YES1 activation induces acquired resistance to neratinib in HER2‐amplified breast and lung cancers

Molecular‐targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan‐HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2‐positive breast cancer. However, acquired resistance of various cancers to molecular‐targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib‐resistant cell lines from HER2‐amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib‐resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1‐amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2‐targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.     

Outcomes of 152 temporomandibular joints following arthroscopic anterolateral capsular release by holmium: YAG laser or electrocautery

OBJECTIVE: The aim of this study was to investigate the clinical results and efficacy of arthroscopic anterolateral capsular release achieved through the use of a holmium:YAG laser or electrocautery for the management of patients with internal derangements of the temporomandibular joint (TMJ). STUDY DESIGN: We studied internal derangement (106 joints) and osteoarthritis (46 joints) of the TMJ in 129 patients. Preoperatively, the mean mouth-opening degree was 31 mm and 129 TMJs exhibited moderate to severe arthralgia. All patients underwent arthroscopic anterolateral capsular release achieved with a holmium:YAG laser (84 TMJs) or through electrocautery (68 TMJs). RESULTS: At the end of each patient's respective follow-up period, which ranged from 2 to 72 months (mean, 19 months), the mean mouth-opening degree was 43 mm (P<.0001). Also during that time, 105 joints were discovered to exhibit no arthralgia and 36 had mild arthralgia. The total success rates with 2 sets of criteria were 92.8% and 95.6%. CONCLUSIONS: Arthroscopic anterolateral capsular release is a minimally invasive and effective surgical method for the treatment of patients with TMJ intracapsular disorders.     

Case report of intra-osseous fibroma: a study on odontogenic and desmoplastic fibromas with a review of the literature

Intra-osseous fibromas of the jaw are classified by origin. Intra-osseous odontogenic fibromas have odontogenic epithelia, while desmoplastic fibromas do not. However, it is often difficult to determine the odontogenic origin for central fibromas. Three subjects with a diagnosis of intra-osseous fibroma were examined. Case 1 was a 35-year-old man found to have a panoramic radiograph from the right premolar to the mandibular ramus in the mandible that exhibited multilocular radiolucency. Within the radiolucency, small-radioopaque bodies were observed. Case 2 was a 13-year-old female, in whom a panoramic radiograph from the left premolar to the molar in the mandible showed multilocular radiolucency. Case 3 was a 51-year-old female who exhibited a heart-shaped radiolucency in the panoramic radiograph of the left first molar area in the mandible. We also reviewed the literature for previously reported cases of intra-osseous odontogenic and desmoplastic fibroma. In 64 cases of intra-osseous odontogenic fibroma and 68 cases of desmoplastic fibroma we extracted data on age, sex, location, and radiographic findings. Based on the analysis of the reported literature cases, re-evaluation of the patients in our study revealed that case 1 could be classified as desmoplastic fibroma, while cases 2 and 3 were intra-osseous odontogenic fibromas.     

Engagement of specific T-cell surface molecules regulates cytoskeletal polarization in HTLV-1-infected lymphocytes

Cell-cell contact is required for efficient transmission of human T-lymphotropic virus type 1 (HTLV-1). An HTLV-1-infected cell polarizes its microtubule-organizing center (MTOC) toward the cell-cell junction; HTLV-1 core (Gag) complexes and the HTLV-1 genome accumulate at the point of contact and are then transferred to the uninfected cell. However, the mechanisms involved in this cytoskeletal polarization and transport of HTLV-1 complexes are unknown. Here, we tested the hypothesis that engagement of a specific T-cell surface ligand is synergistic with HTLV-1 infection in causing polarization of the MTOC to the cell contact region. We show that antibodies to intercellular adhesion molecule-1 (ICAM-1; CD54) caused MTOC polarization at a higher frequency in HTLV-1-infected cells. ICAM-1 is upregulated on HTLV-1-infected cells, and, in turn, ICAM-1 on the cell surface upregulates HTLV-1 gene expression. We propose that a positive feedback loop involving ICAM-1 and HTLV-1 Tax protein facilitates the formation of the virologic synapse and contributes to the T-cell tropism of HTLV-1. In contrast, MTOC polarization induced in T cells by antibodies to CD3 or CD28 was significantly inhibited by HTLV-1 infection.     

Diagnostic Arthroscopy of the TMJ: Differential Diagnoses in Patients with Limited Jaw Opening

Arthroscopy of the temporomandibular joints was performed in patients with limited jaw movement, locking, and trismus. Three different groups of intra-articular pathological characteristics were observed. Traumatic arthritis showed features of synovitis and/or abnormal vascular network on the joint surface. Significant fibrous changes in the artcular disk, with occasional adhesive changes among the intermediate articular spaces, suggested fibrosis of the articular capsule. The last group was suspected of having anterior disk displacement; excessive stretching and occasional rupture on a part of the synovial membrane in the upper posterior pouch were frequently observed. This study indicates a higher differentiation of diagnostic value of arthroscopy for certain TM disorders.     

Interleukin‐17/T‐helper 17 cells in an atopic dermatitis mouse model aggravate orthodontic root resorption in dental pulp

Interleukin (IL)‐17 is an important mediator of orthodontically induced inflammatory root resorption (OIIRR). However, its role in the dental pulp (DP) has not been studied. The aim of this study was to investigate, using an atopic dermatitis (AD) model, how IL‐17 contributes to OIIRR in DP. Atopic dermatitis is the most common IL‐17‐associated allergic disease. Atopic dermatitis model mice (AD group) and wild‐type mice (control group) were subjected to an excessive orthodontic force. The localization of T‐helper (Th)17 cells, IL‐17, IL‐6, and keratinocyte chemoattractant (KC; an IL‐8‐related protein in rodents) were determined in DP. In addition, CD4⁺ T cells, including IL‐17 production cells, were obtained from patients with AD and from healthy donors, and the effects of IL‐17 on the production of IL‐6 and IL‐8 were investigated using a co‐culture of CD4⁺ T cells with human dental pulp (hDP) cells stimulated with substance P (SP). Immunoreactivity for Th17 cells, IL‐17, IL‐6, and KC was increased in DP tissue subjected to orthodontic force in the AD group compared with DP tissue subjected to orthodontic force in the control group. The cells obtained from the AD patients displayed increased IL‐6 and IL‐8 production. These results suggest that IL‐17 may aggravate OIIRR in DP.     

Acute pulmonary edema associated with naphazoline ingestion

In published reports of naphazoline ingestion, clinical effects are hypertension, bradycardia, pallor, diaphoresis, and respiratory distress. We report three cases of acute pulmonary edema after the intentional ingestion of naphazoline-containing antiseptic first aid liquid. These cases presented with altered mental status, hypertension, bradycardia, and diaphoresis. Chest x-ray on admission revealed acute pulmonary edema. Two cases required mechanical ventilation. All of these clinical effects resolved within 24 hours and the patients were discharged with no sequelae. Since naphazoline stimulates the peripheral alpha-2 adrenergic receptor, we speculate that intense vasoconstriction may have elevated cardiac afterload and left atrial-ventricular blood volume and caused acute pulmonary edema.     

Optimum suture material for locking technique in tendon repair: effects of suture friction in mobilization

Background

The 2-strand side-locking loop technique allows secure locking formation easily, yielding maximum tensile force. However, not all suture materials are suitable for this technique.

Methods

The bovine gastrocnemius tendons were transected and repaired end-to-end by the side-locking loop technique using USP2 braided polyblend, braided polyester, monofilament nylon, braided nylon, or monofilament absorbable polydioxanone sutures. A repetitive loading protocol from 10 N to 100 N was used, and the loading was repeated 10,000 times. In ruptured samples during the repetitive loading test, the number of loading was recorded. In samples which did not rupture, the ultimate tensile strength was measured after repetitive loading. After testing, ruptured sutures were examined microscopically. For comparison of ultimate tensile strength before and after repetitive loading, we performed a one-time loading test on samples which did not undergo the repetitive loading.

Findings

With monofilament nylon, braided nylon, or monofilament absorbable polydioxanone, suture rupture occurred during repetitive loading. In contrast, no suture rupture occurred with braided polyblend or braided polyester. Microscopic observation showed abrasion of the surface in braided polyester, though the friction effects were not seen with braided polyblend. The mean ultimate tensile strength before and after repetitive loading was 395 N and 399 N, respectively, for braided polyblend. For braided polyester, they were 208 N and 174 N, respectively.

Interpretation

Braided polyblend suture material has an excellent resistivity to friction and is suitable for the side-locking loop technique.