interstitial brachytherapy (MIB) is less invasive and more convenient than postoperative one. This study aimed to compare ultrashort perioperative MIB-PBI (uPBI) and conventional perioperative MIB-PBI (cPBI) performed during the same period of time. METHODS: Inclusion criteria of the study were patients aged ≥ 40 years and those with T0-2 (≤ 3 cm), N0-mi, and negative margins on mammography. The locoregional recurrence (LRR) and toxicity rates were compared between uPBI at a dose of 25.2 Gy in four fractions and cPBI at a dose of 32 Gy in eight fractions. RESULTS: In total, 198 patients (151 with uPBI and 47 with cPBI) were evaluated. At a median follow-up of 20.1 months, one (0.66%) patient in the uPBI group had LRR. The 2-year ipsilateral breast tumor recurrence-free survival rates of the uPBI and cPBI groups were 98.7% and 100%, respectively. The highest toxicity grades were grade 1 in 23 (15.2%) and grade 2 in 2 (1.3%) patients in the uPBI group, and grade 1 in 8 (17.0%) and grade 2 in 1 (2.1%) patient in the cPBI group. None of the patients in the two groups presented with grade 3 and higher toxicities. The toxicity rates between the two groups did not significantly differ. Further, 22 (14.6%) patients in the uPBI group and 8 (17.0%) in the cPBI group, and 3 (2.0%) patients in the uPBI group and 1 (2.1%) in the cPBI had acute and late toxicities, respectively. The timing of toxicity development between the two groups did not significantly differ. CONCLUSIONS: Although this preliminary report included a small sample size and had a short follow-up period, the local control and toxicity rates were similar between the uPBI and cPBI groups. Further research is warranted to investigate the ideal dose schedule of MIB-PBI.

Impact of de-escalating systemic therapy guided by 21-gene assay on locoregional recurrence after partial-breast irradiation.

PURPOSE: Partial-breast irradiation (PBI) has been performed as alternative to whole-breast irradiation (WBI) in breast-conserving therapy (BCT). Recently, the 21-gene recurrence score (RS) was introduced to determine the adjuvant therapy for estrogen receptor (ER)-positive, and human epidermal growth factor receptor 2 (HER2)-negative diseases. However, the impact of RS-based systemic therapy on locoregional recurrence (LRR) following BCT with PBI remains uninvestigated. METHODS AND MATERIALS: Patients with ER-positive, HER2-negative, and node-negative breast cancer who underwent BCT with PBI were examined during May 2012-March 2022. In addition to immunohistochemistry (IHC), RS was available to decide on adjuvant therapy. RESULTS: In total, 431 patients were evaluated with a median followup of 48.6 months. The 4-year LRR-free survival rates were 97.3% and 96.4% in the IHC and RS cohorts, respectively (p = 0.50). Ki67 of >20% was significantly associated with LRR in the multivariate analysis (HR 4.39, p < 0.05). For patients with Ki67 > 20%, 29 of 71 (40.8%) and 46 of 59 (78.0%) patients received only endocrine therapy in the IHC and RS cohorts, respectively (p < 0.0001). For patients with Ki67 >20% who received only endocrine therapy, the 4-year LRR-free survival rates were 91.8% in the IHC cohort and 94.6% in the RS cohort (p = 0.29) CONCLUSIONS: Although the introduction of RS increased the number of patients receiving endocrine therapy alone for Ki67 >20% of disease by two times, the LRR-free survival after BCT with PBI could be maintained. However, further studies from multiple institutions with longer followup data are required.

Improvement in Decline Rate of Estimated Glomerular Filtration Rate after Febuxostat Treatment in a Fabry Disease Patient with Enzyme Replacement Therapy-resistant Proteinuria.

Fabry disease is an inherited lysosomal disorder caused by mutations in the alpha-galactosidase A gene. We herein report a Fabry disease patient with enzyme replacement therapy (ERT)-resistant proteinuria who showed improvement in the estimated glomerular filtration rate (eGFR) decline rate after uric acid (UA)-lowering therapy. The patient was diagnosed with Fabry disease at 36 years old. After that, even under ERT, proteinuria and eGFR decline persisted. During the clinical course, serum UA levels were elevated with increases in renal tubular damage markers. Febuxostat administration immediately improved tubular damage and prevented further eGFR decline. UA-mediated tubulopathy may become an additional therapeutic target for eGFR decline in Fabry disease.

Inhibition of mitochondrial fission protects podocytes from albumin-induced cell damage in diabetic kidney disease.

AIMS: Identifying the mechanisms that underlie progression from endothelial damage to podocyte damage, which leads to massive proteinuria, is an urgent issue that must be clarified to improve renal outcome in diabetic kidney disease (DKD). We aimed to examine the role of dynamin-related protein 1 (Drp1)-mediated regulation of mitochondrial fission in podocytes in the pathogenesis of massive proteinuria in DKD. METHODS: Diabetes- or albuminuria-associated changes in mitochondrial morphology in podocytes were examined by electron microscopy. The effects of albumin and other diabetes-related stimuli, including high glucose (HG), on mitochondrial morphology were examined in cultured podocytes. The role of Drp1 in podocyte damage was examined using diabetic podocyte-specific Drp1-deficient mice treated with neuraminidase, which removes endothelial glycocalyx. RESULTS: Neuraminidase-induced removal of glomerular endothelial glycocalyx in nondiabetic mice led to microalbuminuria without podocyte damage, accompanied by reduced Drp1 expression and mitochondrial elongation in podocytes. In contrast, streptozotocin-induced diabetes significantly exacerbated neuraminidase-induced podocyte damage and albuminuria, and was accompanied by increased Drp1 expression and enhanced mitochondrial fission in podocytes. Cell culture experiments showed that albumin stimulation decreased Drp1 expression and elongated mitochondria, although HG inhibited albumin-associated changes in mitochondrial dynamics, resulting in apoptosis. Podocyte-specific Drp1-deficiency in mice prevented diabetes-related exacerbation of podocyte damage and neuraminidase-induced development of albuminuria. Endothelial dysfunction-induced albumin exposure is cytotoxic to podocytes. Inhibition of mitochondrial fission in podocytes is a cytoprotective mechanism against albumin stimulation, which is impaired under diabetic condition. Inhibition of mitochondrial fission in podocytes may represent a new therapeutic strategy for massive proteinuria in DKD.

Computed tomography-guided partial-breast brachytherapy using implanted catheters as fiducial markers versus co-registered magnetic resonance imaging.

PURPOSE: Partial-breast irradiation (PBI) needs accurate cavity delineation with computed tomography (CT). In perioperative PBI using multicatheter-interstitial brachytherapy (MIB), catheters implanted during surgery were enabled as fiducial markers. Magnetic resonance imaging (MRI) can also assist delineation with CT. METHODS: Patients receiving MIB-PBI were analyzed. Cavity visualization scores (CVSs) were categorized with CT. With catheter-based delineation (CBD), the relationship between cavity boundaries and catheters were used to contour the tumor bed. Co-registered MRI delineation (CMD) was also performed. The correlation between cavity volume and the excised tissue weight was compared for the two techniques. RESULTS: The association between CVS and preoperative characteristics in 159 patients showed mammographic breast density (MBD) remained correlated to CVS on multiple regression analyses; CVS = 5.2-0.61 x MBD (p < 0.0001). In 43 patients, the cavity volumes determined with CBD vs CMD were 12.8 ±â€¯6.4 cm3 vs 16.1 ±â€¯12.4 cm3 (p < 0.0001), and their plots with excised weights showed the best fitting lines were 0.29 vs 0.48 (p < 0.0001), respectively. The correlation coefficients for CBD vs CMD were 0.65 vs 0.55 (p = 0.20) in low (CVS 1-3, n = 27) and 0.72 vs 0.58 (p = 0.36) in high visualized cavities (CVS 4-5, n = 16), respectively. CONCLUSIONS: The use of implanted catheters as fiducial markers was associated with smaller cavities and greater correlations with the excised tissue weights than co-registration with MRI. This might be a useful technique, especially for patients with dense breasts on mammography.

Predicting adherence of dose-volume constraints for personalized partial-breast irradiation technique.

PURPOSE: Multicatheter interstitial brachytherapy (MIB) and external-beam (EB) radiotherapy are established partial-breast irradiation (PBI) techniques. Although EB-PBI is widely available, it requires extra irradiated margins for target uncertainties. We examined the impact of EB-PBI on dose-volume constraints as compared to MIB-PBI. METHODS AND MATERIALS: Among 653 patients receiving MIB-PBI between October 2008 and April 2020, consequent 159 patients after September 2018 were examined. Clinical target volume (CTV) included the lumpectomy cavity plus 1.0 cm. Planning target volume (PTV) for EB-PBI was defined as CTV with 1.0-cm expansion. Because the ratio of PTV to breast volume (RPB) was related to cosmesis, <25% of RPB was defined as suitable for the ipsilateral breast constraints. Preoperative breast size was classified as very small (<350 cm3), small (350-699 cm3), and medium or large (≥700 cm3). According to each category, the dose-volume constraints of the organs at risk were compared between the two PBI techniques. RESULTS: Patients including 84 very small, 59 small, and 16 moderate to large breasts were examined. Although RPB was suitable in all patients receiving MIB-PBI, it was achieved in 74 patients (46.5%) receiving EB-PBI (p < 0.0001). The suitable RPB in patients with very small, small, and moderate to large breast was 32.1%, 55.9%, and 100%, respectively (p < 0.0001). Normal-tissue constraints for the other organs could be satisfied in patients with moderate to large breasts. CONCLUSION: Although EB-PBI may be an appropriate option for patients with moderate to large breasts, MIB-PBI could still be a crucial technique, especially for patients with small breasts.

SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition.

SGLT2 inhibitors offer strong renoprotection in subjects with diabetic kidney disease (DKD). But the mechanism for such protection is not clear. Here, we report that in damaged proximal tubules of high-fat diet-fed ApoE-knockout mice, a model of non-proteinuric DKD, ATP production shifted from lipolysis to ketolysis dependent due to hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). We further found that empagliflozin raised endogenous ketone body (KB) levels, and thus its use or treatment with 1,3-butanediol, a KB precursor, prevented decreases in renal ATP levels and organ damage in the mice. The renoprotective effect of empagliflozin was abolished by gene deletion of Hmgcs2, a rate-limiting enzyme of ketogenesis. Furthermore, KBs attenuated mTORC1-associated podocyte damage and proteinuria in diabetic db/db mice. Our findings show that SGLT2 inhibition-associated renoprotection is mediated by an elevation of KBs that in turn corrects mTORC1 hyperactivation that occurs in non-proteinuric and proteinuric DKD.

Contrast medium-induced severe thrombocytopenia in patient on maintenance hemodialysis: a case report and literature review.

A 43-year-old male patient on maintenance hemodialysis had an enhanced computed tomography scan examination with iohexol for the first time 10 min before regular hemodialysis therapy. At the start of hemodialysis, no symptoms were observed, and the platelet count was 148,000/µl. Approximately 1 h after starting hemodialysis, dyspnea and chest discomfort appeared. Since oxygen saturation of the peripheral artery decreased to 87%, oxygen administration was immediately started while continuing hemodialysis therapy. Furthermore, gingival hemorrhage was observed, and the platelet count decreased to 5000/µl. We were carefully monitoring his conditions while continuing hemodialysis and oxygen administration, but no further deterioration was observed. Thereafter, these symptoms and severe thrombocytopenia gradually improved without additional treatment. At the end of hemodialysis, these symptoms completely disappeared. As well, the platelet count recovered to 35,000/µl at the end of hemodialysis and increased to 92,000/µl the next morning. From the clinical course, we diagnosed with contrast medium-induced thrombocytopenia. Acute thrombocytopenia is a rare complication induced by the contrast medium. Until now, 16 cases on contrast medium-induced thrombocytopenia have been reported. Our case spontaneously recovered from severe thrombocytopenia relatively earlier than previous reports. Our patient started hemodialysis therapy 10 min after an enhanced computed tomography examination. Early removal of contrast medium by hemodialysis might be associated with early improvement. We should acknowledge that contrast media have potential to induce severe thrombocytopenia, even in patients on maintenance hemodialysis.

Protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes.

To examine the cell-protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes, we analyzed the renal phenotype of tamoxifen (TM)-inducible podocyte-specific Atg5-deficient (iPodo-Atg5-/-) mice with experimental endothelial dysfunction. In both control and iPodo-Atg5-/- mice, high fat diet (HFD) feeding induced glomerular endothelial damage characterized by decreased urinary nitric oxide (NO) excretion, collapsed endothelial fenestrae, and reduced endothelial glycocalyx. HFD-fed control mice showed slight albuminuria and nearly normal podocyte morphology. In contrast, HFD-fed iPodo-Atg5-/- mice developed massive albuminuria accompanied by severe podocyte injury that was observed predominantly in podocytes adjacent to damaged endothelial cells by scanning electron microscopy. Although podocyte-specific autophagy deficiency did not affect endothelial NO synthase deficiency-associated albuminuria, it markedly exacerbated albuminuria and severe podocyte morphological damage when the damage was induced by intravenous neuraminidase injection to remove glycocalyx from the endothelial surface. Furthermore, endoplasmic reticulum stress was accelerated in podocytes of iPodo-Atg5-/- mice stimulated with neuraminidase, and treatment with molecular chaperone tauroursodeoxycholic acid improved neuraminidase-induced severe albuminuria and podocyte injury. In conclusion, podocyte autophagy plays a renoprotective role against diabetes-related structural endothelial damage, providing an additional insight into the pathogenesis of massive proteinuria in diabetic nephropathy.

Efficacy of Single-Plane Implant Technique in Partial Breast Brachytherapy in Small-Breasted Patients.

PURPOSE: Partial-breast irradiation (PBI) using multicatheter-interstitial brachytherapy (MIB) has been supported by some randomized trials to date. However, it remains underused in Asian countries because of the population's typically smaller breasts. Single-plane implantation has been recommended in these individuals, but limited data on the clinical efficacy exist. We performed a retrospective chart review to compare the tumor control and long-term cosmesis in patients treated with the single-plane implant technique. METHODS AND MATERIALS: Patients receiving MIB-PBI between October 2008 and December 2018 were evaluated. PBI was initiated on the same day of the surgery via an intraoperative catheter implant, delivering 32 Gy by 8 fractions. Tumor control based on the rate of freedom from ipsilateral tumor recurrence (IBTR), disease-free survival, and long-term cosmesis using the Harvard scale was evaluated to compare between the single- and double-/triple-plane implant techniques. RESULTS: Five hundred sixteen patients with 526 lesions received MIB-PBI with a median follow-up of 53.1 months. Patients treated by single- and double- or triple-plane implant numbered 288 (54.8%) and 238 (45.2%), respectively. The 4-year probabilities of IBTR-free survival and disease-free survival were 97.5% and 96.5% in single-plane implant and 98.6% (P = .42) and 98.0% (P = .18) in double- or triple-plane implant MIB-PBI, respectively. Although young age (P < .05) and positive surgical margins (P < .01) were selected as independent risk factors for IBTR, single-plane implantation was not recognized as a risk factor of IBTR. Sixty-one of 69 single-plane implant patients (88.4%) and 84 of 92 double-/triple-plane implant patients (91.3%) reported excellent to good cosmetic results (P = .73). CONCLUSIONS: Although this was a retrospective study from a single institution and cosmesis was evaluated using a subjective method, this is the first report to validate single-plane implant MIB-PBI for use in small-breasted patients. Further multicenter research is required.

Moving incision for covert breast-conserving surgery may prevent early wound complications in brachytherapy-based partial-breast irradiation.

PURPOSE: Brachytherapy-based partial-breast irradiation (PBI) is a treatment option for breast-conserving therapy. Although intraoperative catheter implantation has been introduced, early wound complications are a concern. Covert operations with a moving incision are widely performed to hide surgical scars and may reduce the incision-site radiation dose. This study aimed to compare complication rates for moving incision and conventional incision in covert breast-conserving surgery. METHODS AND MATERIALS: Between October 2008 and December 2018, the medical records of all patients who underwent PBI using multicatheter interstitial brachytherapy after breast-conserving surgery were examined. Since July 2016, to hide the scar, we have performed a moving incision from above the tumor to an invisible site at our institution. The planning target volume included 1.0-1.5 cm of tissue surrounding the surgical cavity. High-dose-rate interstitial brachytherapy with a dose of 32 Gy in eight fractions was performed. The cumulative incidences of surgical site infections and symptomatic seromas ≤90 days were analyzed. RESULTS: The study included 516 consecutive patients with 526 lesions. Overall, 40 (7.6%) early wound complications were observed, in which 4 (2.6%) involved 152 moving incisions and 36 (9.6%) involved 374 conventional incisions (p = 0.01). On univariate analysis, age, tumor diameter, re-excision, planning target volume, numbers of catheters and planes, and incision type were risk factors for complications. On multivariate analysis, only incision type was a risk factor. Moving incision reduced the early complication rate by 75% (p = 0.01). CONCLUSION: Moving incision in covert breast-conserving surgery reduced the risk of early wound complications.

Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes.

BACKGROUND: Energy metabolism in proximal tubular epithelial cells (PTECs) is unique, because ATP production largely depends on lipolysis in both the fed and fasting states. Furthermore, disruption of renal lipolysis is involved in the pathogenesis of diabetic tubulopathy. Emerging evidence suggests that protein O-GlcNAcylation, an intracellular nutrient-sensing system, may regulate a number of metabolic pathways according to changes in nutritional status. Although O-GlcNAcylation in PTECs has been demonstrated experimentally, its precise role in lipolysis in PTECs is unclear. METHODS: To investigate the mechanism of renal lipolysis in PTECs-specifically, the role played by protein O-GlcNAcylation-we generated mice with PTECs deficient in O-GlcNAc transferase (Ogt). We analyzed their renal phenotypes during ad libitum feeding, after prolonged fasting, and after mice were fed a high-fat diet for 16 weeks to induce obesity and diabetes. RESULTS: Although PTEC-specific Ogt-deficient mice lacked a marked renal phenotype during ad libitum feeding, after fasting 48 hours, they developed Fanconi syndrome-like abnormalities, PTEC apoptosis, and lower rates of renal lipolysis and ATP production. Proteomic analysis suggested that farnesoid X receptor-dependent upregulation of carboxylesterase-1 is involved in O-GlcNAcylation's regulation of lipolysis in fasted PTECs. PTEC-specific Ogt-deficient mice with diabetes induced by a high-fat diet developed severe tubular cell damage and enhanced lipotoxicity. CONCLUSIONS: Protein O-GlcNAcylation is essential for renal lipolysis during prolonged fasting and offers PTECs significant protection against lipotoxicity in diabetes.

Catheter-based delineation of lumpectomy cavity for accurate target definition in partial-breast irradiation with multicatheter interstitial brachytherapy.

PURPOSE: In partial-breast irradiation (PBI), accurate lumpectomy cavity (LC) delineation is critical. Seroma-based delineation (SBD) using computed tomography (CT) with clips remains uncertain, causing an expansion of the LC and planning target volume (PTV). In catheter-based delineation (CBD), the implanted catheters were used as reference markers for LC delineation in multicatheter interstitial brachytherapy (MIB). MATERIAL AND METHODS: Between October 2008 and October 2018, 513 patients who underwent MIB-PBI were examined. In CBD, anatomical relations of LC to catheters were recorded. In randomly selected 22 CBD cases, the LC volume and PTV were retrospectively recontoured on SBD, and the relationship between the contribution of CBD and cavity visuality was evaluated. The LC volume and PTV before and after the introduction of CBD were compared. RESULTS: The mean LC volumes based on SBD and CBD were 19.1 cm3 and 14.1 cm3, respectively (p < 0.001). The mean PTVs based on SBD and CBD were 47.9 cm3 and 35.7 cm3, respectively (p < 0.0001). More reductions in the LC volume (5.1 cm3) (p < 0.05) and PTV (7.7 cm3) (p = 0.13) were observed in the poorly visible LC than in the visible LC. The LC volume and PTV before the introduction of CBD (n = 411) were compared with those after introduction (n = 102). Significant reductions were observed in the LC volume (5.9 cm3) (p < 0.0001) after the introduction of CBD; moreover, PTV tended to be reduced (3.9 cm3) (p = 0.17). CONCLUSIONS: CBD may help to establish the standardized procedure for MIB-PBI and prevent unnecessary radiation exposure to the normal breast tissue.

Role of dietary amino acid balance in diet restriction-mediated lifespan extension, renoprotection, and muscle weakness in aged mice.

Extending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)-induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age-related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age-dependent decrease in slow-twitch muscle fiber function but reduced absolute fast-twitch muscle fiber function. DR-induced fast-twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum-fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H2 S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet-restricted aged mice, which were accompanied by a recovery in H2 S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans-sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging.

Validating the efficacy of single-stage breast-conserving therapy using multicatheter partial-breast brachytherapy based on updated ASTRO guidelines.

Based on the accumulating evidence for equivalent results of partial-breast irradiation (PBI) and whole-breast irradiation (WBI) in breast-conserving therapy (BCT), the American Society for Radiation Oncology (ASTRO) updated the consensus statement (CS) to expand the range of potential candidates for PBI outside clinical trials. Of the various techniques, PBI using multicatheter interstitial brachytherapy (MCB) is the oldest and has long-term data. In this study, the efficacy of single-stage BCT using MCB-PBI achieved by an intraoperative catheter placement was validated on updated ASTRO guidelines. We retrospectively examined patients undergoing BCT using MCB-PBI or WBI. The updated CS distinguished patients aged 40-49 years with ER+, tumor ≤2 cm, and margin ≥2 mm from unsuitable patients in the previous CS. We compared the ipsilateral breast tumor recurrence (IBTR) rate in MCB-PBI with that in WBI patients with suitable or cautionary (S/C) categories on the updated CS. Between November 2007 and September 2017, 641 patients with 647 lesions underwent BCT (MCB-PBI, 407; WBI, 240). At the median follow-up time of 54.4 months, we observed 8 (1.97%; 95% CI: 0.62-3.31%) and 7 (2.92%; 95% CI: 0.79-5.05%) IBTRs, respectively. Updating the CS increased the S/C patients receiving MCB-PBI from 232 patients (57.0%) to 319 (78.4%). Comparison of clinical outcomes at the 12-month minimum follow-up between 291 MCB-PBI and 103 WBI in S/C patients showed no significant differences in the 4-year rate of IBTR-free (100% vs 98.9%; P = 0.29) and disease-free survival (98.7% vs 95.5%; P = 0.24). Overall, single-stage BCT using MCB-PBI offered similar tumor control rates, compared with WBI, on the updated ASTRO CS.

Overexpression of acetyl CoA carboxylase ß exacerbates podocyte injury in the kidney of streptozotocin-induced diabetic mice.

A single nucleotide polymorphism (SNP) within the acetyl CoA carboxylase (ACC) ß gene (ACACB), rs2268388, has been shown to be associated with susceptibility to development of proteinuria in patients with type 2 diabetes. To investigate the biological roles of ACCß in the pathogenesis of diabetic nephropathy, we examined the effects of overexpression of ACACB using podocyte-specific ACACB-transgenic mice or ACACB-overexpressing murine podocytes. Podocyte-specific ACACB-transgenic mice or littermate mice were treated with streptozotocin (STZ) to induce diabetes, and 12 weeks after induction of diabetes, we examined the expression of podocyte markers to evaluate the degree of podocyte injury in these mice. We also examined the effects of ACCß on podocyte injury in ACACB- or LacZ-overexpressing murine podocytes. Podocyte-specific ACACB overexpression did not cause visible podocyte injury in non-diabetic mice. In STZ-induced diabetic mice, ACACB-transgenic mice showed a significant increase in urinary albumin excretion, accompanied by decreased synaptopodin expression and podocin mislocalization in podocytes, compared with wild-type mice. In cultured murine podocytes, overexpression of ACACB significantly decreased synaptopodin expression and reorganized stress fibers under high glucose conditions, but not in normal glucose conditions. The decrease of synaptopodin expression and reorganized stress fibers observed in ACACB overexpressing cells cultured under high glucose conditions was reversed by a treatment of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), activator of AMP-activated protein kinase (AMPK). The excess of ACCß might contribute to exacerbation of podocyte injury in the kidney of an animal model for diabetes mellitus, and the AMPK/ACCß pathway may be a novel therapeutic target for the prevention of diabetes-related podocyte injury.

Efficacy of single-stage breast-conserving treatment using multicatheter partial breast brachytherapy evaluated by GEC-ESTRO phase 3 trial.

PURPOSE: The GEC-ESTRO has reported the equivalent outcomes of partial breast irradiation (PBI) using multicatheter interstitial brachytherapy (MCB) to whole breast irradiation (WBI) in breast-conserving therapy (BCT). We performed single-stage BCT with partial breast brachytherapy by intraoperative catheter placement. After the categorization of patients into inclusion and exclusion criteria on this trial, our databases were evaluated in order to translate it to Japanese patients. MATERIAL AND METHODS: Patients undergoing BCT were retrospectively examined between November 2007 and December 2015. The technique is an open-cavity implant with a dose of 32 Gy in 8 fractions. The 4-year clinical outcomes of MCB-PBI were evaluated in the 2 distinct categories, and the comparison of the outcomes of MCB-PBI with WBI was performed in patients with unfavorable features. RESULTS: Of a total of 501 lesions undergoing BCT, 301 lesions were treated with MCB-PBI and 200 lesions with WBI. At the median follow-up time of 52 months, the 4-year rate of ipsilateral breast tumor recurrence (IBTR)-free, disease-free (DFS), and overall survival (OS) in patients with MCB-PBI and WBI were 98.9% vs. 98.0% (p = 0.56), 97.0% vs. 95.3% (p = 0.78), and 99.6% vs. 98.2% (p = 0.38), respectively. Although in exclusion cohort treated with MCB-PBI, IBTR-free, and disease-free survival were significantly worse than in inclusion cohort, non-significantly worse outcomes was demonstrated than in exclusion cohort with WBI; IBTR-free survival (95.0% vs. 97.2%, p = 0.24), and disease-free survival (95.0% vs. 95.8%, p = 0.31). CONCLUSIONS: Single-stage BCT using MCB-PBI offered similar tumor control rates compering to WBI. However, further research is needed to define the benefit for patients with an exclusion criteria.

O-linked ß-N-acetylglucosamine modification of proteins is essential for foot process maturation and survival in podocytes.

BACKGROUND: O-linked ß- N -acetylglucosamine modification O-GlcNAcylation) is a post-translational modification of intracellular proteins, serving as a nutrient sensor. Growing evidence has demonstrated its physiological and pathological importance in various mammalian tissues. This study examined the physiological role of O-GlcNAcylation in podocyte function and development. METHODS: O-GlcNAc transferase (Ogt) is a critical enzyme for O-GlcNAcylation and resides on the X chromosome. To abrogate O-GlcNAcylation in podocytes, we generated congenital and tamoxifen (TM)-inducible podocyte-specific Ogt knockout mice (Podo-Ogt y/- and TM-Podo-Ogt y/- , respectively) and analyzed their renal phenotypes. RESULTS: Podo-Ogt y/- mice showed normal podocyte morphology at birth. However, they developed albuminuria at 8 weeks of age, increasing progressively until age 32 weeks. Glomerular sclerosis, proteinuria-related tubulointerstitial lesions and markedly altered podocyte foot processes, with decreased podocin expression, were observed histologically in 32-week-old Podo-Ogt y/- mice. Next, we induced adult-onset deletion of the Ogt gene in podocytes by TM injection in 8-week-old TM-Podo-Ogt y/- mice. In contrast to Podo-Ogt y/- mice, the induced TM-Podo-Ogt y/- mice did not develop albuminuria or podocyte damage, suggesting a need for O-GlcNAcylation to form mature foot processes after birth. To test this possibility, 3-week-old Podo-Ogt y/- mice were treated with Bis-T-23, which stimulates actin-dependent dynamin oligomerization, actin polymerization and subsequent foot process elongation in podocytes. Albuminuria and podocyte damage in 16-week-old Podo-Ogt y/- mice were prevented by Bis-T-23 treatment. CONCLUSIONS: O-GlcNAcylation is necessary for maturation of podocyte foot processes, particularly after birth. Our study provided new insights into podocyte biology and O-GlcNAcylation.

Efficacy of reduced dose of pegfilgrastim in Japanese breast cancer patients receiving dose-dense doxorubicin and cyclophosphamide therapy.

BACKGROUND: This retrospective study aimed to evaluate the efficacy of a 3.6-mg dose of pegfilgrastim for primary prophylaxis in Japanese breast cancer patients receiving dose-dense chemotherapy. METHODS: Patients treated with adjuvant or neoadjuvant chemotherapy for early-stage breast cancer at the Tokyo-West Tokushukai Hospital were included in this analysis. Because 6 mg pegfilgrastim has not yet been approved for use in Japan, we compared the outcomes of a dose-dense doxorubicin and cyclophosphamide regimen plus 3.6 mg pegfilgrastim support with a conventional dose epirubicin and cyclophosphamide regimen. The incidence of febrile neutropenia, relative dose intensity, dose delay, dose reduction, regimen change and hospitalization because of neutropenia were assessed. RESULTS: From November 2013 to March 2016, 97 patients with stage I-III invasive breast cancer were analyzed (dose-dense doxorubicin and cyclophosphamide plus 3.6-mg pegfilgrastim group, n  =  41; epirubicin and cyclophosphamide group, n  =  56; median ages, 49.0 and 48.5 years, respectively). Febrile neutropenia occurred during the first chemotherapy cycle in 7 of 56 patients (12.5%) in the epirubicin and cyclophosphamide group and 0 of 41 patients in the dose-dense doxorubicin and cyclophosphamide group (P  =  0.02). The average relative dose intensities were 97.9% and 96.8%, respectively (P  =  0.28), with corresponding dose delay rates of 4.9% (2/41) and 16.1% (9/56), respectively (P  =  0.11) and dose reduction rates of 0% (0/41) and 7.1% (4/56), respectively (P  =  0.16). CONCLUSIONS: Our results indicate the efficacy of a 3.6-mg pegfilgrastim dose for the primary prevention of febrile neutropenia in dose-dense doxorubicin- and cyclophosphamide-treated Japanese breast cancer patients.