Discovery of Novel N-Substituted Oxindoles as Selective M1 and M4 Muscarinic Acetylcholine Receptors Partial Agonists

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Spinal imaging features in Japanese patients with Marfan syndrome: a case-control study

Purpose

The purpose of our study was to evaluate the morphology of the lumbosacral spine, i.e. the dura and vertebral body shape, of Japanese patients with Marfan syndrome (MFS) by comparing it with sex- and age-matched controls.

Materials and methods

Spinal MR or CT images of 32 MFS patients and 32 controls were retrospectively reviewed. The anteroposterior dural sac diameter (DSD), anteroposterior vertebral body diameter (VBD), and vertebral body height (VBH) were measured from L1 to S1 levels and the dural sac ratio [DSR = (DSD/VBD)] and vertebral body aspect ratio [VAR = (VBH/VBD)] were calculated.

Results

At each level, mean DSD and DSR were significantly higher in MFS patients; VBD was not. The cutoff values for DSR to differentiate between MFS patients and the controls were 0.59, 0.46, 0.42, 0.45, 0.47, and 0.47 from the level of L1 to S1. At a sensitivity of 93.8 % and a specificity of 84.4 % the cutoff value at S1 was most diagnostic. In MFS patients VAR was significantly higher at L3 and L4.

Conclusion

Our cutoff value for DSR >0.47 at S1 may help to identify MFS in the Japanese population. A square-like appearance of the L3 and L4 vertebral bodies is a supplementary finding in MFS patients.     

IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment

Insulin-like growth factor binding protein 3 (IGFBP3), a hypoxia-inducible gene, regulates a variety of cellular processes including cell proliferation, senescence, apoptosis and epithelial-mesenchymal transition (EMT). IGFBP3 has been linked to the pathogenesis of cancers. Most previous studies focus upon proapoptotic tumor suppressor activities of IGFBP3. Nevertheless, IGFBP3 is overexpressed in certain cancers including esophageal squamous cell carcinoma (ESCC), one of the most aggressive forms of squamous cell carcinomas (SCCs). The tumor-promoting activities of IGFBP3 remain poorly understood in part due to a lack of understanding as to how the tumor microenvironment may influence IGFBP3 expression and how IGFBP3 may in turn influence heterogeneous intratumoral cell populations. Here, we show that IGFBP3 overexpression is associated with poor postsurgical prognosis in ESCC patients. In xenograft transplantation models with genetically engineered ESCC cells, IGFBP3 contributes to tumor progression with a concurrent induction of a subset of tumor cells showing high expression of CD44 (CD44H), a major cell surface receptor for hyaluronic acid, implicated in invasion, metastasis and drug resistance. Our gain-of-function and loss-of-function experiments reveal that IGFBP3 mediates the induction of intratumoral CD44H cells. IGFBP3 cooperates with hypoxia to mediate the induction of CD44H cells by suppressing reactive oxygen species (ROS) in an insulin-like growth factor-independent fashion. Thus, our study sheds light on the growth stimulatory functions of IGFPB3 in cancer, gaining a novel mechanistic insight into the functional interplay between the tumor microenvironment and IGFBP3.     

Effect of screening mammography on cumulative survival of Japanese women aged 40–69 years with breast cancer

Background

The effectiveness of screening mammography (MMG) has mainly been demonstrated by studies in western countries. This study was conducted to evaluate cumulative survival and the risk of breast cancer death among Japanese women aged 40–69 years with screening-detected and interval breast cancer divided into three groups: MMG with clinical breast examination (CBE), CBE alone, and self-detection.

Methods

By matching a list of 126,537 women (358,242 person-screenings) who participated in the Miyagi Cancer Society Screening program between 1 April 1995 and 31 December 2002 with the Miyagi Prefectural Cancer Registry, 429 MMG with CBE, 522 CBE, and 3,047 self-detected cases were included in this study. Follow-up was performed until the date of death or 31 December 2007. Survival was estimated by the Kaplan–Meier method. The Cox proportional hazards model was used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for breast cancer death.

Results

Five-year survival for women in the MMG with CBE, CBE, and self-detection groups was 96.8, 92.7, and 86.6 %, respectively. The HR (95 % CI) for breast cancer death was 2.38 (0.72–7.94) among CBE-screened and 4.44 (1.42–13.89) among self-detected cases for women aged 40–49 years, but was 3.00 (1.63–5.50) among CBE-screened and 4.51 (2.69–7.56) among self-detected cases for women aged 50–69 years relative to cases screened by use of MMG with CBE.

Conclusions

In terms of the survival and risk of breast cancer death, MMG with CBE may be more effective than MMG alone or self-detection for Japanese women aged 40–69 years.     

Bortezomib therapy‐related lung disease in Japanese patients with multiple myeloma: Incidence,mortality and clinical characterization

Because of the potentially high mortality rate (6.5%) associated with bortezomib‐induced lung disease (BILD) in Japanese patients with relapsed or refractory multiple myeloma, we evaluated the incidence, mortality and clinical features of BILD in a Japanese population. This study was conducted under the Risk Minimization Action Plan (RMAP), which was collaboratively developed by the pharmaceutical industry and public health authority. The RMAP consisted of an intensive dissemination of risk information and a recommended countermeasure to health‐care professionals. All patients treated with bortezomib were consecutively registered in the study within 1 year and monitored for emerging BILD. Of the 1010 patients registered, 45 (4.5%) developed BILD, 5 (0.50%) of whom had fatal cases. The median time to BILD onset from the first bortezomib dose was 14.5 days, and most of the patients responded well to corticosteroid therapy. A retrospective review by the Lung Injury Medical Expert Panel revealed that the types with capillary leak syndrome and hypoxia without infiltrative shadows were uniquely and frequently observed in patients with BILD compared with those with conditions associated with other molecular‐targeted anticancer drugs. The incidence rate of BILD in Japan remains high compared with that reported in other countries, but the incidence and mortality rates are lower than expected before the introduction of bortezomib in Japan. This study describes the radiographic pattern and clinical characterization of BILD in the Japanese population. The RMAP seemed clinically effective in minimizing the BILD risk among our Japanese population.     

Clinicopathological and prognostic impact of imaging of breast cancer angiogenesis and hypoxia using diffuse optical spectroscopy

Near‐infrared diffuse optical spectroscopy (DOS) imaging can non‐invasively measure tumor hemoglobin concentration using high contrast to normal tissue, thus providing vascularity and oxygenation status. We assessed the clinical usefulness of DOS imaging in primary breast cancer. In all, 118 women with a histologically confirmed diagnosis of primary malignant tumor were enrolled. All participants underwent testing using time‐resolved DOS before treatment initiation. Visual assessment of DOS imaging for detecting tumors was carried out by two readers blinded to the clinical data. Relative total hemoglobin (rtHb) and oxygen saturation (stO₂) of the tumors was compared with clinicopathological variables and 10‐year prognosis was calculated. Sensitivity for detecting a tumor based on the rtHb breast map was 62.7% (74/118). The sensitivity depended on T stage: 100% (7/7) for T3, 78.9% (45/57) for T2, 44.7% (17/38) for T1, and 31.3% (5/16) for T_is. Tumors showed unique features of higher rtHb with a wider range of stO₂ than normal breast tissue, depending on histological type. There was a significant correlation of rtHb with tumor size, lymphatic vascular invasion, and histological grade, and of stO₂ with age and tumor size. Neither rtHb nor stO₂ correlated with intrinsic biomarkers such as estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2; rtHb inversely correlated with 10‐year relapse‐free survival and overall survival, with statistical significance. Diffuse optical spectroscopy imaging has limited utility for the early detection of breast cancer; nonetheless, the findings suggest that the degree of tumor angiogenesis and hypoxia may be associated with tumor aggressiveness and poor prognosis.     

Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway‐induced resistance to vascular endothelial growth factor receptor inhibitor

Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF‐induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted.     

A PCR-based protocol for generating West Nile virus replicons

A new protocol for the generation of West Nile virus (WNV) replicons was developed. Fragmented cDNAs that covered the entire WNV RNA sequence, except the sequence corresponding to nucleotides 190-2379, were amplified separately by polymerase chain reactions (PCRs) using primer set franking with overlapping sequences of 40-50 bp at the 5'- and the 3'-ends of each fragment. All amplified fragments were mixed together and annealed to each other at the overlapping sequences. The annealed-DNA fragments were elongated by DNA polymerase and amplified by short-cycle PCRs to generate full-sized WNV replicon cDNAs. The WNV replicons were transcribed in vitro using the replicon cDNAs as templates. When the in vitro-transcribed replicon was introduced into mammalian cells, the viral envelope protein and viral positive- and negative-strand RNAs were detected in the replicon-transfected cells. It is noteworthy that the synthesis of the replicon cDNAs and the replicons took just 1 week, and that the use of a high-fidelity DNA polymerase afforded stability to the sequence of the synthetic replicon.     

Salivary duct carcinoma cytologically diagnosed distinctly from salivary gland carcinomas with squamous differentiation

It has been difficult cytologically to distinguish salivary duct carcinoma (SDC) from high-grade carcinoma. We investigated the microscopic cytological findings, morphometric image analyses, and immunohistochemical features of SDC, focusing on how we achieved an accurate differential diagnosis distinguishing SDC from salivary gland carcinomas with squamous differentiation. Immunohistochemical staining was performed for androgen receptor (AR), gross cystic disease fluid protein-15 (GCDFP15), mammaglobin, human gastric mucin, MUC1, MUC2, p63, and cytokeratin high molecular weight. Of the 13 cases of SDC, 9 cases showed typical cytological findings of sheet clusters with polygonal granular cytoplasm with fine chromatin. The other 4 cases showed unusual cytological findings of a pseudo-papillary cluster or scattered cells only, and the tumor cells showed coarse chromatin. Morphometric image analysis showed that the nucleus area was statistically different between SDC and salivary gland carcinomas with squamous differentiation. AR-positive expression (P = 0.008), GCDFP15-positive expression (P = 0.005) and p63-negative expression (P = 0.001) were effective as SDC-specific markers in immunohistochemistry. An accurate cytological diagnosis of SDC can be determined by immunostaining with AR, GCDFP15, and p63, based on the nuclear findings.