Chemotherapy effects on bone mineral density and microstructure in women with breast cancer.

INTRODUCTION: Chemotherapy involves the administration of steroids to prevent nausea and vomiting; however, its effect on bone microstructure remains unknown. This study aimed to evaluate the changes in bone mineral density (BMD) and bone microstructure associated with chemotherapy using high-resolution peripheral quantitative computed tomography (HR-pQCT) in women with early breast cancer. MATERIALS AND METHODS: This prospective single-arm observational study included non-osteoporotic, postmenopausal women with breast cancer. The patients underwent dual-energy X-ray absorptiometry (DXA), HR-pQCT, and tartrate-resistant acid phosphatase-5b (TRACP-5b) or procollagen type-I N-terminal propeptide (P1NP) measurements at baseline, end of chemotherapy, and 6 months after chemotherapy. The primary endpoint was the change in total volumetric BMD at the distal tibia and radius. RESULTS: Eighteen women were included in the study (median age: 57 years; range: 55-62 years). At 6 months after chemotherapy, HR-pQCT indicated a significant decrease in total volumetric BMD (median: distal tibia -4.5%, p < 0.01; distal radius -2.3%, p < 0.01), cortical volumetric BMD (-1.9%, p < 0.01; -0.8%, p = 0.07, respectively), and trabecular volumetric BMD (-1.1%, p = 0.09; -3.0%, p < 0.01, respectively). The DXA BMD also showed a significant decrease in the lumbar spine (median: -4.5%, p < 0.01), total hip (-5.5%, p < 0.01), and femoral neck (-4.2%, p < 0.01). TRACP-5b and P1NP levels were significantly increased at the end of chemotherapy compared to baseline. CONCLUSION: Postmenopausal women undergoing chemotherapy for early breast cancer experienced significant BMD deterioration in weight-bearing bone, which was further reduced 6 months after chemotherapy.

TERT promoter mutations increase tumor aggressiveness by altering TERT mRNA splicing in papillary thyroid carcinoma.

CONTEXT: Telomerase reverse transcriptase promoter (TERT-p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT-p mutations, but such tumors show less aggressiveness and better prognosis compared with TERT-p mutation-positive tumors. OBJECTIVE: TERT has multiple splicing variants whose relationships with the TERT-p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT-p mutational status, the TERT splicing pattern, and clinicopathological features. METHODS: We investigated the expression of two major variants, α deletion (dA) and ß deletion (dB), in a series of 207 PTCs operated between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital. RESULTS: The TERT-p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into three groups: the TERT-p mutation-negative/expression-negative group (mut-/exp-), the TERT-p mutation-negative/expression-positive group (mut-/exp+), and the TERT-p mutation-positive group (mut+/exp+). The +A + B/dB ratio in mut+/exp + was significantly higher than that in mut-/exp + PTCs. Analysis with clinicopathological data revealed that +A + B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor suppressive role. CONCLUSION: These results provide evidence that the TERT-p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness.

Simultaneous bilateral mastectomy and RRSO for BRCA2-positive non-invasive breast cancer in Japan: a case report and analysis of initial experience.

BACKGROUND: In Japan, genetic testing, surveillance, and risk-reducing surgery for hereditary breast and ovarian cancer (HBOC) syndrome have been covered by the Japanese national insurance system since April 2020. On the other hand, the current situation is that medical care, including surveillance of undiagnosed (cancer-free) patients, is self-funded even for individuals with HBOC. We report a case in which breast cancer was diagnosed at an early stage during surveillance for cancer-free HBOC at the patient's own expense, and risk-reducing surgery was performed at the same time as treatment for breast cancer. CASE PRESENTATION: The patient was a 63-year-old woman. Her sister had a history of breast cancer in her 30s and was found to be a BRCA2 pathogenic variant carrier by genetic testing. The patient therefore presented to the genetic department of our hospital and underwent genetic testing (out-of-pocket). A pathogenic variant was found at the same site. During annual breast and ovarian surveillance at the patient's own expense, a physician with sufficient expertise in contrast-enhanced breast magnetic resonance imaging (MRI) noticed a change in the contrast enhancement pattern on breast MRI and performed needle biopsy, revealing ductal carcinoma in situ. At the request of the patient, she underwent concurrent contralateral risk-reducing mastectomy and risk-reducing salpingo-oophorectomy in addition to breast cancer treatment. CONCLUSIONS: We encountered a case in which cancer treatment and risk-reducing surgery were performed at the same time for a pathogenic variant carrier who was very anxious about developing cancer. Surveillance of cancer-free BRCA1/2 mutation carriers and expansion of insurance coverage for surgery are important future issues.

Resting phase-administration of lemborexant ameliorates sleep and glucose tolerance in type 2 diabetic mice.

Sleep disorders are associated with increased risk of obesity and type 2 diabetes. Lemborexant, a dual orexin receptor antagonist (DORA), is clinically used to treat insomnia. However, the influence of lemborexant on sleep and glucose metabolism in type 2 diabetic state has remained unknown. In the present study, we investigated the effect of lemborexant in type 2 diabetic db/db mice exhibiting both sleep disruption and glucose intolerance. Single administration of lemborexant at the beginning of the light phase (i.e., resting phase) acutely increased total time spent in non-rapid eye movement (NREM) and REM sleep in db/db mice. Durations of NREM sleep-, REM sleep-, and wake-episodes were also increased by this administration. Daily resting-phase administration of lemborexant for 3-6 weeks improved glucose tolerance without changing body weight and glucose-stimulated insulin secretion in db/db mice. Similar improvement of glucose tolerance was caused by daily resting-phase administration of lemborexant in obese C57BL/6J mice fed high fat diet, whereas no such effect was observed in non-diabetic db/m+ mice. Diabetic db/db mice treated daily with lemborexant exhibited increased locomotor activity in the dark phase (i.e., awake phase), although they did not show any behavioral abnormality in the Y-maze, elevated plus maze, and forced swim tests. These results suggest that timely promotion of sleep by lemborexant improved the quality of wakefulness in association with increased physical activity during the awake phase, and these changes may underlie the amelioration of glucose metabolism under type 2 diabetic conditions.

Impact of spinal surgery on locomotive syndrome in patients with lumbar spinal stenosis in clinical decision limit stage 3: a retrospective study.

BACKGROUND: Locomotive syndrome (LS) is characterized by reduced mobility. Clinical decision limit (CDL) stage 3 in LS indicates physical frailty. Lumbar spinal canal stenosis (LSS) is one of the causes of LS, for which lumbar surgery is considered to improve the CDL stage. This study aimed to investigate the efficacy of lumbar surgery and independent factors for improving the CDL stage in patients with LSS. METHODS: This retrospective study was conducted at the Department of Orthopaedic Surgery at our University Hospital. A total of 157 patients aged ≥ 65 years with LSS underwent lumbar surgery. The 25-Question Geriatric Locomotive Function scale (GLFS-25) was used to test for LS, and the Timed Up and Go test (TUG) was used to evaluate functional ability. Lower limb pain was evaluated using a visual analog scale. Patients with at least one improvement in the CDL stage following lumbar surgery were included in the improvement group. Differences in lower limb pain intensity between the groups were evaluated using the Wilcoxon rank-sum test. The Spearman's rank correlation coefficient was used to determine correlations between Δ lower limb pain and Δ GLFS-25. Logistic regression analysis was used to identify factors associated with improvement in LS. RESULTS: The proportion of patients with improved CDL stage was 45.1% (improvement/non-improvement: 32/39). Δ Lower limb pain was significantly reduced in the improvement group compared with that in the non-improvement group (51.0 [36.3-71.0] vs 40.0 [4.0-53.5]; p = 0.0107). Δ GLFS-25 was significantly correlated with Δ lower limb pain (r = 0.3774, p = 0.0031). Multiple logistic regression analysis revealed that TUG and age were significantly associated with improvement in LS (odds ratio, 1.22; 95% confidence interval: 1.07-1.47). CONCLUSIONS: Lumbar surgery effectively improved the CDL stage in patients with LSS. In addition, TUG was an independent factor associated with improvement in the CDL.

EFFICACY AND SAFETY OF A DEXAMETHASONE-BASED MOUTHWASH TO PREVENT CHEMOTHERAPY-INDUCED STOMATITIS IN WOMEN WITH BREAST CANCER: A MULTICENTRE, OPEN-LABEL, RANDOMISED PHASE 2 STUDY.

PURPOSE: No standard approach other than oral care is available for preventing chemotherapy-induced stomatitis in patients with breast cancer. In this randomized, controlled phase 2 trial, we aimed to assess the efficacy and safety of a dexamethasone-based mouthwash in preventing chemotherapy-induced stomatitis in patients with early breast cancer. BASIC PROCEDURES: Patients with breast cancer scheduled for epirubicin and cyclophosphamide (EC) or docetaxel and cyclophosphamide (TC) therapy were selected and allocated in a 1:1 ratio to the intervention and control groups. The intervention group received chemotherapy, oral care, and a dexamethasone-based mouthwash, whereas the control group received chemotherapy and oral care. The primary endpoint was the incidence of stomatitis. This was a phase 2 study, and the significance level for the analysis of the primary endpoint was set a priori at 0.2. MAIN FINDINGS: Data pertaining to 58 patients in the control group and 59 patients in the intervention group were analyzed. Stomatitis incidence was 55% and 38% in the control and intervention groups, respectively (risk ratio, 0.68; 80% confidence interval, 0.52-0.88; P = .052). Stomatitis severity was lower in the intervention group than in the control group (P = .03). The proportion of patients who adhered to the mouthwash regimen was 87% (interquartile range, 67.8%-95.3%). No severe oral infections were observed. PRINCIPAL CONCLUSIONS: The dexamethasone-based mouthwash safely reduced stomatitis incidence and severity in patients receiving chemotherapy for early breast cancer. Phase 3 clinical trials are warranted for validating our results.

Phase angle is related to physical function and quality of life in preoperative patients with lumbar spinal stenosis.

Lumbar spinal stenosis (LSS) can interfere with daily life and quality of life (QOL). Evaluating physical function and QOL and helping patients to improve is the focus of rehabilitation. Phase angle (PhA) assessment is widely used to measure body composition and is considered an indicator of physical function and QOL. This study investigated the relationship between PhA and physical function, physical activity, and QOL in patients with LSS. PhA, handgrip strength, walking speed, Timed Up and Go test (TUG), Life Space Assessment (LSA), Prognostic Nutritional Index (PNI), Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), and EQ-5D were assessed and statistically analyzed. The study included 133 patients with LSS. Multiple regression analysis of PhA adjusted for age, sex, and body mass index (Model 1) and for Model 1 + PNI (Model 2) showed significant correlations (P < 0.05) with handgrip strength, walking speed, TUG, and LSA. Regarding QOL, PhA was significantly correlated (P < 0.05) with lumbar function in JOABPEQ. PhA was associated with physical function and QOL in patients with LSS and might be a new clinical indicator in this population.

Association of quantitative analysis of intratumoral reduced E-cadherin expression with lymph node metastasis and prognosis in patients with breast cancer.

Loss of E-cadherin expression is a poor prognostic factor in patients with breast cancer. Breast cancer cells co-cultured with adipocytes reportedly promote E-cadherin attenuation and tumor progression. The current study aimed to investigate the association of reduced E-cadherin expression with adipose tissue invasion (ATI) and prognosis in breast cancer. Surgical specimens were collected from 188 women with invasive ductal carcinoma of the breast who had undergone surgery without neoadjuvant treatment. We compared E-cadherin expression in ATI and invasive front (IF) using immunohistochemistry with ImageJ. Reduced E-cadherin expression was detected not only in the ATI area but also in the IF, and the degree of reduced E-cadherin expression was positively correlated with both areas. In patients with lymph node metastasis compared to those without, E-cadherin expression was reduced and this reduction was associated with poor recurrence-free survival. We concluded that E-cadherin expression is reduced not only at the ATI area but also at the IF of the tumor. Reduced E-cadherin expression is a clear prognostic factor for breast cancer. Hence, future research is warranted for establishing an objective and quantitative E-cadherin staining assay that will allow clinical use of E-cadherin as a prognostic factor.

A Survey of the Awareness and Educational Needs of Nurses in Nagasaki Prefecture Regarding Hereditary Breast and Ovarian Cancer.

The aim of this study was to evaluate the knowledge and educational needs with regard to hereditary breast and ovarian cancer among nurses working in breast cancer care in the Nagasaki Prefecture. In breast cancer care, the identification of patients at risk for hereditary breast and ovarian cancer is necessary for the implementation of genetic testing and counseling. Nurses should be involved in this process, since they play a crucial role in the care of patients with breast cancer. However, the knowledge regarding hereditary breast and ovarian cancer among nurses working in oncology care in Japan has not been assessed. The design of this study is cross-sectional design. We distributed 597 surveys to nurses working in breast cancer care. The surveys assessed the nurses' demographic data, their current knowledge and practices regarding cancer genetics and hereditary breast and ovarian cancer, and their attitude and preferences regarding learning about the condition. We received 317 valid replies. Nurses had limited knowledge about hereditary breast and ovarian cancer characteristics: 41.6% reported that they do not know about the condition, whereas less than 10% knew its characteristics. However, nurses were aware of hereditary breast and ovarian cancer significance and were willing to learn about it: 91% wished to learn about the condition, and 88.6% wanted to participate in study group meetings. Further, nurses' preferences regarding educational programs were clarified. Overall, our results show that educational programs should be implemented to advance nurses' knowledge of hereditary breast and ovarian cancer characteristics.

Development and evaluation of an original phantom model of ultrasonography-guided thyroid gland biopsy for the training of surgical residents and students.

PURPOSES: Fine-needle aspiration cytology (FNAC) is a specific and important test used for the diagnosis of thyroid gland cancer. We developed a thyroid gland phantom using original manufacturing techniques and direct three-dimensional (3D) printing. The aim of this study was to confirm the effectiveness of this phantom by collecting data to evaluate puncture training. METHODS: Data from 45 ultrasonography-guided thyroid nodule FNAC procedures performed on our thyroid phantom were evaluated in our department. The first group comprised qualified physicians who specialized in thyroid gland treatment (group A; n = 10). The second and third groups comprised senior and junior residents (group B; n = 8 and group C; n = 12; respectively). The fourth group comprised students (group D; n = 15). We measured the times taken by these groups to complete each task. RESULTS: The skills of all participants in groups B, C, and D improved after using this phantom involving the major (parallel)- (0.47 ± 0.07) and short (orthogonal)-axes (0.52 ± 0.07) methods (P < 0.001). The number of erroneous punctures decreased from 53 to 3. CONCLUSIONS: Our original phantom improved the puncture skills of students and junior doctors and was suitable as a tailored training model for practicing thyroid gland transfixion.

Severe thrombocytopenia and anemia as an initial presentation of breast cancer: A case report.

Breast cancer patients with bone marrow metastasis (BMM) having profound thrombocytopenia and anemia are rare and there is no definitive treatment guideline. We present a case of successful initial treatment with anti-disseminated intravascular coagulation therapy and endocrine therapy, followed by chemotherapy to avoid deterioration of severe thrombocytopenia and anemia.

An Evaluation of the Efficacy of Compression Therapy Using Sleeves and Stockings to Prevent Docetaxel-induced Peripheral Neuropathy in Breast Cancer Patients.

Taxanes are key drugs for patients with breast cancer. A major adverse effect of taxanes is peripheral neuropathy (PN). To investigate the ability of compression therapy using sleeves and stockings to prevent PN due to the taxane docetaxel, we conducted a single-center historical control trial. Patients receiving docetaxel at 75 mg/m2 every 3 weeks for 4 cycles as first-line chemotherapy for breast cancer were eligible. PN was evaluated using the common terminology criteria for adverse events version 4.0. The primary endpoint was the incidence of allgrade PN until 3 weeks after the fourth docetaxel administration. We evaluated 26 patients in the intervention group and compared their data to those collected retrospectively from 52 patients treated with docetaxel without compression. Neither the incidence of all-grade PN until 3 weeks after the fourth docetaxel administration (63.5% in the control group vs. 76.9% in the intervention group, p=0.31) nor that of PN grade ≥ 2 (13.5% vs. 15.4%, p=0.99) differed between the groups. In this study, the efficacy of compression therapy using sleeves and stockings to prevent PN induced by docetaxel was not demonstrated. Further clinical studies including medications or intervention are needed to reduce the incidence and severity of PN induced by chemotherapy.

Food odor perception promotes systemic lipid utilization.

Food cues during fasting elicit Pavlovian conditioning to adapt for anticipated food intake. However, whether the olfactory system is involved in metabolic adaptations remains elusive. Here we show that food-odor perception promotes lipid metabolism in male mice. During fasting, food-odor stimulation is sufficient to increase serum free fatty acids via adipose tissue lipolysis in an olfactory-memory-dependent manner, which is mediated by the central melanocortin and sympathetic nervous systems. Additionally, stimulation with a food odor prior to refeeding leads to enhanced whole-body lipid utilization, which is associated with increased sensitivity of the central agouti-related peptide system, reduced sympathetic activity and peripheral tissue-specific metabolic alterations, such as an increase in gastrointestinal lipid absorption and hepatic cholesterol turnover. Finally, we show that intermittent fasting coupled with food-odor stimulation improves glycemic control and prevents insulin resistance in diet-induced obese mice. Thus, olfactory regulation is required for maintaining metabolic homeostasis in environments with either an energy deficit or energy surplus, which could be considered as part of dietary interventions against metabolic disorders.

Human antibody recognition and neutralization mode on the NTD and RBD domains of SARS-CoV-2 spike protein.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). Variants of concern (VOCs) such as Delta and Omicron have developed, which continue to spread the pandemic. It has been reported that these VOCs reduce vaccine efficacy and evade many neutralizing monoclonal antibodies (mAbs) that target the receptor binding domain (RBD) of the glycosylated spike (S) protein, which consists of the S1 and S2 subunits. Therefore, identification of optimal target regions is required to obtain neutralizing antibodies that can counter VOCs. Such regions have not been identified to date. We obtained 2 mAbs, NIBIC-71 and 7G7, using peripheral blood mononuclear cells derived from volunteers who recovered from COVID-19. Both mAbs had neutralizing activity against wild-type SARS-CoV-2 and Delta, but not Omicron. NIBIC-71 binds to the RBD, whereas 7G7 recognizes the N-terminal domain of the S1. In particular, 7G7 inhibited S1/S2 cleavage but not the interaction between the S protein and angiotensin-converting enzyme 2; it suppressed viral entry. Thus, the efficacy of a neutralizing mAb targeting inhibition of S1/2 cleavage was demonstrated. These results suggest that neutralizing mAbs targeting blockade of S1/S2 cleavage are likely to be cross-reactive against various VOCs.

Prognosis of asymptomatic versus symptomatic metastatic breast cancer: a multicenter retrospective study.

In Japan, asymptomatic metastatic breast cancer (MBC) is often detected using tumor markers or imaging tests. We aimed to investigate differences in clinicopathological features, prognosis, and treatment between asymptomatic and symptomatic MBCs. Patients with MBC were retrospectively divided into asymptomatic and symptomatic groups to compare their prognosis by breast cancer subtype: luminal, human epidermal growth factor receptor 2 positive, and triple negative. Of 204 patients with MBC (114 asymptomatic, 90 symptomatic), the symptomatic group had a higher frequency of multiple metastatic sites and TN subtype. All cohorts in the asymptomatic group tended to or had longer post-recurrence survival (PRS) than those in the symptomatic group. In contrast, all cohorts and TN patients in the asymptomatic group tended to have or had longer overall survival (OS) than those in the symptomatic group, although no significant difference was observed in the luminal and HER2 subtypes. In the multivariate analysis, TN, recurrence-free survival, multiple metastatic sites, and symptomatic MBC were independently predictive of PRS. Regarding the luminal subtype, the asymptomatic group had longer chemotherapy duration than the symptomatic group, with no significant difference in OS between the groups. Asymptomatic and symptomatic MBCs differ in terms of subtypes and prognosis, and whether they require different treatment strategies for each subtype warrants further investigation.

Monoclonal antibody therapeutics for infectious diseases: Beyond normal human immunoglobulin.

Antibody therapy is effective for treating infectious diseases. Due to the coronavirus disease 2019 (COVID-19) pandemic and the rise of drug-resistant bacteria, rapid development of neutralizing monoclonal antibodies (mAbs) to treat infectious diseases is urgently needed. Using a therapeutic human mAb with the lowest immunogenicity is recommended, because chimera and humanized mAbs are occasionally immunogenic. In order to directly obtain naïve human mAbs, there are three methods: phage display, B cell receptor (BCR) cDNA sequencing of a single cell, and antibody-encoding gene and amino acid sequencing of immortalized cells using memory B cells, which are isolated from human peripheral blood mononuclear cells of healthy, vaccinated, infected, or recovered individuals. After screening against the antigen and performing neutralization assays, a human neutralizing mAb is constructed from the antibody-encoding DNA sequences of these memory B cells. This review describes examples of obtaining human neutralizing mAbs against various infectious diseases using these methods. However, a few of these mAbs have been approved for therapy. Therefore, antigen characterization and evaluation of neutralization activity in vitro and in vivo are indispensable for the development of therapeutic mAbs. These results will accelerate the development of antibody drug as therapeutic agents.

Lymphedema After Axillary Lymph Node Dissection in Breast Cancer: Prevalence and Risk Factors-A Single-Center Retrospective Study.

Background: Lymphedema may develop when axillary lymph node dissection (ALND) injures and obstructs the lymph ducts in the upper limb. In patients with breast cancer, lymphedema is difficult to treat and can cause arm swelling, heaviness, and restricted movement. We aimed to identify the prevalence and risk factors for lymphedema after ALND in patients with breast cancer. Methods and Results: This retrospective study included 175 patients with breast cancer who underwent ALND in the Nagasaki University Hospital, Japan, between 2005 and 2018. Lymphedema was defined as symptomatic arm swelling with a >2-cm difference in the arm circumference between the affected and contralateral arms. Patients were divided into two groups according to the presence or absence of lymphedema. Surgical and pathological findings were compared between the two groups. Univariate and multivariate analyses were performed, including the chi-square test, Student's t-test, and logistic regression analysis. Lymphedema was prevalent in 20% of the study participants, and the mean time interval from surgery to development of lymphedema was 479 days. In the univariate analysis, a body mass index of >26 kg/m2, smoking, radiotherapy (RT), and dissection of >18 axillary lymph nodes (ALNs) significantly increased the risk of lymphedema. In the multivariate analysis, smoking, RT, and dissection of >18 ALNs significantly increased the risk of lymphedema. Conclusions: The prevalence of lymphedema in our study was 20%. Our findings suggest that smoking, RT, and dissection of >18 ALNs are risk factors for lymphedema. Aggressive and empiric ALND might be associated with axillary lymph duct damage.

Optimization of anti-ADAMTS13 antibodies for the treatment of ADAMTS13-related bleeding disorder in patients receiving circulatory assist device support.

ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motif 13)-related bleeding disorder has been frequently observed as a life-threatening clinical complication in patients carrying a circulatory assist device. Currently, treatment modalities for the bleeding disorder are very limited and not always successful. To address the unmet medical need, we constructed humanized antibodies of mouse anti-ADAMTS13 antibody A10 (mA10) by using complementarity-determining region (CDR) grafting techniques with human antibody frameworks, 8A7 and 16E8. The characteristics of the two humanized A10 antibodies, namely A10/8A7 and A10/16E8, were assessed in vitro and in silico. Among the two humanized A10 antibodies, the binding affinity of A10/16E8 to ADAMTS13 was comparable to that of mA10 and human-mouse chimeric A10. In addition, A10/16E8 largely inhibited the ADAMTS13 activity in vitro. The results indicated that A10/16E8 retained the binding affinity and inhibitory activity of mA10. To compare the antibody structures, we performed antibody structure modeling and structural similarity analysis in silico. As a result, A10/16E8 showed higher structural similarity to mA10, compared with A10/8A7, suggesting that A10/16E8 retains a native structure of mA10 as well as its antigen binding affinity and activity. A10/16E8 has great potential as a therapeutic agent for ADAMTS13-related bleeding disorder.

Novel neutralizing human monoclonal antibodies against tetanus neurotoxin.

Tetanus is a fatal disease caused by tetanus neurotoxin (TeNT). TeNT is composed of a light chain (Lc) and a heavy chain, the latter of which is classified into two domains, N-terminus Hn and C-terminus Hc. Several TeNT-neutralizing antibodies have been reported, but it remains unclear which TeNT domains are involved in neutralization. To further understand the mechanism of these antibodies, we isolated TeNT-reactive human antibody clones from peripheral blood mononuclear cells. We then analyzed the reactivity of the isolated antibody clones to each protein domain and their inhibition of Hc-ganglioside GT1b binding, which is critical for TeNT toxicity. We also investigated the TeNT-neutralizing ability of isolated antibody clones and showed that an Hn-reactive clone protected strongly against TeNT toxicity in mice. Furthermore, combination treatment of Hn-reactive antibody clones with both Hc-reactive and TeNT mix (the mixture of Hc, Hn, and Lc proteins)-reactive antibody clones enhanced the neutralizing effect. These results indicated that antibody clones targeting Hn effectively neutralized TeNT. In addition, the use of a cocktail composed of Hc-, Hn-, and TeNT mix-reactive antibodies provided enhanced protection compared to the use of each antibody alone.

Adjuvant endocrine therapy effects on bone mineral density and microstructure in women with breast cancer.

INTRODUCTION: Although aromatase inhibitors (AIs) are typical drugs for cancer treatment-induced bone loss, their effects on the bone microstructure remain unclear. In this study, we evaluated changes in the bone mineral density (BMD) and bone microstructure associated with AI treatment using high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with early breast cancer. MATERIALS AND METHODS: This prospective, single-arm, observational study included non-osteoporotic, postmenopausal women with hormone receptor-positive breast cancer. Patients underwent dual-energy X-ray absorptiometry (DXA), HR-pQCT, and tartrate-resistant acid phosphatase-5b (TRACP-5b) or procollagen type-I N-terminal propeptide measurements at baseline and 6 and 12 months after AI therapy. The primary endpoint was changes in the total volumetric BMD (Tt.vBMD), trabecular vBMD (Tb.vBMD), and cortical vBMD (Ct.vBMD) longitudinally at the distal radius and tibia. RESULTS: Twenty women were included (median age 57.5 years; range 55-72 years). At 12 months, HR-pQCT indicated a significant decrease in the Tt.vBMD (median distal radius - 5.3%, p < 0.01; distal tibia - 3.2%, p < 0.01), Tb.vBMD (- 3.2%, p < 0.01; - 1.0%, p < 0.05, respectively), and Ct.vBMD (- 3.2%, p < 0.01; - 2.7%, p < 0.01, respectively). Estimated bone strength was also significantly decreased. The DXA BMD value in the total hip (p < 0.01) and femoral neck (p = 0.03), but not in the lumbar spine, was significantly decreased. The TRACP-5b levels was significantly negatively associated with changes in the Tt.vBMD in both the distal radius and tibia (r =  - 0.53, r =  - 0.47, respectively) CONCLUSION: Postmenopausal women who received AIs for early breast cancer experienced significant trabecular and cortical bone deterioration and a decrease in estimated bone strength within only 1 year.