[Three Cases of Appendiceal Goblet Cell Adenocarcinoma in Our Institution].

Appendiceal goblet cell adenocarcinoma(AGCA)is a newly designated pathological term adopted in the 5th edition of the WHO classification. It is synonymous with goblet cell carcinoid, which was previously categorized as a part of appendiceal carcinoid. However, since 2018, it has been classified as a subtype of adenocarcinoma. We have experienced 3 cases of this relatively rare tumor, of which 2 were initially diagnosed with acute appendicitis and were diagnosed with AGCA by pathological examination after an emergency appendectomy. Each of them underwent additional ileocolic resection with lymph node dissection as the second surgery. In the 3rd case, an appendiceal tumor was detected during preoperative examinations for an ovarian tumor. Staging laparoscopy revealed comorbid peritoneal dissemination, and only the appendix and right ovary were removed in the consecutive surgery. The ovarian tumor was pathologically diagnosed as a metastasis of AGCA. In this case, the introduction of oxaliplatin-based systemic chemotherapy after surgery achieved a complete response after more than 2 years. Although no recurrence has been observed in all 3 cases to date, AGCA is considered highly malignant compared to conventional appendiceal carcinoids. Therefore, it is crucial to practice multidisciplinary treatments, including sufficient radical surgery based on a precise diagnosis of AGCA, as is performed for advanced colorectal cancer.

A tailored tetravalent peptide displays dual functions to inhibit amyloid ß production and aggregation.

Inhibition of amyloid-ß peptide (Aß) accumulation in the brain is a promising approach for treatment of Alzheimer's disease (AD). Aß is produced by ß-secretase and γ-secretase in endosomes via sequential proteolysis of amyloid precursor protein (APP). Aß and APP have a common feature to readily cluster to form multimers. Here, using multivalent peptide library screens, we identified a tetravalent peptide, LME-tet, which binds APP and Aß via multivalent interactions. In cells, LME-tet-bound APP in the plasma membrane is transported to endosomes, blocking Aß production through specific inhibition of ß-cleavage, but not γ-cleavage. LME-tet further suppresses Aß aggregation by blocking formation of the ß-sheet conformation. Inhibitory effects are not observed with a monomeric peptide, emphasizing the significance of multivalent interactions for mediating these activities. Critically, LME-tet efficiently reduces Aß levels in the brain of AD model mice, suggesting it may hold promise for treatment of AD.

Site-specific amino acid D-isomerization of Tau R2 and R3 peptides changes the fibril morphology, resulting in attenuation of Tau aggregation inhibitor potency.

Tau, a microtubule-binding protein, is a major component of neurofibrillary tangles in the brains of Alzheimer's disease patients. Tau aggregation following fibril formation induces Alzheimer's disease pathogenesis. The accumulation of D-isomerized amino acids in proteins that occurs in several tissues with aging is thought to be implicated in age-related diseases. D-isomerized Asp accumulation has also been found in Tau in neurofibrillary tangles. We previously demonstrated the effects of D-isomerization of Asp within microtubule-binding repeat peptides of Tau, Tau R2, and R3 on the rates of structural transition and fibril formation. Here, we investigated the potency of Tau aggregation inhibitors on fibril formation of wild-type Tau R2 and R3 peptides and D-isomerized Asp-containing Tau R2 and R3 peptides. D-isomerization of Asp within Tau R2 and R3 peptides attenuated the potency of inhibitors. We next investigated the fibril morphology of D-isomerized Asp-containing Tau R2 and R3 peptides by electron microscopy. D-isomerized Asp-containing Tau R2 and R3 fibrils showed significantly different fibril morphology from that of wild-type peptides. Our results indicate that D-isomerization of Asp within Tau R2 and R3 peptides affects fibril morphology, resulting in attenuation of the potency of Tau aggregation inhibitors.

Enhanced social reward response and anxiety-like behavior with downregulation of nucleus accumbens glucocorticoid receptor in BALB/c mice.

Social anhedonia is a psychological state with difficulty in experiencing pleasure from social interactions and is observed in various diseases, such as depressive disorders. Although the relationships between social reward responses and anxiety- and depression-like behaviors have remained unclear, a social reward conditioned place preference (SCPP) test can be used to analyze the rewarding nature of social interactions. To elucidate these relationships, we used 5-week-old male mice of AKR, BALB/c, and C57BL/6J strains and conducted behavioral tests in the following order: elevated plus-maze test (EPM), open field test (OFT), SCPP, saccharin preference test (SPT), and passive avoidance test. The nucleus accumbens of these mice were collected 24 hr after these behavioral tests and were used for western blotting to determine the levels of receptors for brain-derived neurotrophic factors and glucocorticoids. BALB/c mice displayed the highest levels of anxiety-like behavior in EPM and OFT as well as physical anhedonia-like behaviors in SPT. They also showed increased responses to social rewards and huddling behaviors in SCPP, with downregulated glucocorticoid receptor (GR). Regression analysis results revealed positive influences of anxiety- and physical anhedonia-like behaviors and expressions of GR on social reward responses. Collectively, temperament associated with anxiety and physical anhedonia may affect social reward responses, which possibly is influenced by the expression of GR that can modify these psychological traits.

Changes in the expression of annexin A1 in the anterior pituitary gland after ovariectomy in rats.

The expression of annexin A1 (ANXA1) is augmented by gonadotrophin releasing hormone (GnRH) in LßT2 gonadotroph. We examined the distribution of ANXA1 in the pituitary tissues and the effect of ovariectomy. ANXA1 was mainly stained on folliculostellate cell-like irregular shaped cells with extended process of adult female rats. Large gonadotroph, so called castration cells, appeared two weeks after the ovariectomy. ANXA1 in castration cells exists around cells although another GnRH responsive annexin, ANXA5, was apparent also in the cytoplasm. The pituitary expression of ANXA1 after ovariectomy was significantly higher than intact rats. These difference in tissue distribution of two annexins suggest ANXA1 and ANXA5 bear different physiological function in the gonadotroph under GnRH regulation.

Changes in the expressions of annexin A1, annexin A5, inhibin/activin subunits, and vitamin D receptor mRNAs in pituitary glands of female rats during the estrous cycle: correlation analyses among these factors.

Pituitary gonadotropin secretion is regulated by several pituitary factors as well as GnRH and ovarian hormones. To elucidate the regulatory mechanisms of pituitary gonadotropin secretions, we observed changes in the mRNA levels of pituitary factors, namely annexin A1 (Anxa1) and Anxa5, inhibin/activin subunits, follistatin (Fst), and vitamin D receptor (Vdr), in female rat pituitary glands during the estrous cycle. Additionally, levels of LHß subunit (Lhb), FSHß subunit (Fshb), and GnRH receptor (Gnrh-r) mRNA were examined. During proestrus, Anxa1, Anxa5, Vdr, and inhibin α-subunit (Inha) exhibited the lowest levels, while during estrus, activin ßB-subunit (Actbb), Lhb, and Gnrh-r were the lowest. Moreover, Fshb exhibited the highest value during metestrus, whereas Fst did not differ significantly. Correlation analyses revealed 16 statistically significant gene combinations. In particular, four combinations, namely Anxa5 and Inha, Anxa5 and Actbb, Inha and Vdr, and Inha and Actbb, were highly significant (P<0.0001), while four combinations, Anxa1 and Anxa5, Anxa1 and Vdr, Anxa5 and Vdr, and Lhb and Gnrh-r, were moderately significant (P<0.001). The remaining eight combinations that exhibited statistical significance were Anxa1 and Inha, Anxa1 and Actbb, Vdr and Actbb, Anxa1 and Fshb, Inha and Lhb, Actbb and Fshb, Actbb and Lhb, and Fst and Fshb (P<0.05). These results highlight strong correlations among Anxa1, Anxa5, Vdr, Inha, and Actbb, thereby suggesting that an interaction among ANXA1, ANXA5, and VDR may lead to further communications with inhibin and/or activin in the pituitary gland.

Activin A specifically suppresses the expression of annexin A5 mRNA and augments gonadotropin-releasing hormone stimulation of A1 expression in LßT2 gonadotrope cells.

Recently, we reported that gonadotropin-releasing hormone (GnRH) stimulates annexin A1 (Anxa1) and A5 (Anxa5) mRNA expression through the GnRH-receptor-mitogen-activated protein kinase cascade in LßT2 cells. As LßT2 cells respond to activin, we examined the effect of activin A on Anxa1 and a5 expression in LßT2 cells. Activin A (0.4 and 4 ng/mL) treatment decreased Anxa5 mRNA levels in a dose-dependent manner, but did not affect Anxa1 mRNA levels at concentrations up to 40 ng/mL. After activin A treatment (4 ng/mL), Anxa5 mRNA levels significantly decreased at 6 h, gradually declined until 24 h, and remained low until 48 h, whereas Anxa1 mRNA levels did not significantly change following treatment. Pretreatment with activin A for 24 h increased GnRH agonist (GnRHa)-induced Anxa1 increase by approximately 7-fold compared with GnRHa stimulation alone, but Anxa5 was not affected. As previously reported, these activin A treatments increased gonadotropin ß subunit and GnRH receptor mRNA levels and slightly decreased common α-glycoprotein subunit mRNA levels. Furthermore, we examined the effect of activin A on Nr4a3, which is repressed by ANXA5 and which reduces Fshb expression, and found that activin A augmented Nr4a3 expression and slightly decreased the GnRHa-induced increase in Nr4a3. These results suggest that in gonadotrope cells, the mechanism regulating Anxa1 and a5 expression is differentially coupled with activin A signal transduction. Activin A suppresses Anxa5 expression under increased Nr4a3 expression, whereas activin A and GnRH synergistically stimulate Anxa1 expression. These GnRH-inducible annexins may have different specific functions in gonadotropes.

Gonadotropin-releasing hormone stimulation of annexin A5 expression in the thymus of male rats.

As gonadotropin-releasing hormone (GnRH) is expressed in the thymus, its direct action on thymic cells, including thymic involution, has been suggested. Annexin A5 (ANXA5), a biomarker of GnRH, was used to determine whether GnRH affects the thymus of male rats. Immunohistochemistry showed positive reactions for ANXA5 in large medullary epithelial cells at 30 days of age, and the expression continued until 180 days of age. Organ culture of thymus pieces was performed to examine the direct action of a GnRH agonist (GnRHa) on the expression of Anxa5 and Gnrh mRNA. Thymus tissues obtained from male rats (40-60 days old) were cut into small pieces (2-3 mm3) and incubated for 3 hr with the GnRHa. The expression levels of Anxa5 and Gnrh mRNA were augmented by the GnRHa. Immunohistochemistry of these tissue fragments showed that ANXA5 expression was enhanced, especially in medullary epithelial cells. These results revealed that GnRH synthesis in the thymus could affect thymic epithelial cells after puberty.

An artificial intelligence-assisted diagnostic system improves the accuracy of image diagnosis of uterine cervical lesions.

The present study created an artificial intelligence (AI)-automated diagnostics system for uterine cervical lesions and assessed the performance of these images for AI diagnostic imaging of pathological cervical lesions. A total of 463 colposcopic images were analyzed. The traditional colposcopy diagnoses were compared to those obtained by AI image diagnosis. Next, 100 images were presented to a panel of 32 gynecologists who independently examined each image in a blinded fashion and diagnosed them for four categories of tumors. Then, the 32 gynecologists revisited their diagnosis for each image after being informed of the AI diagnosis. The present study assessed any changes in physician diagnosis and the accuracy of AI-image-assisted diagnosis (AISD). The accuracy of AI was 57.8% for normal, 35.4% for cervical intraepithelial neoplasia (CIN)1, 40.5% for CIN2-3 and 44.2% for invasive cancer. The accuracy of gynecologist diagnoses from cervical pathological images, before knowing the AI image diagnosis, was 54.4% for CIN2-3 and 38.9% for invasive cancer. After learning of the AISD, their accuracy improved to 58.0% for CIN2-3 and 48.5% for invasive cancer. AI-assisted image diagnosis was able to improve gynecologist diagnosis accuracy significantly (P<0.01) for invasive cancer and tended to improve their accuracy for CIN2-3 (P=0.14).

The expression of Annexin A1 and A5 mRNA by gonadotropin-releasing hormone in LßT2 gonadotrope cells.

Gonadotropin-releasing hormone (GnRH) stimulation of annexin A1 (ANXA1) and A5 (ANXA5) mRNA expression was analyzed in LßT2 gonadotrope cells. Quantitative polymerase chain reaction results showed that a GnRH analog (GnRHa) stimulated the expression of both ANXA1 and A5 mRNA with a peak at 12 h of incubation; however, ANXA1 mRNA was extremely stimulated (60 folds). Immunocytochemical analysis confirmed these findings. A GnRH antagonist inhibited the effect of GnRHa. ANXA1 and A5 mRNA levels were significantly increased by protein kinase C (PKC) activator (12-O-Tetradecanoylphorbol-13-acetate; TPA), but not by dibutyryl cAMP. GnRHa-stimulated induction of ANXA1 and A5 mRNA was inhibited by PKC (GF109203) and MEK inhibitors (PD98059). TPA increased ANXA1 and A5 mRNA expression in a dose-dependent manner (1 nM to 10 µM), while the extent of the increase was much greater in ANXA1. After stimulation with 10 nM or 1 µM TPA, ANXA1 and A5 mRNA levels were increased at 6 h. ANXA1 mRNA levels were higher in the 1 µM TPA than in the 10 nM TPA treatment, whereas 1 µM TPA did not show further stimulation of ANXA5 mRNA compared to 10 nM TPA. These results clearly show that ANXA1 mRNA expression is stimulated by GnRH through PKC like ANXA5, and the response of ANXA1 is much larger than that of ANXA5. A close relationship between these annexins and a significant role for ANXA1 in GnRH action at gonadotropes is suggested.

A Case of Rare Matrix-producing Triple-negative Breast Carcinoma for Which Drug Response in a Patient-derived Orthotopic Xenograft Mouse Model Was Correlated With Patient Response.

BACKGROUND: Matrix-producing breast carcinoma (MPBC) is a very rare and usually aggressive triple-negative breast cancer. We successfully established a patient-derived orthotopic xenograft (PDOX) model from a patient with MPBC and used it to study tumor sensitivity to various agents. CASE REPORT: A 40-year-old woman was diagnosed with MPBC with a triple-negative phenotype. Due to axillary lymph-node metastases found during radical mastectomy, the patient was subsequently treated with epirubicin, cyclophosphamide and paclitaxel. In addition, radiotherapy was directed to the chest wall and subclavicular fossa. A portion of the cancer tissue from the mastectomy was used to establish a PDOX nude-mouse model. The PDOX model was resistant to paclitaxel, bevacizumab, vinorelbine, cisplatinum and olaparib, and sensitive to eribulin. Metastases in mediastinal lymph nodes and the right ovary were observed in the patient 14 months after mastectomy. Thoracoscopic mediastinal lymph-node biopsy and laparoscopic oophorectomy were performed, and both confirmed breast-cancer metastasis. The patient was then treated with paclitaxel and bevacizumab but no response was observed, which correlated with the inability of these drugs to arrest tumor growth in the PDOX models of the patient's tumor. The patient was then given eribulin based on the PDOX-model result, but treatment had to be stopped because of rapid progression of metastasis into the cervical lymph nodes and thyroid gland. The patient was subsequently treated with atezolizumab and nab-paclitaxel. Unfortunately, the patient died of her cancer 8 months after recurrence. CONCLUSION: The present study demonstrates that the PDOX model of a patient's triple-negative MPBC accurately predicted that paclitaxel and bevacizumab would not arrest the patient's tumor growth. Eribulin may have been effective if administered at an earlier stage of the patient's cancer course. Drug-screening results from PDOX models should be used as early as possible in order to improve patient outcome.

Salmonella typhimurium A1-R Exquisitely Targets and Arrests a Matrix-producing Triple-negative Breast Carcinoma in a PDOX Model.

BACKGROUND/AIM: Triple-negative matrix-producing breast carcinoma (MPBC) is rare, recalcitrant, and highly aggressive. The present study aimed to determine the efficacy of tumor-targeting leucine-arginine auxotroph Salmonella typhimurium (S. typhimurium) A1-R on a triple-negative MPBC in a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX MPBC model was established in the left second mammary gland of nude mice by surgical orthotopic implantation (SOI). PDOX models were randomized into two groups when the tumor volume reached over 70 mm3: a control group (n=6); and a tumor-targeting S. typhimurium A1-R group (n=7), [intravenous (i.v.) injection of S. typhimurium A1-R via the tail vein, weekly, for two weeks]. All mice were sacrificed on day 14. Tumor volume and body weight were measured once per week. RESULTS: S. typhimurium A1-R exquisitely targeted and arrested the growth of the MPBC PDOX compared to the control group (p=0.017). CONCLUSION: S. typhimurium A1-R has future clinical potential for triple-negative MPBC patients.

Physicochemical characterization of the G51D mutation of α-synuclein that is responsible for its severe cytotoxicity.

Fibril formation and aggregation of α-synuclein are important for the pathogenesis of neurodegenerative disorders including Parkinson's disease. In familial Parkinson's disease, the G51D mutation of α-synuclein causes severe symptoms and rapid progression. α-Synuclein, an intrinsically disordered protein, was shown to adopt an α-helical tetrameric state that resists fibrillation and aggregation. Here, we isolated the stable dimeric state of recombinant wild-type (WT) α-synuclein and G51D α-synuclein protein. Using circular dichroism spectroscopy, we determined that the α-synuclein dimer and monomer structures were unfolded. The WT α-synuclein dimer was more resistant to fibril formation than the monomer. However, the fibril formation rate of the G51D α-synuclein dimer was similar to that of the G51D α-synuclein monomer. The fibril morphology and properties of the G51D α-synuclein monomer were different from those of the WT α-synuclein monomer and dimer and G51D α-synuclein dimer. Additionally, G51D α-synuclein monomer fibrils were more cytotoxic than other fibrils. Our findings indicate that the structural differences between G51D α-synuclein monomer fibrils and other fibrils are critically responsible for its severe neurotoxicity in familial Parkinson's disease.

Oral recombinant methioninase combined with paclitaxel arrests recalcitrant ovarian clear cell carcinoma growth in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

PURPOSE: Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX). METHODS: The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks. RESULTS: The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p < 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93). CONCLUSION: PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.

Co-implantation of Tumor and Extensive Surrounding Tissue Improved the Establishment Rate of Surgical Specimens of Human-Patient Cancer in Nude Mice: Toward the Goal of Universal Individualized Cancer Therapy.

BACKGROUND/AIM: The discovery of the nude mouse model enabled the experimental growth of human-patient tumors. However, the low establishment rate of tumors in nude and other immunodeficient strains of mice has limited wide-spread clinical use. MATERIALS AND METHODS: In order to increase the establishment rate of surgical specimens of patient tumors, we transplanted tumors to nude mice subcutaneously along with large amounts of surrounding tissue of the tumor. RESULTS: The new transplantation method increased the establishment rate in nude mice to 66% compared to the old method of implanting the surgical tumor specimen with surrounding tissue removed (14%). High stage and presence of metastasis in the patient donor are positively correlated to tumor engraftment in nude mice. CONCLUSION: The new method can potentially allow most cancer patients who undergo surgery or biopsy to have their own mouse model for drug-sensitivity testing.

The dynamic structure of Rab35 is stabilized in the presence of GTP under physiological conditions.

Rab proteins, a family of small guanosine triphosphatases, play key roles in intracellular membrane trafficking and the regulation of various cellular processes. As a Rab isoform, Rab35 is crucial for recycling endosome trafficking, cytokinesis and neurite outgrowth. In this report, we analyzed dynamic structural changes and physicochemical features of Rab35 in response to different external conditions, including temperature, pH, salt concentration and guanosine triphosphate (GTP), by circular dichroism (CD) spectroscopy. CD spectra revealed that the α-helix content of Rab35 varies under different conditions considerably. The addition of GTP increases the α-helix content of Rab35 when the temperature, pH and salt concentration match physiological conditions. The results suggest that the external environment affects the secondary structure of Rab35. In particular, the presence of GTP stabilized the α-helices of Rab35 under physiological conditions. These structural changes may translate to changes in Rab35 function and relate to its role in membrane trafficking.

Eribulin Regresses a Cisplatinum-resistant Rare-type Triple-negative Matrix-producing Breast Carcinoma Patient-derived Orthotopic Xenograft Mouse Model.

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. RESULTS: The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). CONCLUSION: Eribulin has clinical potential for triple-negative MPBC patients.

A Triple-negative Matrix-producing Breast Carcinoma Patient-derived Orthotopic Xenograft (PDOX) Mouse Model Is Sensitive to Bevacizumab and Vinorelbine, Regressed by Eribulin and Resistant to Olaparib.

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In this study, we determined drug sensitivity for a triple-negative MPBC, without BRCA mutations, in a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The MPBC PDOX model was established in the left 2nd mammary gland of nude mouse by implantation of the patient tumor using surgical orthotopic implantation (SOI). We randomized MPBC PDOX mice into 5 groups (n=5 mice/per treatment group) when the tumor volume reached 80 mm3: G1, control-no treatment; G2, bevacizumab [intra-peritoneal (i.p.), weekly, for 2 weeks]; G3, vinorelbine (i.p., weekly, for 2 weeks); G4, olaparib (oral., daily, for 2 weeks); G5, eribulin [intravenous (i.v.), weekly, for 2 weeks]. The mice in each treatment group were sacrificed on day 15. Tumor volume and body weight were measured once/week. RESULTS: The MPBC PDOX model was resistant to olaparib (p=0.22). The MPBC PDOX model treated with bevacizumab and vinorelbine showed significantly suppressed tumor growth compared to the untreated group (p=0.005 and 0.002, respectively). However, only eribulin regressed the tumor (p=0.0001). Eribulin was more effective than olaparib (p=0.0001), bevacizumab (p=0.0025) and vinorelbine (p=0.0061). CONCLUSION: Eribulin has clinical potential as treatment for triple-negative MPBC patients that are resistant to a PARP inhibitor such as olaparib.

Tumor-targeting Salmonella typhimurium A1-R overcomes nab-paclitaxel resistance in a cervical cancer PDOX mouse model.

PURPOSE: Cervical cancer is a recalcitrant disease. To help overcome this problem, we previously established a patient-derived orthotopic xenograft (PDOX) model of cervical cancer. In the previous study, we found the tumor to be resistant to nab-paclitaxal (nab-PTX). We also previously developed the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R). The aim of the present study was to investigate the efficacy of S. typhimurium A1-R to overcome nab-PTX resistance in the cervical cancer PDOX model. METHODS: Cervical-cancer tumor fragments were implanted orthotopically into the neck of the uterus of nude mice. The cervical-cancer PDOX models were randomized into the following four groups after the tumor volume reached 60 mm3: G1: untreated group; G2: nab-PTX (i.v., 10 mg/kg, biweekly, 3 weeks); G3: Salmonella typhimurium A1-R (i.v., 5 × 107 CFU/body, weekly, 3 weeks); G4: nab-PTX combined with Salmonella typhimurium A1-R (nab-PTX, 10 mg/kg, i.v., biweekly, 3 weeks; S. typhimurium A1-R, 5 × 107 CFU/body, i.v., weekly, 3 weeks). Each group comprised eight mice. All mice were sacrificed on day 22. Tumor volume was measured on day 0 and day 22. Body weight was measured twice a week. RESULTS: Nab-PTX and Salmonella typhimurium A1-R did not show significant efficacy as monotherapy compared to the control group (P = 0.564 and P = 0.120, respectively). In contrast, nab-PTX combined with Salmonella typhimurium A1-R significantly suppressed tumor growth compared to the untreated control group and nab-PTX group (P < 0.001 and P = 0.026, respectively). CONCLUSIONS: Salmonella typhimurium A1-R has potential future clinical application to overcome drug resistance in cervical cancer.

Effects of altering plantar flexion resistance of an ankle-foot orthosis on muscle force and kinematics during gait training.

Ankle-foot orthosis (AFO) can improve gait in stroke patients. Addition of plantar flexion resistance (PFR) can improve the first foot rocker function. However, the effect of changing the PFR on the ankle muscle force during gait training is unclear. This study aimed to determine the effect of changing the PFR of an AFO on spatiotemporal parameters (speed, bilateral step length, and cadence), peak angle of ankle plantar flexion and knee flexion, and muscle force (tibialis anterior [TA], medial head of the gastrocnemius [MGAS], and soleus) during early stance using a musculoskeletal model. Ten healthy adult men walked under five conditions: a no-AFO condition and PFR conditions 1-4. Spatiotemporal parameters and peak joint angles during the early stance phase were measured from experimental data, with muscle force estimated from simulations of a musculoskeletal model. Increasing the PFR of the AFO decreased TA muscle force and increased MGAS muscle force but had no influence on spatiotemporal parameters and joint angles. Adjustment of the PFR modifies the muscle force around the ankle, which can maximize the effect of AFO during gait training.