[The Association of Docetaxel Side Effects and Introduction of Subsequent Cabazitaxel for Castration-Resistant Prostate Cancer : A Clinical Study].

The administration of cabazitaxel for patients with castration-resistant prostate cancer (CRPC) requires prior docetaxel therapy. Sequential chemotherapy may have to be discontinued due to docetaxelassociated side effects. This study investigated the relationship between treatment outcome of docetaxel and cabazitaxel and their associated side effects. We retrospectively analyzed 69 patients with CRPC who had been administered docetaxel withand without subsequent cabazitaxel at Toyonaka Municipal Hospital from October 2014 to June 2022. Twenty-eight patients (41%) discontinued docetaxel because of side effects, and the median number of docetaxel cycles at discontinuation was 2 (range : 1-11). Fourteen of these patients received no treatment following docetaxel. A comparison of the 28 patients who had discontinued docetaxel due to side effects with 41 patients who had not revealed a significant difference in the total numbers of chemotherapy cycles (2.5 vs 9 ; P＜0.001) and time to treatment failure (56 days vs 301 days ; P＝ 0.001), with a trend toward shorter overall survival from the start of docetaxel treatment (259 days vs 512 days ; P＝0.06). Multivariate analysis identified discontinuation of docetaxel due to side effects (OR＝0.07 ; P＜0.001) and lower hemoglobin (OR＝0.01 ; P＝0.001) as significant factors inhibiting the introduction of cabazitaxel. Reducing the side effects of docetaxel, including early drug switching, may allow more CRPC patients to be reached with cabazitaxel. Consequently, the resulting taxane-based chemotherapy may contribute to an additional survival advantage.

Mobility and Biomechanical Functions in the Aging Male: Testosterone and the Locomotive Syndrome.

In the current aging society, the occurrence of the locomotive syndrome, a condition in which the locomotive organs are impaired, is increasing. The locomotive system includes support (bones), mobility and impact absorption (joints and intervertebral disks), drive and control (muscles, nerves), and network (blood vessels). The impairment of any of those systems can lead to a major decrease in quality of life. In recent years, several studies on methods to improve and prevent conditions impairing the locomotive syndrome have been conducted. Almost in parallel with the structure supporting mobility and body functions, testosterone levels decrease with age. Testosterone is a hormone-regulating several pathways affecting each aspect of the locomotive syndrome. Testosterone is regulated by the pituitary gland triggering several processes in the body through genomic and non-genomic pathways, affecting muscles, bones, nerves, joints, intervertebral discs, and blood vessels. The purpose of this review is to investigate the role of testosterone in each of the systems involved in the locomotive syndrome.

Local cyclical compression modulates macrophage function in situ and alleviates immobilization-induced muscle atrophy.

Physical inactivity gives rise to numerous diseases and organismal dysfunctions, particularly those related to aging. Musculoskeletal disorders including muscle atrophy, which can result from a sedentary lifestyle, aggravate locomotive malfunction and evoke a vicious circle leading to severe functional disruptions of vital organs such as the brain and cardiovascular system. Although the significance of physical activity is evident, molecular mechanisms behind its beneficial effects are poorly understood. Here, we show that massage-like mechanical interventions modulate immobilization-induced pro-inflammatory responses of macrophages in situ and alleviate muscle atrophy. Local cyclical compression (LCC) on mouse calves, which generates intramuscular pressure waves with amplitude of 50 mmHg, partially restores the myofiber thickness and contracting forces of calf muscles that are decreased by hindlimb immobilization. LCC tempers the increase in the number of cells expressing pro-inflammatory proteins, tumor necrosis factor-α and monocyte chemoattractant protein-1 (MCP-1), including macrophages in situ The reversing effect of LCC on immobilization-induced thinning of myofibers is almost completely nullified when macrophages recruited from circulating blood are depleted by administration of clodronate liposomes. Furthermore, application of pulsatile fluid shear stress, but not hydrostatic pressure, reduces the expression of MCP-1 in macrophages in vitro Together with the LCC-induced movement of intramuscular interstitial fluid detected by µCT analysis, these results suggest that mechanical modulation of macrophage function is involved in physical inactivity-induced muscle atrophy and inflammation. Our findings uncover the implication of mechanosensory function of macrophages in disuse muscle atrophy, thereby opening a new path to develop a novel therapeutic strategy utilizing mechanical interventions.

Adenocarcinoma in ectopic prostatic tissue at the trigone of urinary bladder.

Introduction: Ectopic prostatic tissue is prostatic tissue located distant from the prostate gland. Although its existence is not uncommon, the occurrence of adenocarcinoma in ectopic prostatic tissue is rare. Case presentation: A 68-year-old man was suspected to have a nodular-type tumor in the bladder trigone and a tumor in the prostate based on magnetic resonance imaging and cystoscopy results. Transurethral tumor resection and transrectal prostate needle biopsy revealed the coexistence of ectopic prostatic adenocarcinoma in the bladder trigone and low-risk orthotopic prostate cancer. Four years later, the tumor evolved to intermediate-risk prostate cancer during active surveillance, and the patient underwent prostatectomy with resection of the bladder trigone. Pathology indicated no residual ectopic prostatic tissue or adenocarcinoma at the bladder trigone. Conclusion: Adenocarcinoma in ectopic prostatic tissue is very rare; however, when found, the possibility of concurrent cancer in the prostate gland should be considered.

A case of retroperitoneal liposarcoma extending through the inguinal canal to the thigh and lesser trochanter.

Introduction: Liposarcoma is the most common retroperitoneal soft tissue tumor. Liposarcomas are often asymptomatic and are discovered after they become huge. Surgical resection is the first-line treatment for retroperitoneal liposarcoma, but the surrounding organs are often resected with the liposarcoma. Case presentation: A man saw a hospital with a complaint of left lower abdominal distention, and a left retroperitoneal mass was noted on imaging examination. The patient was referred to our hospital. The mass extended from the retroperitoneum through the inguinal canal to the thigh and involved the femoral nerve and psoas major muscle. A well-differentiated liposarcoma was suspected, and an open surgical resection was performed. Complete resection of a retroperitoneal liposarcoma extending to the thigh was achieved without postoperative complications. Conclusion: Treatment strategies for huge retroperitoneal liposarcomas are important to balance antitumor efficacy and postoperative quality of life.

Interstitial-fluid shear stresses induced by vertically oscillating head motion lower blood pressure in hypertensive rats and humans.

The mechanisms by which physical exercise benefits brain functions are not fully understood. Here, we show that vertically oscillating head motions mimicking mechanical accelerations experienced during fast walking, light jogging or treadmill running at a moderate velocity reduce the blood pressure of rats and human adults with hypertension. In hypertensive rats, shear stresses of less than 1 Pa resulting from interstitial-fluid flow induced by such passive head motions reduced the expression of the angiotensin II type-1 receptor in astrocytes in the rostral ventrolateral medulla, and the resulting antihypertensive effects were abrogated by hydrogel introduction that inhibited interstitial-fluid movement in the medulla. Our findings suggest that oscillatory mechanical interventions could be used to elicit antihypertensive effects.

Multi-Functional Silver Nanoparticles for High-Throughput Endospore Sensing.

In spore-forming bacteria such as Bacillus and Clostridium, the vegetative cells form highly durable hard shells called endospores inside the bacteria to survive as the growth environment deteriorates. Because of these properties, endospores can cause food poisoning and medical accidents if they contaminate food, medicine, or other products, and it is required for technology to detect the spores at the manufacturing site. In this study, we focused on the surface-enhanced Raman scattering (SERS) method for the sensitive detection of dipicolinic acid (DPA), a molecular marker of endospores. We constructed Fe3O4/Ag core-shell functional silver nanoparticles that specifically bind to DPA, and investigated a method for the qualitative detection of DPA by SERS and the quantitative detection of DPA by fluorescence method using a terbium complex formed on the surface. As a result, the concentration of the functional silver nanoparticles constructed could detect spore-derived DPA by fluorescence detection method, and SERS was several tens of nM. The functionalized nanoparticles can detect DPA quantitatively and qualitatively, and are expected to be applied to detection technology in the production of food and pharmaceuticals.

Application of Passive Head Motion to Generate Defined Accelerations at the Heads of Rodents.

Exercise is widely recognized as effective for various diseases and physical disorders, including those related to brain dysfunction. However, molecular mechanisms behind the beneficial effects of exercise are poorly understood. Many physical workouts, particularly those classified as aerobic exercises such as jogging and walking, produce impulsive forces at the time of foot contact with the ground. Therefore, it was speculated that mechanical impact might be implicated in how exercise contributes to organismal homeostasis. For testing this hypothesis on the brain, a custom-designed ''passive head motion'' (hereafter referred to as PHM) system was developed that can generate vertical accelerations with controlled and defined magnitudes and modes and reproduce mechanical stimulation that might be applied to the heads of rodents during treadmill running at moderate velocities, a typical intervention to test the effects of exercise in animals. By using this system, it was demonstrated that PHM recapitulates the serotonin (5-hydroxytryptamine, hereafter referred to as 5-HT) receptor subtype 2A (5-HT2A) signaling in the prefrontal cortex (PFC) neurons of mice. This work provides detailed protocols for applying PHM and measuring its resultant mechanical accelerations at rodents' heads.

Human chorionic gonadotropin treatment: a viable option for management of secondary hypogonadism and male infertility.

Introduction: Low testosterone and its symptoms is a condition affecting many males with severe repercussions on health. Testosterone affects metabolism, bones, joints, and ligaments, the cardiovascular system, liver, sexual functions, muscle mass, and the nervous system. Nowadays, due to recent research showing the benefits of testosterone replacement therapy, this treatment is gaining in popularity among aging men. However, testosterone replacement can increase the risk of infertility. Areas covered: Human chorionic gonadotropin (HCG) is used in the treatment of male infertility due to its luteinizing hormone (LH)-like action triggering testosterone and sperm production. Due to these positive effects on testosterone production, HCG has also been used to treat secondary hypogonadism. In this review, based on a literature review for the years 1977-2020 via Google Scholar, we summarize the current research on HCG as treatment for patients suffering from low testosterone and provide an overview of the pros and contras for HCG therapy as compared to testosterone replacement therapy for the treatment of secondary hypogonadism. Expert opinion: The testosterone and sperm production triggering effects of HCG without the side effects on fertility seen in testosterone replacement therapy make HCG therapy a prime candidate for patients suffering from secondary hypogonadism.

Mechanical Regulation Underlies Effects of Exercise on Serotonin-Induced Signaling in the Prefrontal Cortex Neurons.

Mechanical forces are known to be involved in various biological processes. However, it remains unclear whether brain functions are mechanically regulated under physiological conditions. Here, we demonstrate that treadmill running and passive head motion (PHM), both of which produce mechanical impact on the head, have similar effects on the hallucinogenic 5-hydroxytryptamine (5-HT) receptor subtype 2A (5-HT2A) signaling in the prefrontal cortex (PFC) of rodents. PHM generates interstitial fluid movement that is estimated to exert shear stress of a few pascals on cells in the PFC. Fluid shear stress of a relevant magnitude on cultured neuronal cells induces ligand-independent internalization of 5-HT2A receptor, which is observed in mouse PFC neurons after treadmill running or PHM. Furthermore, inhibition of interstitial fluid movement by introducing polyethylene glycol hydrogel eliminates the effect of PHM on 5-HT2A receptor signaling in the PFC. Our findings indicate that neuronal cell function can be physiologically regulated by mechanical forces in the brain.

Anabolic-androgenic steroids: procurement and administration practices of doping athletes.

Performance enhancing substances are becoming increasingly popular amongst bodybuilders and people who want to enhance their physiques. However, due to the rise of the Internet and laws prohibiting sales of these substances without prescription, the route of procurement and administration practices have become more and more dangerous. Prior to the mid-1970's, anabolic steroids were not regulated and easily available from physicians and pharmacies in several countries. In 1990, the United States enacted the Anabolic Steroid Control Act, leading to the proliferation of black markets and underground laboratories. The shift from pharmacy to underground online sites for the procurement of anabolic steroids led to an increase of fake products with low purity and the ability to potentially endanger the health of anabolic steroid users. Underground laboratories emerged both locally and in countries with lax legal regulations. 'Anabolic steroid tourism' and large networks of online resellers emerged, leading to the banalisation of the illegal procurement of anabolic steroids. Furthermore, the increase of anecdotal information spreading on the internet among anabolic steroid user forums nourishes the rampant misinformation and dangerous practices that currently exist. The dosages and ways of administration recommended on these forums can be false and misleading to those who lack a medical background and cannot go to their physician to seek advice because of the fear of repercussions. This review aims to elucidate and describe current practices of the anabolic-androgenic steroids black market and draw attention to potential dangers for users.

Application of Consistent Massage-Like Perturbations on Mouse Calves and Monitoring the Resulting Intramuscular Pressure Changes.

Massage is generally recognized to be beneficial for relieving pain and inflammation. Although previous studies have reported anti-inflammatory effects of massage on skeletal muscles, the molecular mechanisms behind are poorly understood. We have recently developed a simple device to apply local cyclical compression (LCC), which can generate intramuscular pressure waves with varying amplitudes. Using this device, we have demonstrated that LCC modulates inflammatory responses of macrophages in situ and alleviates immobilization-induced muscle atrophy. Here, we describe protocols for the optimization and application of LCC as a massage-like intervention against immobilization-induced inflammation and atrophy of skeletal muscles of mouse hindlimbs. The protocol that we have developed can be useful for investigating the mechanism underlying beneficial effects of physical exercise and massage. Our experimental system provides a prototype of the analytical approach to elucidate the mechanical regulation of muscle homeostasis, although further development needs to be made for more comprehensive studies.

Electrically evoked local muscle contractions cause an increase in hippocampal BDNF.

High-intensity exercise has recently been shown to cause an increase in brain-derived neurotropic factor (BDNF) in the hippocampus. Some studies have suggested that myokines secreted from contracting skeletal muscle, such as irisin (one of the truncated form of fibronectin type III domain-containing protein 5 (FNDC5)), play important roles in this process. Thus, we hypothesized that locally evoked muscle contractions may cause an increase of BDNF in the hippocampus through some afferent mechanisms. Under anesthesia, Sprague-Dawley rats were fixed on a custom-made dynamometer and their triceps surae muscles were made to maximally contract via delivery of electric stimulations of the sciatic nerve (100 Hz with 1-ms pulse and 3-s duration). Following 50 repeated maximal isometric contractions, the protein expressions of BDNF and activation of its receptor in the hippocampus significantly increased compared with the sham-operated control rats. However, the expression of both BDNF and FNDC5 within stimulated muscles did not significantly increase, nor did their serum concentrations change. These results indicate that local muscular contractions under unconsciousness can induce BDNF expression in the hippocampus. This effect may be mediated by peripheral reception of muscle contraction, but not by systemic factors.

Correlation between Ribosome Biogenesis and the Magnitude of Hypertrophy in Overloaded Skeletal Muscle.

External loads applied to skeletal muscle cause increases in the protein translation rate, which leads to muscle hypertrophy. Although some studies have demonstrated that increases in the capacity and efficiency of translation are involved in this process, it remains unclear how these two factors are related to the magnitude of muscle hypertrophy. The present study aimed to clarify the roles played by the capacity and efficiency of translation in muscle hypertrophy. We used an improved synergist ablation in which the magnitude of compensatory hypertrophy could be controlled by partial removal of synergist muscles. Male rats were assigned to four groups in which the plantaris muscle was unilaterally subjected to weak (WK), moderate (MO), middle (MI), and strong (ST) overloading by four types of synergist ablation. Fourteen days after surgery, the weight of the plantaris muscle per body weight increased by 8%, 22%, 32% and 45%, in the WK, MO, MI and ST groups, respectively. Five days after surgery, 18+28S rRNA content (an indicator of translational capacity) increased with increasing overload, with increases of 1.8-fold (MO), 2.2-fold (MI), and 2.5-fold (ST), respectively, relative to non-overloaded muscle (NL) in the WK group. rRNA content showed a strong correlation with relative muscle weight measured 14 days after surgery (r = 0.98). The phosphorylated form of p70S6K (a positive regulator of translational efficiency) showed a marked increase in the MO group, but no further increase was observed with further increase in overload (increases of 22.6-fold (MO), 17.4-fold (MI), and 18.2-fold (ST), respectively, relative to NL in the WK group). These results indicate that increases in ribosome biogenesis at the early phase of overloading are strongly dependent on the amount of overloading, and may play an important role in increasing the translational capacity for further gain of muscular size.