The Impact of Reduced Skeletal Muscle Mass on Patients with Knee Osteoarthritis

Although several studies have suggested a possible association between sarcopenia and knee osteoarthritis (OA) in the elderly, there remains no definitive evidence. Recently, however, the serum creatinine/cystatin C ratio (sarcopenia index: SI) was reported to correlate with skeletal muscle mass. The present retrospective study therefore investigated the impact of reduced skeletal muscle mass on advanced knee OA using SI. In 55 individuals scheduled for knee osteotomy or knee arthroplasty, correlations between SI and patient-reported outcomes such as the Knee Society Score (KSS), Knee Injury and Osteoarthritis Outcome Score (KOOS), and Oxford Knee Score (OKS) were explored. Significant associations were found between SI and the KSS functional activity score (β=0.37; p=0.022), KOOS subscale for activities of daily living (β=0.42; p=0.0096), and OKS (β=0.42; p=0.0095). This study underscores the role of reduced muscle mass in functional outcomes and introduces SI as a valuable marker for assessing muscle loss in knee OA patients

Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands

Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through design of new allosteric ligands aimed at modulating its functional dynamics is proposed. Based on the characterization of a first set of 2-phenylbenzofurans showing stimulatory effects on Hsp90 ATPase and conformational dynamics, new ligands were developed that activate Hsp90 by targeting an allosteric site, located 65 æ from the active site. Specifically, analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis. The molecules’ effects on Hsp90 enzymatic, conformational, cochaperone and client-binding properties were characterized through biochemical, biophysical and cellular approaches. These designed probes act as allosteric activators of the chaperone and affect the viability of cancer cell lines for which proper functioning of Hsp90 is necessary

HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response

A case of perirenal extra-adrenal myelolipoma mimicking liposarcoma

Myelolipoma is a benign tumor composed of mature adipose tissue and normal hematopoietic components. It usually occurs in the adrenal glands but rarely in the extra-adrenal region. However, it is difficult to differentiate extra-adrenal myelolipoma from well-differentiated liposarcoma on the basis of the radiological findings. We report the case of a 66-year-old male with perirenal and extra-adrenal myelolipoma who underwent radical tumor resection with nephrectomy after a preoperative diagnosis of liposarcoma. Intraoperative assessment by the surgeon and intraoperative pathological evaluation are important considering the divergent prognoses of myelolipoma and liposarcoma

A case of testicular torsion successfully treated with tunica albuginea incision and tunica vaginalis patch

Previous studies indicated the occurrence of compartment syndrome after testicular detorsion. In such cases, testicular blood flow may improve with tunica albuginea incision. A 14-year-old man presented with right-sided testicular torsion. No improvement in testicular appearance after detorsion led to a tunica albuginea incision for immediate recovery of testicular blood flow. The affected testis, covered with a tunica vaginalis patch, exhibited no atrophy at the 6-month follow-up. Magnetic resonance imaging revealed that the affected testis had blood flow comparable to that on the unaffected side. This technique is useful for avoiding orchiectomy in testes with poor blood flow after detorsion

Zoledronic acid sensitizes renal cell carcinoma cells to radiation by downregulating STAT1.

Zoledronic acid (ZOL), a third-generation bisphosphonate that strongly inhibits osteoclast activity, is widely used for the treatment of bone metastasis from a variety of malignancies, including renal cell carcinoma (RCC). We previously reported that zoledronic acid (ZOL) clinically potentiates antitumor effects of radiotherapy (RT) on bone metastases from RCC. To date, however, it remains unknown whether ZOL radiosensitizes RCC and if it does, how. Here, we demonstrated that ZOL directly radiosensitizes RCC cells independent of osteoclast activity by potentiating the caspase-3-mediated apoptosis pathway. The radiosensitization by ZOL was observed in 786-O, A-498, and ACHN cells but not in Caki-1 cells. As its underlying molecular mechanism, we found that the signal transducer and activator of transcription 1 (STAT1) plays a key role. The three RCC cell lines, in which ZOL exerted a radiosensitizing effect, expressed STAT1 abundantly but Caki-1 cells did not. ZOL downregulated endogenous STAT1 expression in 786-O, A-498, and ACHN cells by a post-transcriptional modification. We confirmed that knockdown of endogenous STAT1 by siRNA sensitized 786-O cells to RT equivalently to ZOL, and that introduction of exogenous STAT1 rendered Caki-1 cells more RT-resistant. This is the first study to clarify the molecular mechanism by which ZOL directly radiosensitizes tumor cells. Because tumor cells commonly overexpress STAT1 and ZOL reportedly radiosensitizes various types of tumor cells, ZOL warrants further clinical and translational studies as a potent radiosensitizer against RT-resistant tumors overexpressing STAT1

Evaluation of Sagittal Spine-Pelvis-Lower Limb Alignment in Elderly Women with Pelvic Retroversion while Standing and Walking Using a Three-Dimensional Musculoskeletal Model

Study DesignIn vivo biomechanical study using a three-dimensional (3D) musculoskeletal model for elderly individuals with or without pelvic retroversion.PurposeTo evaluate the effect of pelvic retroversion on the sagittal alignment of the spine, pelvis, and lower limb in elderly females while standing and walking.Overview of LiteraturePatients with hip–spine syndrome have concurrent hip-joint and spine diseases. However, the dynamic sagittal alignment between the hip joint and spine has rarely been investigated. We used a 3D musculoskeletal model to evaluate global spinopelvic parameters, including spinal inclination and pelvic tilt (PT).MethodsA total of 32 ambulant females (mean age=78 years) without assistance were enrolled in the study. On the basis of the radiographic measurement for PT, participants were divided into the pelvic retroversion group (R-group; PT≥20°) and the normal group (N-group; PT<20°). A 3D musculoskeletal motion analysis system was used to analyze the calculated value for the alignment of spine, pelvis, and lower limb, including calculated (C)-PT, sagittal vertical axis (C-SVA), pelvic incidence, lumbar lordosis, T1 pelvic angle (C-TPA), as well as knee and hip flexion angles while standing and walking.ResultsWhile standing, C-PT and C-TPA in the R-group were significantly larger than those in the N-group. Hip angle was significantly smaller in the R-group than in the N-group, unlike knee angle, which did not show difference. While walking, C-SVA and C-TPA were significantly increased, whereas C-PT decreased compared with those while standing. The maximum hip-flexion angle was significantly smaller in the R-group than in the N-group. There was a significant correlation between the radiographic and calculated parameters.ConclusionsThe 3D musculoskeletal model was useful in evaluating the sagittal alignment of the spine, pelvis, and leg. Spinopelvic sagittal alignment showed deterioration while walking. C-PT was significantly decreased while walking in the R-group, indicating possible compensatory mechanisms attempting to increase coverage of the femoral head. The reduction in the hip flexion angle in the R-group was also considered as a compensatory mechanism