Overexpression of the DNA sensor proteins, absent in melanoma 2 and interferon-inducible 16, contributes to tumorigenesis of oral squamous cell carcinoma with p53 inactivation

The development of oral squamous cell carcinoma (OSCC) is a multistep process that requires the accumulation of genetic alterations. To identify genes responsible for OSCC development, we performed high-density single nucleotide polymorphism array analysis and genome-wide gene expression profiling on OSCC tumors. These analyses indicated that the absent in melanoma 2 (AIM2) gene and the interferon-inducible gene 16 (IFI16) mapped to the hematopoietic interferon-inducible nuclear proteins. The 200-amino-acid repeat gene cluster in the amplified region of chromosome 1q23 is overexpressed in OSCC. Both AIM2 and IFI16 are cytoplasmic double-stranded DNA sensors for innate immunity and act as tumor suppressors in several human cancers. Knockdown of AIM2 or IFI16 in OSCC cells results in the suppression of cell growth and apoptosis, accompanied by the downregulation of nuclear factor kappa-light-chain-enhancer of activated B cells activation. Because all OSCC cell lines have reduced p53 activity, wild-type p53 was introduced in p53-deficient OSCC cells. The expression of wild-type p53 suppressed cell growth and induced apoptosis via suppression of nuclear factor kappa-light-chain-enhancer of activated B cells activity. Finally, the co-expression of AIM2 and IFI16 significantly enhanced cell growth in p53-deficient cells; in contrast, the expression of AIM2 and/or IFI16 in cells bearing wild-type p53 suppressed cell growth. Moreover, AIM2 and IFI16 synergistically enhanced nuclear factor kappa-light-chain-enhancer of activated B cells signaling in p53-deficient cells. Thus, expression of AIM2 and IFI16 may have oncogenic activities in the OSCC cells that have inactivated the p53 system.     

An ethnobotanical study of medicinal plants and traditional therapies on Batan Island,the Philippines

Ethnopharmacological relevance

We studied the local knowledge and uses of medicinal plants among the Ivatan people of Batan Island by documenting their traditional practices.

Aim of the study

To identify the types of medicinal plants used in self-care by the indigenous people of Batan Island, the Philippines and to investigate the extent to which the plants are used. Conservation of medicinal plants and natural resources is becoming increasingly important; thus, this research aims to collect information from local people concerning the use of medicinal plants on Batan Island.

Materials and methods

A total of 116 informants were interviewed, allowing for calculated informant consensus factors (ICF), use value (UV), and fidelity levels (FL) for each medicinal plant species used to cure various ailments. This helped to establish a consensus on which species are effective for particular ailments, as well as the species’ relative importance, and enabled us to understand the extent of the potential utilization of each species.

Results

We describe the therapeutic effects of 112 plant species used medicinally against 13 categories of ailments. The highest ICF value (1.00) was cited for diseases of the ear and respiratory system and for use during pregnancy, childbirth and the postnatal period. The maximum FL of 100% was found for Carica papaya, Stachytarpheta jamaicensis, Musa sapientum, and Pedilanthus tithymaloides, used for the treatment of constipation, cuts and wounds, diarrhea, and dislocations and fractures, respectively. The highest UV was for Hibiscus rosa-sinensis (0.67). All plants with high UV were used for exogenous diseases, certain infectious and parasitic diseases, injuries, poisonings and other consequences of external factors, and diseases of the skin and subcutaneous tissues. In addition to its use for endogenous disease and lifestyle-related diseases and illnesses, Moringa oleifera is also used for diseases of the circulatory system, with a UV of 0.57 and Cocos nucifera is used for diseases of the genitourinary system, with a UV of 0.56.

Conclusions

This study demonstrates that many plant species play an important role in local healing practices and that knowledge of traditional medicine is still utilized and plays a significant role on Batan Island. The documentation of this rich traditional ethno-medicinal knowledge has furnished us with novel information that not only will provide recognition of this undocumented knowledge but also could provide new avenues for pharmacological investigations to improve healthcare for a range of ailments.     

Magnetic resonance imaging findings of age-related distance esotropia in Japanese patients with high myopia

Graefe's Archive for Clinical and Experimental Ophthalmology - This study aimed to investigate the characteristics of the extraocular muscles and the orbital connective tissue pulleys in...     

A case of IgG4-related tubulointerstitial nephritis with left hydronephrosis after a remission of urinary tract tuberculosis

IgG4-related systemic disease encompasses multi-organ disorders, including tubulointerstitial nephritis. This disease is accompanied by a high serum IgG4 concentration and IgG4-positive plasma cell infiltration. We herein describe a 63-year-old woman with renal failure and dryness of the eyes and mouth, who had been treated with antituberculosis agents for urinary tract tuberculosis. She had a negative finding for a PCR analysis for Mycobacterium tuberculosis, a positive QuantiFERON-TB test, high serum IgG4 concentrations (2,660 mg/dl), and low serum IgM and IgA concentrations (34 and 82 mg/dl, respectively). Imaging tests revealed swelling in the submandibular glands, pancreas, and right kidney. A renal biopsy showed IgG4-positive plasma cell infiltration in the interstitium and tubular atrophy. This case was diagnosed as IgG4-related systemic disease. Corticosteroid therapy improved renal failure and swelling in the submandibular glands, pancreas, and right kidney. The case suggests that an abnormal reaction to tuberculosis may be associated with a predominance of type-2 helper T-cell immunity, thus resulting in IgG4-related systemic disease.     

Circulating naïve and effector memory T cells correlate with prognosis in head and neck squamous cell carcinoma

T‐cell memory is an important mechanism for long‐term protection against diverse pathogens. Generation and persistence of memory T cells are vital components of anti‐tumor immunity, given their ability to persist for prolonged durations, as well as activate and migrate rapidly. In the present study, we investigated the clinical and prognostic significance of T‐cell subsets in the peripheral circulation of patients with head and neck squamous cell carcinoma (HNSCC). Moreover, we calculated the enrichment scores of T‐cell subsets in primary tumor tissues and compared their clinical characteristics using a public database. Multivariate survival analyses of circulating T‐cell parameters revealed that clinical parameters, except M factor, were not independent prognostic factors, whereas proportions of CD8⁺ T cells, naïve T cells (T_Ns), effector memory T cells (T_EMs), and CD38⁺CD8⁺ T cells were independent prognostic factors, suggesting the importance of these peripheral T‐cell parameters as independent prognostic biomarkers. Consistent with these results, the T‐cell enrichment analysis indicated that enrichment of CD8⁺ T_Ns in the tumor microenvironment was an independent prognostic factor. Moreover, an ex vivo experiment demonstrated significantly less cytotoxic activity in CD38⁺ T cells than in CD38⁻ T cells. These findings suggest that T‐cell memory‐related parameters in both systemic immunity and the tumor microenvironment could be used as prognostic biomarkers regardless of clinical characteristics. Further characterization of circulating T cells would lead to the development of novel biomarkers for patients with HNSCC.     

The first year results of mizoribine/tacrolimus-based multitarget treatment for consecutive patients with lupus nephritis

Background

Despite the high efficacy of mycophenolate mofetil (MMF)/tacrolimus-based multitarget treatment, risks of infections are a matter of concern. In the present study, we clarified the potential of multitarget therapy using mizoribine opposed to MMF.

Methods

A total of 36 patients with biopsy-proven lupus nephritis were treated with mizoribine, tacrolimus, and glucocorticoids and then retrospectively evaluated. To determine the efficacy, proteinuria remission (≤?0.2 g/day), complete remission (Liu et al. in Ann Intern Med 162:18–26, 2015) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) remission rates, and the prednisolone dose at months 6 and 12 were evaluated. The associations between serum mizoribine/tacrolimus levels and clinical parameters were investigated. To assess safety, adverse events were inspected.

Results

All patients could continue the original treatment regimen without withdrawal or exacerbations through month 12. At month 6, the proteinuria remission, complete remission, SLEDAI remission rates, and prednisolone dose were 69, 53, 36%, and 12.1 mg/day, respectively, whereas the values at 12 months were 92, 67, 50%, and 8.8 mg/day, respectively. The treatment was efficacious for every histologic type of nephritis and non-renal manifestations of SLE. Excluding one patient who was hospitalized due to upper respiratory tract infection, serious infections, including pneumonia and cytomegalovirus disease, were not observed. Higher trough tacrolimus levels were associated with normalization of complement, whereas higher peak mizoribine levels with prevention of cytomegalovirus viremia.

Conclusions

Our results suggest that multitarget therapy using mizoribine opposed to MMF is highly safe and effective through 12 months. The therapy may enable faster dose reduction of concomitant glucocorticoids.

     

Clinical characteristics of Pneumocystis carinii pneumonia in patients with connective tissue diseases

The characteristics of Pneumocystis carinii pneumonia (PCP) in patients with connective tissue diseases (CTDs) were examined retrospectively. Nine patients were enrolled in this study. Their mean age was 57.1 years. All the patients received a high-dose steroid or immunosuppressant. The onset (mean 6.6 days) of fever, cough, breathlessness, and geographical ground-glass opacities revealed by chest computed tomography was acute. The serum β-d-glucan level increased with a simultaneous increase in the Krebs von den Lungen (KL)-6 or surfactant protein D level. The serum immunoglobulin G (IgG) and albumin levels and the peripheral blood lymphocyte count at the onset of PCP were low, but only the serum IgG level decreased significantly. The patients were treated with trimethoprim-sulfamethoxazole or pentamidine isetionate. Six patients died eventually: two patients of progressive respiratory failure, two probably due to a recurrence of the PCP, and two with microbial respiratory infections other than PCP. Five of the six patients required mechanical ventilation. Three patients received secondary prophylaxis and survived. In conclusion, the acute onset was characteristic of PCP in patients with CTDs. High-dose steroids, immunosuppressants, and hypogammaglobulinemia are risk factors; and respiratory failure requiring mechanical ventilation, severe secondary infections, and a lack of secondary prophylaxis are poor prognostic factors. Secondary prophylaxis is recommended for all of these patients.     

Prevalence of human papillomavirus 16/18/33 infection and p53 mutation in lung adenocarcinoma

Human papillomavirus (HPV) infection is a causative event for the development of uterine cervical carcinoma. Human papillomavirus (HPV) 16, 18, and 33 DNA has been also detected frequently in lung adenocarcinomas (AdCs) in East Asian countries; however, its prevalence in Japan remains unclear. We therefore screened for HPV 16/18/33 DNA in 297 lung AdCs in a Japanese population by multiplex PCR with type‐specific primers. As reported previously, HPV 16 DNA was detected in two cervical cancer cell lines, CaSki and SiHa, while HPV 18 DNA was detected in HeLa cells, and 0.1–1.0 copies of HPV‐DNA per cell were detectable by this method. However, with this method, none of the 297 lung AdCs showed positive signals for HPV 16/18/33 DNA, indicating that HPV‐DNA is not or is very rarely integrated in lung AdC genomes in the Japanese. Furthermore, none of the lung AdCs showed positive signals by nested PCR with HPV 16/18 type‐specific primers. Therefore, we further attempted to detect HPV 16/18/33 DNA in 91 lung cancer cell lines, including 40 AdC cell lines. Among them, 30 have been established in Japan and the remaining 61 in the USA. No HPV signals were obtained in any of the 91 cell lines by either multiplex or nested PCR, while the p53 gene was mutated in 81 of them including 35 of the 40 AdC cell lines. These results indicate that HPV 16/18/33 infection does not play a major role in the development of lung AdC in Japan nor in the USA. (Cancer Sci 2010)     

Optimal Breast Density Characterization Using a Three-Dimensional Automated Breast Densitometry System

Dense breasts are a risk factor for breast cancer. Assessment of breast density is important and radiologist-dependent. We objectively measured mammographic density using the three-dimensional automatic mammographic density measurement device Volpara™ and examined the criteria for combined use of ultrasonography (US). Of 1227 patients who underwent primary breast cancer surgery between January 2019 and April 2021 at our hospital, 441 were included. A case series study was conducted based on patient age, diagnostic accuracy, effects of mammography (MMG) combined with US, size of invasion, and calcifications. The mean density of both breasts according to the Volpara Density Grade (VDG) was 0–3.4% in 2 patients, 3.5–7.4% in 55 patients, 7.5–15.4% in 173 patients, and ≥15.5% in 211 patients. Breast density tended to be higher in younger patients. Diagnostic accuracy of MMG tended to decrease with increasing breast density. US detection rates were not associated with VDG on MMG and were favorable at all densities. The risk of a non-detected result was high in patients without malignant suspicious calcifications. Supplementary use of US for patients without suspicious calcifications on MMG and high breast density, particularly ≥25.5%, could improve the breast cancer detection rate.     

Open Questions that Can Bridge Intermolecular Interactions and Macroscopic Wetting/Dewetting Behaviors of Thin Films

Polymer films and coatings are ubiquitous in nanoscale applications where confined macromolecules experience greater interfacial effects, causing deviations from bulk material properties; however, the fundamental physics dictating their wetting behavior remains poorly understood. This review provides a perspective on thickness-dependent surface wettability in thin polymer films characterized by critical thickness, where surface energy and contact angle measurements deviate from bulk values. In contrast with dewetting behaviors, which are well-modeled by van der Waals (vdW) potentials to afford several nanometers of critical thickness, an unexpectedly large critical thickness of ≈100 nm is reported for thin polystyrene films via surface energy and contact angle measurements. This deviation in the critical thickness highlights an opportunity to modify the current theoretical understanding of the vdW potential model. In addition, possible explanations to interpret the long critical length scales are discussed: 1) challenges in sample preparations and contact angle measurements; 2) temperature dependence of surface energy; and 3) the cooperative nature of polymers. This review invites researchers to bridge the knowledge gap between macroscopic behaviors (e.g., wetting/dewetting) and molecular-level understanding (e.g., vdW potentials) in polymer thin films.