The Comprehensive Characterization of B7-H3 Expression in the Tumor Microenvironment of Lung Squamous Cell Carcinoma: A Retrospective Study.

Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer; therefore, new therapeutic approaches are required to improve the prognosis of LSCC. Although immunotherapies targeting B7 family molecules were explored as treatments for several cancer types, the expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated in detail. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression using 110 surgically resected pathological specimens retrospectively. We examined the correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells. High B7-H3 expression in tumor cells was associated with a better prognosis and a significant increase in the number of CD163+PD-L1+ macrophages. Quantitative analysis revealed that there is a positive correlation between B7-H3 and PD-L1 expression in tumor and stromal cells, as well as in intratumoral tumor-infiltrating lymphocytes and tumor-associated macrophages in the same cells. CD68+, CD163+, and CK+ cells with PD-L1+ phenotypes had higher B7-H3 expression compared to PD-L1- cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies.

A case of lenticulostriate artery infarction presenting with peripheral type facial palsy.

An 82-year-old woman developed a droopy right eyelid with ipsilateral hemiparesis. Her ocular symptom was caused by weakness of the right frontalis, which is usually seen in patients with peripheral facial nerve palsy. However, head MRI showed acute cerebral infarction of the left lenticulostriate artery, and electroneurography did not detect damage to the right facial nerve. To explain the pathophysiology in this patient, asymmetrical bilateral cortex innervation to the right upper face was hypothesized. This case suggested that patients with some hemispheric strokes could develop upper facial weakness mimicking facial nerve palsy, and clinicians should pay attention to this potential pitfall in the differential diagnosis of facial nerve palsy.

A case of spinal cord infarction presenting with unilateral C5 palsy.

A 75-year-old man developed sudden-onset tetraparesis preceded by chest pain. MRI of the cervical spine on the day of onset showed no abnormalities. Although his motor symptoms improved gradually, the weakness of the muscles innervated by the C5 nerve root persisted. Sensory and autonomic deficits were detected on an additional neurological examination, and follow-up MRI eight days after onset revealed spinal cord infarction at the right anterior horn at C3-C4. This case suggests that motor symptoms mimicking a radiculopathy could be present during the course of spinal cord infarction.

An autopsy case of intravascular large B-cell lymphoma showing a rapid transition to embolic strokes with occlusion of the major cerebral arteries.

Intravascular large B-cell lymphoma can induce central nervous system manifestations, including strokes, due to small-vessel occlusion caused by lymphoma cells. However, involvement in large-sized vessels is rare. Here, we present an unusual autopsy case of an 88-year-old man showing a rapid transition from multiple strokes due to small vessel occlusion, typical of intravascular lymphoma, to progressive embolic strokes caused by the occlusion of major cerebral arteries. Magnetic resonance angiography demonstrated the major cerebral arteries associated with those multiple progressive strokes, including the right posterior cerebral artery, left anterior cerebral artery, and right middle cerebral artery, but the detectability was poor. A random skin biopsy at the abdomen confirmed the diagnosis of intravascular large B-cell lymphoma. The patient died 106 days after hospitalization despite intensive treatment. An autopsy revealed broad liquefactive necrosis in the area governed by the major cerebral arteries and multiple small infarctions caused by intravascular lymphoma cells in the small-sized vessels. In addition, the major cerebral arteries showed multiple thromboembolism with partial organization and clusters of intravascular lymphoma cells. Notably, those cells were shown aggregated and attached along the vascular wall of the basilar artery, which might have caused focal hypercoagulation in the near vessels. This aggregation might have disseminated widely in the other major cerebral arteries. Moreover, the cluster of intravascular lymphoma cells in the basilar artery was positive for tumor necrosis factor α, and similar histopathology findings were observed in the splenic veins. However, the pathogenesis of this rare phenomenon involving these cells remains unknown. From a clinical perspective, we should consider the possibility that intravascular lymphoma cells may provoke similar progressive embolic strokes.

Effectiveness of knee pad as an additional device for wheelchairs in improving upper-limb dexterity during seated tasks: a pilot study.

[Purpose] This study aimed to examine how supporting the knee from the front with a knee pad affected upper-limb dexterity while sitting. [Participants and Methods] A total of 14 healthy adult males were included in the study. As a measure of upper-limb dexterity, the number of pins was counted when the Purdue pegboard test was performed for 60 seconds. In addition, the ease of task performance was assessed using the visual analogue scale. There were two experimental conditions, with and without knee pad. The paired t-test was used to detect differences between the two conditions. A p-value of 0.05 was considered statistically significant. [Results] The Purdue pegboard test was 29.4 ± 2.5 and 27.9 ± 3.6 pins with and without knee pad, respectively. The VAS was 76.1 ± 10.3 and 62.9 ± 14.1 with and without knee pad, respectively. Both measured values were significantly higher with knee pad than without. [Conclusion] Supporting the knees from the front with knee pad improves upper-limb functionality while sitting, making it easier to perform seated tasks.

Effect of shape of back support adjustment on shear force applied to buttocks when tilt-in-space and reclining functions are combined in wheelchairs.

PURPOSE: This study aimed to investigate the effect of the shape of the back support adjustment on the shear force applied to the buttocks when tilt-in-space and reclining functions are combined in wheelchairs. MATERIALS AND METHODS: Fourteen healthy adult men were included in the study. The force plate was used to measure the parallel force as shear force. The measurement posture, leaning against the back support of an experimental chair, was a comfortable sitting posture. The tilt-in-space angle was set to 15°. The back support was inclined at increasing angles, starting from the upright position (IUP), proceeding to a fully reclined position (FRP), and returning to the upright position (RUP). The experimental conditions were as follows: adjusting the back-support shape (aBS) and non-adjusting the back support shape (non-aBS). RESULTS: Positive values indicate a parallel force applied to the buttocks posteriorly. The average values in the aBS condition were 3.4 ± 2.3, 13.6 ± 2.2, and -7.1 ± 2.4% body weight in the IUP, FRP, and RUP, respectively. The average values in the non-aBS condition were 3.8 ± 2.5, 11.4 ± 2.1, and -6.2 ± 3.1% body weight in the IUP, FRP, and RUP, respectively. There were significant differences between the two conditions in FRP (p < 0.01). CONCLUSION: These findings suggest that the shape of the back support adjustment function increased the shear force applied to the buttocks posteriorly when the back support was inclined backwards using both the tilt-in-space and reclining functions.IMPLICATIONS FOR REHABILITATIONWhen utilizing both the tilt-in-space and reclining functions to incline the back support, the shear force applied to the buttocks is greatly affected by the shape of the back support.The shape of back support adjustment is a function that can stabilize elderly persons' sitting posture, but it may increase the external force applied to the buttocks and back.

Leukemia inhibitory factor shortens primary cilia by upregulating C-C motif chemokine 2 in human neural stem/progenitor cells.

Primary cilia on neural stem/progenitor cells (NSPCs) play an important role in determining cell fate, although the regulatory mechanisms involved in the ciliogenesis remain largely unknown. In this study, we analyzed the effect of the leukemia inhibitory factor (LIF) for the primary cilia in immortalized human NSPCs. LIF withdrawal elongated the primary cilia length, whereas the addition of LIF shortened it. Microarray gene expression analysis revealed that differentially expressed genes (DEGs) associated with LIF treatment were related with the multiple cytokine signaling pathways. Among the DEGs, C-C motif chemokine 2 (CCL2) had the highest ranking and its increase in the protein concentration in the NSPCs-conditioned medium after the LIF treatment was confirmed by ELISA. Interestingly, we found that CCL2 was a negative regulator of cilium length, and LIF-induced shortening of primary cilia was antagonized by CCL2-specific antibody, suggesting that LIF could influence cilia length via upregulating CCL2. The shortening effect of LIF and CCL2 on primary cilia was also observed in SH-SY5Y cells. The results of the study suggested that the LIF-CCL2 axis may well be a regulator of NSPCs and its primary cilia length, which could affect multiple cellular processes, including NSPC proliferation and differentiation.

Fever of Unknown Origin With Normal Inflammatory Markers Due to Latent Pulmonary Embolism and Deep Vein Thrombosis: A Case Report.

An 86-year-old woman who was hospitalized due to cerebral hemorrhage developed an intermittent fever of up to 39.3°C. A computed tomography angiography of the chest with venous runoff to the legs showed pulmonary embolism (PE) and deep vein thrombosis (DVT) of the legs. Intravenous heparin rapidly reduced the fever, indicating that these thrombi were the primary cause of her fever. During her course, white blood cell count and serum C-reactive protein levels were always within normal limits. This case suggested that latent PE and DVT can be a cause of intermittent fever with normal inflammatory markers.

Association of wastewater SARS-CoV-2 load with confirmed COVID-19 cases at a university hospital in Sapporo, Japan during the period from February 2021 to February 2023.

Wastewater surveillance for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been used to monitor trends in SARS-CoV-2 prevalence in a community without being influenced by clinical testing resources or healthcare-seeking behaviors. Since the rate of mortality from COVID-19 is higher in elderly patients with comorbidities, it is important to protect hospitalized patients from nosocomial infections caused by SARS-CoV-2. SARS-CoV-2 dissemination within a hospital ward was mostly mediated by healthcare workers (HCWs) and patients. HCWs need to understand the occurrence of COVID-19 and reflect this in their infection control measures. The aim of the present study was to determine the potential of SARS-CoV-2 RNA in wastewater as a leading indicator of confirmed COVID-19 cases at a university hospital. The trend of the geometric mean RNA concentrations in wastewater collected in Sapporo corresponded well with that of the number of newly confirmed COVID-19 cases at Hokkaido University Hospital between February 15, 2021 and February 26, 2023 (Pearson's r = 0.8823, p < 0.0001). Our results showed that monitoring SARS-CoV-2 RNA in municipal wastewater was useful for estimating the number of COVID-19 patients in healthcare facilities in the city.

Spatial and Quantitative Analysis of Tumor-Associated Macrophages: Intratumoral CD163-/PD-L1+ TAMs as a Marker of Favorable Clinical Outcomes in Triple-Negative Breast Cancer.

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint inhibitors, acts as a suppressive signal for the surrounding immune system; however, its expression and effect on TAMs and the clinical outcome in breast cancer are unknown. In this study, we used high-throughput multiple immunohistochemistry to spatially and quantitatively analyze TAMs. We subjected 81 breast cancer specimens to immunostaining for CD68, CD163, PD-1, PD-L1, CD20, and pan-CK. In both stromal and intratumoral areas, the triple-negative subtype had significantly more CD68/CD163, CD68/PD-L1, and CD163/PD-L1 double-positive cells than the estrogen receptor (ER)/progesterone receptor (PR) subtype. Interestingly, a higher number of CD68+/PD-L1+/CK-/CD163- TAMs in the intratumoral area was correlated with a favorable recurrence rate (p = 0.048). These findings indicated that the specific subpopulation and localization of TAMs in the TME affect clinical outcomes in breast cancer.

Quantitative high-throughput analysis of tumor infiltrating lymphocytes in breast cancer.

In breast cancer (BC), the development of cancer immunotherapy including immune checkpoint inhibitors has progressed. Tumor infiltrating lymphocytes (TILs) is one of the important factors for an immune response between tumor cells and immune cells in the tumor microenvironment, and the presence of TILs has been identified as predictors of response to chemotherapy. However, because complex mechanisms underlies the crosstalk between immune cells and cancer cells, the relationship between immune profiles in the tumor microenvironment and the efficacy of the immune checkpoint blocked has been unclear. Moreover, in many cases of breast cancer, the quantitative analysis of TILs and immuno-modification markers in a single tissue section are not studied. Therefore, we quantified detailed subsets of tumor infiltrating lymphocytes (TILs) from BC tissues and compared among BC subtypes. The TILs of BC tissues from 86 patients were classified using multiplex immunohistochemistry and an artificial intelligence-based analysis system based on T-cell subset markers, immunomodification markers, and the localization of TILs. The levels of CD4/PD1 and CD8/PD1 double-positive stromal TILs were significantly lower in the HER2- BC subtype (p <0.01 and p <0.05, respectively). In triple-negative breast cancer (TNBC), single marker-positive intratumoral TILs did not affect prognosis, however CD4/PDL1, CD8/PD1, and CD8/PDL1 double-positive TILs were significantly associated with TNBC recurrence (p<0.05, p<0.01, and p<0.001, respectively). TIL profiles differed among different BC subtypes, suggesting that the localization of TILs and their tumor-specific subsets influence the BC microenvironment.

An investigation into the effectiveness of a novel wheelchair seat-cover assembly for the reduction of forces exerted onto the buttocks.

PURPOSE: This purpose was to investigate developed seat-cover assemblies' effect on decreasing the fluctuation of the shear force exerted onto the buttocks as the factors causing decubitus ulcers when the back-support was inclined. MATERIALS AND METHODS: The participants were 10 wheelchair users. The force plate was used to measure the horizontal force as the shear force. The back-support was inclined at increasing angles, starting from the upright position (IUP), then proceeding to a fully reclined position (FRP), and returning to the upright position (RUP). The experimental conditions were two conditions; the seat-cover assembly conditions and without the seat-cover assembly as the control conditions. RESULTS: The average values in the seat-cover assembly condition were 14.4 ± 3.3, 13.9 ± 2.3, and 17.3 ± 3.3% body weight in the IUP, FRP, and RUP, respectively. The average values in the control condition were 14.8 ± 2.6, 11.4 ± 1.7, and 24.0 ± 6.7% body weight in the IUP, FRP, and RUP, respectively. In the FUP and the RUP, there were significant differences between two conditions (p < .01). CONCLUSION: These results suggested that the shear force exerted onto the buttocks may to be decreased by using novel seat-cover assembly.Implications for rehabilitationIt is possible to decrease the fluctuations in the shear force by moving the body up and down according the novel seat-cover assembly attached the back-support incline.Disabled, older individuals can be provided with a comfortable life on a reclining wheelchair while preventing decubitus ulcers.

Investigation of the effect of a 15-degree tilt-in-space on the fluctuation of shear forces exerted on the buttocks when the back support is reclined.

[Purpose] This study aimed to investigate the effect of the combination of 15° tilt-in-space and recline angles on the fluctuation of shear forces exerted on the buttocks. [Participants and Methods] The participants were 11 healthy adult males. The parameters of the shear forces were the parallel and perpendicular forces exerted on the buttocks as measured by a force plate. The two conditions tested were T0R100-130 and T15R100-130. The tilt-in-space angles were set to 0° and 15° in the T0R100-130 and T15R100-130 conditions, respectively. The reclining angles were determined to be 100° to 130° in both conditions. [Results] Upon comparing the two conditions, the parallel and the perpendicular forces exerted on the buttocks in the T15R100-130 condition were significantly lower than those in the T0R100-130 condition in all positions of back support. Upon comparing the fluctuation values of the parallel and perpendicular forces, those applied in the T15R100-130 condition were significantly higher than those in the T0R100-130 condition. [Conclusion] These results suggest that the fluctuation of shear forces exerted on the buttocks could be decreased by using a combination of 15° tilt-in-space and reclining functions.

An autopsy case of corticobasal syndrome due to asymmetric degeneration of the motor cortex and substantia nigra with TDP-43 proteinopathy, associated with Alzheimer's disease pathology.

We herein report a case of corticobasal syndrome (CBS) due to asymmetric degeneration of the motor cortex and substantia nigra with transactivation response DNA-binding protein of 43 kDa (TDP-43) proteinopathy, associated with Alzheimer's disease (AD) pathology. An 85-year-old man initially noticed that he had difficulty in walking and had trouble in moving his right hand and lower limb one year later. His gait disturbance was aggravated, and at the age of 87 years, his neurological examination revealed parkinsonism and positive frontal lobe signs. Brain magnetic resonance imaging (MRI) revealed atrophy of the left frontotemporal lobe and cerebral peduncle, and cerebral blood flow scintigraphy revealed hypoperfusion of the left frontotemporal lobe, leading to a possible diagnosis of CBS. At the age of 89 years, he was bedridden, and rarely spoke. He died of aspiration pneumonia five years after the onset of initial symptoms. At the autopsy, the brain weighed 1280 g and showed left-sided hemiatrophy of the cerebrum and cerebral peduncle. Neuropathological examination revealed AD pathology (Braak AT8 stage V, Braak stage C, CERAD B, Thal classification 5). Phosphorylated TDP-43 (p-TDP-43) immunohistochemistry revealed widespread deposits of dystrophic neurites (DNs), glial cytoplasmic inclusions (GCIs), and neuronal cytoplasmic inclusions (NCIs), which were most remarkable in layers II/III of the motor cortex and predominant on the left hemisphere of the frontal cortex, these neuropathology being consistent with frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) type A. Interestingly, neuronal loss in the substantia nigra was more severe on the left than the right side, with a few phosphorylated tau (p-tau) and p-TDP-43 deposits. It is highly likely that asymmetric TDP-43 pathology rather than symmetric tau pathology contributed to the laterality of degeneration of the cerebral cortex, substantia nigra, and pyramidal tract, which led us to suggest that TDP-43 proteinopathy might be a primary cause.

Improving Low-contrast Detectability and Noise Texture Pattern for Computed Tomography Using Iterative Reconstruction Accelerated with Machine Learning Method: A Phantom Study.

RATIONALE AND OBJECTIVES: To evaluate the performance of iterative reconstruction (IR) and filtered back projection (FBP) images in terms of low-contrast detectability at different radiation doses, IR levels, and slice thickness using the mathematical model observer with a focus on low-contrast detectability. MATERIALS AND METHODS: The CCT189 MITA CT IQ Low-Contrast Phantom was used and helical scans were performed using a 64-detector CT scanner. Tube voltage was set at 120 kVp and tube current was adjusted from 45 to 600 mA. Images were reconstructed at slice thicknesses of 0.625 and 5.0 mm with FBP and five types of iterative progressive reconstruction with visual modeling (IPV) algorithms. The noise power spectrum (NPS) and normalized NPS were calculated. To evaluate low-contrast detectability, the model observer with the channelized Hotelling observer model was applied using low-contrast modules in the phantom. RESULTS: The NPS and normalized NPS for IPV images had similar curves as that for FBP images. At a slice thickness of 0.625 mm and equivalent radiation dose level, the mean improvement of low-contrast detectability for IPV images was 1.19-2.15-fold greater than FBP images with corresponding noise reduction levels. At equivalent noise levels of 5.0-8.0 HU, low-contrast detectability of the IPVstd2 to IPVstr2 images as almost the same or better than that of the FBP images. However, the detectability of the IPVstr4 image was lower than that of the FBP image (p = 0.02). CONCLUSION: Low-contrast detectability of the IPV images was improved with a similar normalized NPS as with FBP images. Furthermore, a radiation reduction of >50% was achieved for the IPV images, while maintaining similar low-contrast detectability.

Discovery of Novel 7-[(1R,5S)-1-Amino-5-fluoro-3-azabicyclo[3.3.0]octan-3-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane]-8-(methoxy or methyl)quinolones.

A series of 8-methoxy or 8-methylquinolones bearing novel 3-aminooctahydrocyclopenta[c]pyrrole derivatives at the C-7 position was synthesized, and the pharmacological, physicochemical, and toxicological properties of the individual compounds were evaluated. Novel 8-methylquinolone 7, which includes a 3-amino-7-fluorooctahydrocyclopenta[c]pyrrole moiety at the C-7 position, showed potent antibacterial activity against both Gram-positive and negative pathogens. Compound 7 also demonstrated favorable pharmacokinetic and pharmacodynamic properties and an acceptably safe toxicological profile. Consequently, compound 7 was selected as a clinical candidate.

Design, Synthesis, and Biological Evaluation of Novel 7-[(3 aS,7 aS)-3 a-Aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-8-methoxyquinolines with Potent Antibacterial Activity against Respiratory Pathogens.

Novel 7-[(3 aS,7 aS)-3 a-aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-6-fluoro-1-[(1 R,2 S)-2- fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5 (DS21412020) was designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Compound 5 possessing a trans-fused pyranose ring on the pyrrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens, including quinolone-resistant and methicillin-resistant Staphylococcus aureus (QR- MRSA) and quinolone-resistant Escherichia coli (QR- E. coli). Furthermore, compound 5 showed in vivo activity against the experimental murine pneumonia model due to penicillin-resistant Streptococcus pneumoniae ( PRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies. In particular, the reduced lipophilicity and basicity of compound 5 as compared to those of the previously synthesized carba-type compound 4 resulted in a significant reduction in the human ether-a-go-go (hERG) related gene channel inhibition, which have the potential to prolong the QT interval.

Stroke-like Migraine Attacks after Radiation Therapy (SMART) Syndrome Followed by Cerebral Infarction.

A 36-year-old man with a history of irradiation for acute lymphoblastic leukemia developed headache with cortical dysfunction lasting for 4 weeks. The clinical features were consistent with stroke-like migraine attacks after radiation therapy (SMART) syndrome. Six months later, he developed cerebral infarction due to occlusions of the left anterior and middle cerebral arteries. This is the first case report describing SMART syndrome followed by severe cerebral infarction. Although an association between the two episodes was not assumed, this case indicates that protective therapies against infarction might need to be considered for patients with SMART syndrome.

Acute Tetraparesis with Respiratory Failure after Steroid Administration in a Patient with a Dural Arteriovenous Fistula at the Craniocervical Junction.

A 63-year-old man developed vomiting, paraparesis, dysuria, bulbar palsy, and orthostatic hypotension over a period of 5 months. Neuroradiological examinations showed a swollen lower brainstem with a dural arteriovenous fistula at the craniocervical junction (DAVF-CCJ). A steroid was administered intravenously in the hospital to relieve brainstem edema. A few hours later, however, the patient developed acute tetraparesis with respiratory failure. Recently, there have been several reports describing the acute worsening of paraparesis in patients with a spinal dural arteriovenous fistula after steroid treatment. In addition to these reports, the present case suggests the risk of administering steroids to patients with DAVF-CCJ, especially those with brainstem dysfunction.