Quantifying and Mitigating Motor Phenotypes Induced by Antisense Oligonucleotides in the Central Nervous System.

Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogues, DNA induces the strongest motor phenotypes while 2'-substituted RNA modifications improve the tolerability of PS-ASOs. Reducing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile, but in some cases also reduces efficacy or duration of effect. We show that this acute toxicity is not mediated by major nucleic acid sensing immune pathways. Formulating ASOs with divalent ions before injection and avoiding phosphate-based buffers modestly improved tolerability through mechanisms at least partially distinct from reduced PS content. Overall, our work identifies and quantifies an understudied aspect of oligonucleotide toxicology in the CNS, explores its mechanism, and presents platform-level medicinal chemistry and formulation approaches that improve tolerability of this class of compounds.

Long-term estrogen-deprived estrogen receptor α-positive breast cancer cell migration assisted by fatty acid 2-hydroxylase.

The risk of breast cancer (BC) recurrence is high in postmenopausal women, though the underlying molecular mechanisms are not yet fully understood. We developed a long-term estrogen-deprived (LTED) cell line from MCF-7 cells, which we used as an in vitro model for aromatase inhibitor (AI)-resistant estrogen receptor α (ERα)-positive postmenopausal BC. We also describe the involvement of fatty acid 2-hydroxylase (FA2H) in the modulation of LTED cell migration. Small interfering RNA specific to FA2H (siFA2H) could reduce cell migration, whereas the introduction of plasmid expressing FA2H, but not its inactive mutant, resulted in enhanced migration. Moreover, proliferation of the LTED cells was not affected by modulation of FA2H expression. Fulvestrant (FUL), a selective estrogen receptor degrader used to treat AI-resistant ERα-positive postmenopausal BC, was found to induce degradation of ERα together with a decrease in ER-mediated transcription; however, FA2H protein expression and migration remained unchanged. Overall, the findings of this study suggest that FA2H is one of the drivers of LTED cell migration, and that LTED cells resistant to FUL therapy may be involved in malignancy and metastatic mechanisms.

Heteroduplex oligonucleotide technology boosts oligonucleotide splice switching activity of morpholino oligomers in a Duchenne muscular dystrophy mouse model.

The approval of splice-switching oligonucleotides with phosphorodiamidate morpholino oligomers (PMOs) for treating Duchenne muscular dystrophy (DMD) has advanced the field of oligonucleotide therapy. Despite this progress, PMOs encounter challenges such as poor tissue uptake, particularly in the heart, diaphragm, and central nervous system (CNS), thereby affecting patient's prognosis and quality of life. To address these limitations, we have developed a PMOs-based heteroduplex oligonucleotide (HDO) technology. This innovation involves a lipid-ligand-conjugated complementary strand hybridized with PMOs, significantly enhancing delivery to key tissues in mdx mice, normalizing motor functions, muscle pathology, and serum creatine kinase by restoring internal deleted dystrophin expression. Additionally, PMOs-based HDOs normalized cardiac and CNS abnormalities without adverse effects. Our technology increases serum albumin binding to PMOs and improves blood retention and cellular uptake. Here we show that PMOs-based HDOs address the limitations in oligonucleotide therapy for DMD and offer a promising approach for diseases amenable to exon-skipping therapy.

DNA/RNA heteroduplex technology with cationic oligopeptide reduces class-related adverse effects of nucleic acid drugs.

Antisense oligonucleotides (ASOs) are a therapeutic modality for incurable diseases. However, systemic injection of gapmer-type ASOs causes class-related toxicities, including prolongation of activated partial thromboplastin time (aPTT) and thrombocytopenia. We previously reported that cholesterol-conjugated DNA/RNA heteroduplex oligonucleotides (Chol-HDOs) exhibit significantly enhanced gene-silencing effects compared to ASOs, even in the central nervous system, by crossing the blood-brain barrier. In the present study, we initially evaluated the effect of the HDO structure on class-related toxicities. The HDO structure ameliorated the class-related toxicities associated with ASOs, but they remained to some extent. As a further antidote, we have developed artificial cationic oligopeptides, L-2,4-diaminobutanoic acid oligomers (DabOs), which bind to the phosphates in the major groove of the A-type double-helical structure of HDOs. The DabO/Chol-HDO complex showed significantly improved aPTT prolongation and thrombocytopenia in mice while maintaining gene-silencing efficacy. Moreover, the conjugation with DabOs effectively prevented cerebral infarction, a condition frequently observed in mice intravenously injected with high-dose Chol-HDO. These approaches, combining HDO technology with DabOs, offer distinct advantages over conventional strategies in reducing toxicities. Consequently, the DabO/HDO complex represents a promising platform for overcoming the class-related toxicities associated with therapeutic ASOs.

Circular walking is useful for assessing the risk of falls in early progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by early onset postural instability and frequent falls. Circular walking necessitates dynamic postural control, which is impaired in patients with PSP. We aimed to explore gait parameters associated with the risk of falls in patients with PSP, focusing on circular walking. METHODS: Sixteen drug-naïve patients with PSP, 22 drug-naïve patients with Parkinson's disease (PD), and 23 healthy controls were enrolled. Stride lengths/velocities and their coefficients of variation (CV) during straight and circular walking (walking around a circle of 1-m diameter) were measured under single-task and cognitive dual-task conditions. Correlation analysis was performed between gait parameters and postural instability and gait difficulty (PIGD) motor subscores, representing the risk of falls. RESULTS: Patients with PSP had significantly higher CVs of stride lengths/velocities during circular walking than those during straight walking, and the extent of exacerbation of CVs in patients with PSP was larger than that in patients with PD under single-task conditions. Stride lengths/velocities and their CVs were significantly correlated with PIGD motor subscores in patients with PSP only during single-task circular walking. In addition, patients with PSP showed progressive decrements of stride lengths/velocities over steps only during single-task circular walking. CONCLUSIONS: Worse gait parameters during circular walking are associated with an increased risk of falls in patients with PSP. Circular walking is a challenging task to demand the compromised motor functions of patients with PSP, unmasking impaired postural control and manifesting sequence effect. Assessing circular walking is useful for evaluating the risk of falls in patients with early PSP.

Is there a spinal tap responder in progressive supranuclear palsy? The first prospective study.

OBJECTIVE: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease, and sometimes shows idiopathic normal pressure hydrocephalus (iNPH)-like presentations. We aimed to evaluate spinal tap responsiveness in patients with PSP, including the effect of sham spinal tap. METHODS: Eleven patients with PSP, ten with probable/definite iNPH, and eight control patients were prospectively enrolled. All participants underwent sham spinal tap and spinal tap procedures. Gait was evaluated using wearable inertial sensors. We defined "tap responders" as individuals with a 10% or more improvement from baseline in any of the gait parameters (timed up-and-go test total time, stride length, and velocity during straight walking under single-task and cognitive dual-task conditions). We compared the ratio of responders in patients with PSP to patients with iNPH and controls. RESULTS: The ratio of tap responders and the ratio of sham tap responders in patients with PSP were significantly higher than those in control patients, and not different from those in patients with iNPH. PSP patients with iNPH-like MRI features tended to respond to the spinal tap compared to those without such imaging features. Notably, one patient with PSP, who responded to the spinal tap beyond the effect of sham spinal tap, was treated by the shunt operation. CONCLUSION: This is the first prospective study to demonstrate tap and shunt responsiveness in patients with PSP while highlighting the placebo effects of the spinal tap in patients with PSP or iNPH. Our findings suggest that some PSP patients have impaired cerebrospinal fluid circulation, contributing to a distinct component of the clinical spectrum.

[Challenges to Distinguish Idiopathic Normal Pressure Hydrocephalus from Progressive Supranuclear Palsy].

Idiopathic normal pressure hydrocephalus (iNPH) is a clinical condition characterized by symptoms of gait disturbance, cognitive dysfunction, and urinary disturbance. In contrast, progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease characterized by supranuclear gaze palsy, akinetic rigidity, gait disturbance, and dementia. PSP manifests various clinical phenotypes that mimic other diseases and occasionally present iNPH-like presentations. Our previous publication showed that PSP develops iNPH-like magnetic resonance imaging (MRI) features more frequently than other neurodegenerative diseases. It is thus sometimes challenging to distinguish iNPH from PSP. Recently, we showed that patients with PSP, particularly those with iNPH-like MRI findings, often demonstrate amelioration of their gait disturbance following a spinal tap or shunt operation. Moreover, our study revealed that both patients with iNPH and PSP often manifest a placebo effect that can be evaluated by implementing a sham spinal tap. Therefore, although a positive response to a spinal tap has been thought of as a distinct feature of iNPH, it may not be useful in differentiating iNPH and PSP. However, in clinical practice, comparing the response to a spinal tap with that of a sham spinal tap may help accurately specify patients with iNPH or PSP who definitively respond to the shunt operation.

Comprehensive prognostic prediction of metastatic breast cancer treated with eribulin using blood­based parameters and ratio.

Eribulin is widely used to treat metastatic breast cancer (BC). Higher neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are associated with higher mortality in several cancer types. However, the association between BC prognosis and peripheral immune status remains controversial. In the present study, the relative effects of NLR and PLR on survival in patients with metastatic BC were quantified and their clinical prognostic value was evaluated. This retrospective study included 156 patients with metastatic BC who received eribulin monotherapy at Saitama Medical University International Medical Center. Clinicopathological features were examined (peripheral blood findings and biochemical liver and kidney function test results) and univariate and multivariate analyses were conducted of the overall survival (OS). The 156 patients treated with eribulin had a median follow-up duration of 18.3 months. Before eribulin treatment, patients with absolute lymphocyte counts (ALC) >1,500/µl, NLR <3.0, and PLR <150 had significantly longer OS than those with lower ALC, and higher NLR and PLR (median OS, 25.5 vs. 15.5 months; P<0.01; 20.3 vs. 13.6 months, P<0.01; and 29.2 vs. 14.8 months; P<0.001, respectively). Patients with anemia [hemoglobin (Hb) <10 g/dl] or liver dysfunction [albumin-bilirubin (ALBI) grade 2/3] had significantly shorter OS than those without (P<0.001, respectively). Multivariate analysis revealed low ALBI grade (P<0.001), high Hb (P<0.01) and low PLR (P<0.05) as independent factors of longer OS after eribulin administration. Low PLR, anemia and liver dysfunction might be factors associated with prolonged OS in patients with metastatic BC on eribulin therapy, which could be clinically useful, as their evaluation requires neither new equipment nor invasive testing.

Aberrant morphometric networks in Alzheimer's disease have hemispheric asymmetry and age dependence.

Alzheimer's disease (AD) is associated with abnormal accumulations of hyperphosphorylated tau and amyloid-ß proteins, resulting in unique patterns of atrophy in the brain. We aimed to elucidate some characteristics of the AD's morphometric networks constructed by associating different morphometric features among brain areas and evaluating their relationship to Mini-Mental State Examination total score and age. Three-dimensional T1-weighted (3DT1) image data scanned by the same 1.5T magnetic resonance imaging (MRI) were obtained from 62 AD patients and 41 healthy controls (HCs) and were analysed by using FreeSurfer. The associations of the extracted six morphometric features between regions were estimated by correlation coefficients. The global and local graph theoretical measures for this network were evaluated. Associations between graph theoretical measures and age, sex and cognition were evaluated by multiple regression analysis in each group. Global measures of integration: global efficiency and mean information centrality were significantly higher in AD patients. Local measures of integration: node global efficiency and information centrality were significantly higher in the entorhinal cortex, fusiform gyrus and posterior cingulate cortex of AD patients but only in the left hemisphere. All global measures were correlated with age in AD patients but not in HCs. The information centrality was associated with age in AD's broad brain regions. Our results showed that altered morphometric networks due to AD are left-hemisphere dominant, suggesting that AD pathogenesis has a left-right asymmetry. Ageing has a unique impact on the morphometric networks in AD patients. The information centrality is a sensitive graph theoretical measure to detect this association.

Impact of Intermittent Deposition on Spontaneous Orientation Polarization of Organic Amorphous Films Revealed by Rotary Kelvin Probe.

The control of the molecular orientation and resultant polarization is essential for improving the performance of organic optoelectronic devices. Conventionally, the substrate temperature and deposition rate are tuned to control the molecular orientation of vapor-deposited films. In this study, we proposed a novel method, referred to as "intermittent deposition", in which the polarization direction and magnitude are controlled by introducing intervals during physical vapor deposition. The rotary Kelvin probe measurement of the Alq3 and TPBi films clearly showed a time-dependent decrease in the surface potential owing to the surface relaxation of the molecular orientation immediately after deposition. Through a series of intermittent depositions, in which the deposition shutter is repeatedly opened and closed at certain intervals, a relaxed surface layer was built up, and we could control the polarization magnitude. For the Alq3 film, even the polarization direction was switched. The proposed new deposition method is applicable to general organic molecules, not limited to polar molecules, thereby potentially tuning the conduction properties of organic devices and fabricating novel devices.

Assessment of the expression of microRNAs­221­3p, ­146a­5p, ­16­5p and BCL2 in oncocytic carcinoma of the breast: A case report.

Oncocytic carcinoma of the breast is rare and its molecular profiles remain poorly understood. MicroRNAs (miRNAs/miRs) have been identified as contributors to carcinogenesis at the post-transcriptional level; thus, an aberrant expression of miRNAs has attracted attention as a potential biomarker of numerous diseases, including cancer. The present study reports the case of a 76-year-old woman diagnosed with oncocytic carcinoma of the breast. Considering the distinctive feature of oncocytic carcinoma of the breast, which is the presence of granular eosinophilic cytoplasm containing numerous mitochondria, the present study hypothesized that the expression of mitochondria-related miRNAs could be altered in oncocytic carcinomas. Aberrant expression levels of the miRNAs previously reported as mitochondria-related miRNAs, such as miR-221-3p, -146a-5p and -16-5p, were revealed in tissue from specimens of oncocytic carcinoma of the breast, compared with that of a more typical type of invasive ductal carcinoma of the breast. The present study highlights the changes in miRNA expression in oncocytic carcinoma of the breast, suggesting its potential as a biomarker for diagnosis.

Clinicopathological prognostic characteristics and long­term outcomes of patients with breast cancer and collagen disorder in comparison to those without collagen disorder.

Collagen disorders are chronic autoimmune diseases with a complex clinical course; however, the risk of breast cancer in patients with collagen disorders remains unclear. The present study aimed to investigate long-term outcomes in women with breast cancer and collagen disorders. A total of 25 patients with breast cancer and collagen disorders who were treated between January 2004 and December 2011 were included. The clinicopathological factors, treatment, recurrence-free survival (RFS) and overall survival (OS) were reviewed. The mean age was 56.4±12.6 years, and 14, eight and three patients had cancer of clinical stages I, II and III, respectively. Regarding comorbid collagen disorders, 11 patients had rheumatoid arthritis, four had systemic lupus erythematosus, four had polymyositis/dermatomyositis, two had mixed connective tissue disease, two had Sjogren's syndrome, one had scleroderma and one had adult-onset Still's disease. The expression statuses of hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2) were HR(+), HER2(+) and HR(-)HER2(-) in 20 (80.0%), four (16.0%) and four (16.0%) patients, respectively. A total of 22 (84.0%) patients received steroids or immunosuppressive drugs for collagen disorders. The collagen disorder group had a higher mean Ki-67 labeling index than the control group (41.1 vs. 20.8%; P=0.007). After median observation periods of 103 and 114 months, the RFS and OS rates were lower in the collagen group than in the control group (64.5 and 80.7% vs. 85.3 and 94.3%, respectively; P<0.01). Patients with breast cancer and collagen disorders had relatively high Ki-67 expression, and relatively low RFS and OS rates. Thorough follow-up is necessary for patients with breast cancer who also have collagen disorders and high Ki-67 values.

Cystoid Macular Edema following Treatment with Nanoparticle Albumin-Bound Paclitaxel and Atezolizumab for Metastatic Breast Cancer.

Cystoid macular edema (CME) is a rare side effect associated with chemotherapy. Although the development of CME has been reported to occur following treatment with taxane drugs, such as nanoparticle albumin-bound paclitaxel (Nab-PTX), the occurrence of CME with treatment with atezolizumab has not yet been reported. Here, we report the case of a 49-year-old woman who developed CME 19 months into chemotherapy with Nab-PTX and atezolizumab. Improvement was not achieved with steroid injections into the Tenon's sac, and Nab-PTX and atezolizumab treatments were ceased. One month later, there was subjective improvement in her symptoms. Although many reports have indicated that cessation of chemotherapy has successfully improved CME, a specific treatment for CME has not yet been established. Clinicians should be aware of the ophthalmologic side effects and offer immediate treatment if symptoms develop.

[A Case of Spinal Cord Metastasis from Breast Cancer Successfully Treated with Trastuzumab Deruxtecan].

OBJECTIVE: Intramedullary spinal cord metastases(ISCM)are very rare in patients with breast cancer and have a poor prognosis with no established treatment. We report a case of ISCM in a patient with HER2-positive breast cancer who was successfully treated with a novel anti-HER2 agent, trastuzumab deruxtecan(T-DXd, ENHERTU®). CASE: The patient was a 44- year-old woman who underwent surgery for right breast cancer. T-DXd was introduced as the fourth-line metastatic treatment for multiple metastases, including liver, bone, pituitary, brain, and spinal cord metastases. Hematologic and non- hematologic toxicities did not occur during the treatment with T-DXd. T-DXd could be administered continuously for 25 cycles, and symptoms such as numbness in the left lower limb were controlled without progression of the brain and spinal cord, although T-DXd-induced interstitial lung disease was a concern. DISCUSSION: ISCM is a rare metastatic lesion that is difficult to treat with chemotherapy due to the blood-brain barrier (BBB), and there is no established treatment for ISCM. T-DXd has shown promising results in previous clinical trials, including in patients with central nerve system (CNS) metastases, and is expected to be a good treatment option for CNS metastases in clinical practice. CONCLUSION: This successful case of T-DXd for ISCM suggests that T-DXd is an effective treatment option for patients with breast cancer and CNS metastases.

Revision of the genus Atholus Thomson, 1859 (Coleoptera, Histeridae, Histerinae) from the Philippines with additional records.

The Philippine species of the genus Atholus Thomson, 1859 are revised and re-examined based on museum as well as freshly collected specimens. Atholustorquatus (Marseul, 1854) is re-described, and SEM micrographs and illustrations of both male and female genitalia are provided. Atholusbakeri (Bickhardt, 1914) and Atholusnitidissimus Desbordes, 1925 are also re-described based on images of syntypes. Atholuspirithous (Marseul, 1873) and A.torquatus (Marseul, 1854) are new to the Philippine archipelago. Atholuscoelestis (Marseul, 1857) and A.philippinensis (Marseul, 1854) are provided with diagnostic descriptions and images. A key to the Philippine species is provided.

Long-term levodopa ameliorates sequence effect in simple, but not complex walking in early Parkinson's disease patients.

BACKGROUND: The sequence effect (SE) is characterized by the progressive decrement of movements and is often observed in Parkinson's disease (PD) patients. While acute effect of levodopa does not ameliorate the SE, the effect of long-term levodopa treatment for the SE remains unknown. OBJECTIVE: We aimed to elucidate the SEs during various gait conditions and their response to long-term levodopa treatment in drug-naïve PD patients. METHODS: Nineteen drug-naïve PD patients and 21 healthy controls were enrolled. Gait parameters were measured via wearable inertial sensors in the following conditions:1) straight walking, 2) circular walking: walking a circle of 1 m diameter in a clock-wise direction for 3 laps, 3) straight or circular walking under cognitive-motor dual-task (serial 7s subtractions). PD patients were evaluated at baseline, within 1 h after intravenous administration of levodopa, and after one, three, and six months treatment with levodopa. The SE was measured by a linear regression slope by plotting consecutive stride lengths over steps. Patients were also separately analyzed depending on laterality of symptoms. RESULTS: Long-term levodopa treatment ameliorated the SE only during single-task straight walking. The SE during circular walking was exacerbated after long-term levodopa treatment for right-side dominant patients. During dual-task straight walking, the SE at baseline was greater in right-side dominant PD patients. CONCLUSIONS: The SE only during single-task straight walking can be ameliorated by long-term levodopa treatment. However, the SE may be exaggerated by cognitive motor interference or by asymmetrical stride length with/without long-term levodopa treatment, depending on the laterality of symptoms.

Correlation of callosal angle at the splenium with gait and cognition in normal pressure hydrocephalus.

OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) is characterized by ventricular enlargement that deforms the corpus callosum, making the callosal angle (CA) small. The authors aimed to evaluate the clinical usefulness of the CA in different planes in iNPH. METHODS: Forty patients with iNPH were included in the study. As a control group, 241 patients with other neurological diseases and 50 healthy controls were included. The subjects had been seen at the authors' institutions from 2010 to 2020. The Timed Up and Go (TUG) test total time and Mini-Mental State Examination (MMSE) total score were evaluated. CAs were measured in the axial plane at the splenium and genu and in the coronal plane at the anterior commissure and posterior commissure by using 3-dimensional T1-weighted MR images. As other hydrocephalus parameters, the Evans index, frontal-occipital horn ratio, and third ventricular width were also measured in patients with iNPH. Associations between each CA or hydrocephalus parameter and clinical parameters were evaluated. The classification efficacy of each CA in differentiating between iNPH and other neurological diseases and healthy controls was evaluated. RESULTS: The CA at the splenium, but no other hydrocephalus parameters, was correlated with TUG total time or MMSE total score in patients with iNPH. Receiver operating characteristic analysis showed that a CA of 71.1° at the splenium has 90.0% sensitivity and 89.0% specificity in discriminating iNPH from other neurological diseases and healthy controls. Probabilistic tractography analysis showed that neuronal fibers via the splenium connect the superior parietal lobules, temporal lobes, and occipital lobes. CONCLUSIONS: The study results suggest that interhemispheric disconnections at the splenium are, at least in part, responsible for gait and cognitive disturbance in iNPH. The CA at the splenium is a unique morphological feature that correlates with gait and cognition in iNPH, and it is useful for discriminating iNPH from other neurological diseases and healthy controls.

Turning and multitask gait unmask gait disturbance in mild-to-moderate multiple sclerosis: Underlying specific cortical thinning and connecting fibers damage.

Multiple sclerosis (MS) causes gait and cognitive impairments that are partially normalized by compensatory mechanisms. We aimed to identify the gait tasks that unmask gait disturbance and the underlying neural correlates in MS. We included 25 patients with MS (Expanded Disability Status Scale score: median 2.0, interquartile range 1.0-2.5) and 19 healthy controls. Fast-paced gait examinations with inertial measurement units were conducted, including straight or circular walking with or without cognitive/motor tasks, and the timed up and go test (TUG). Receiver operating characteristic curve analysis was performed to distinguish both groups by the gait parameters. The correlation between gait parameters and cortical thickness or fractional anisotropy values was examined by using three-dimensional T1-weighted imaging and diffusion tensor imaging, respectively (corrected p < .05). Total TUG duration (>6.0 s, sensitivity 88.0%, specificity 84.2%) and stride velocity during cognitive dual-task circular walking (<1.12 m/s, 84.0%, 84.2%) had the highest discriminative power of the two groups. Deterioration of these gait parameters was correlated with thinner cortical thickness in regional areas, including the left precuneus and left temporoparietal junction, overlapped with parts of the default mode network, ventral attention network, and frontoparietal network. Total TUG duration was negatively correlated with fractional anisotropy values in the deep cerebral white matter areas. Turning and multitask gait may be optimal to unveil partially compensated gait disturbance in patients with mild-to-moderate MS through dynamic balance control and multitask processing, based on the structural damage in functional networks.

Beetles of the Genus Lewisister (Coleoptera, Histeridae), with Description of a New Species from Taiwan.

The genus Lewisister Bickhardt, 1912 was previously only known to contain a single species, L. excellens Bickhardt, 1912, and had only been recorded from Southeast Asia. In this study, a new species found in Taiwan, L. masumotoi sp. nov., is described and the male genitalia are illustrated. Additional morphological characters are presented for L. excellens Bickhardt, 1912 and an illustration of its male genitalia is provided. The pairwise genetic distance of COI sequences of Lewisister are also provided to support the delimitation of both species. Both species are distributed in Taiwan, and the distribution records from Taiwan are discussed.

Association between CA 15­3 and progression of interstitial lung disease in a case of coexisting systemic sclerosis and recurrent breast cancer: A case report.

Carbohydrate antigen 15-3 (CA 15-3) is known as a specific tumor marker for breast cancer, the main use of which is monitoring therapy in patients with advanced breast cancer. Either systemic sclerosis (SSc)-interstitial lung disease (ILD) or pulmonary arterial hypertension is currently the leading cause of disease-related morbidity and mortality in patients with scleroderma. Although CA 15-3 has been investigated as a biomarker in SSc-ILD, its role remains unclear. The current report presented a case of recurrent breast cancer diagnosed with SSc-ILD during treatment. The patient, at 63 years old, experienced shortness of breath with minimal exertion after four cycles of perutuzumab, trastuzumab and weekly paclitaxel. Computed tomography (CT) revealed ground-glass opacities and linear shadows in the peripheral lower lobes of both lungs. Although the development of lung involvement associated with breast cancer, such as carcinomatous lymphangitis, was initially suspected, because of the increase in CA 15-3, skin biopsies were taken from the left index finger base and extension side of the left elbow, which demonstrated increased thickness of the dermis, leading to a diagnosis of SSc-ILD. The findings in this case suggested the importance of considering a differential diagnosis, including ILD, concurrently while screening for the progression of recurrent breast cancer when encountering patients with breast cancer and elevated levels of CA 15-3.