The estrogen metabolites 2-methoxyestradiol and 2-hydroxyestradiol inhibit endometriotic cell proliferation in estrogen-receptor-independent manner

Endometriosis, a painful disorder associated with infertility, is estimated to occur in approximately 7–10% of reproductive age women. Although endometriosis is considered as an estrogen-dependent disease, the role of estrogen metabolites via receptor-independent mechanisms has not yet been comprehensively clarified. In the present study, growth studies were performed comparing the effect of estradiol (E2), estrogen metabolites, that is, 2-hydroxyestradiol (2-OHE2) and 2-methoxyestradiol (2-ME), as well as estrogen-receptor-independent mechanisms using the estrogen receptor antagonist fulvestrant, on cell proliferation of endometriotic cells. The estrogen metabolites 2-OHE2 and 2-ME inhibited cell growth in a dose-dependent manner in pharmacological doses. Lower concentrations of 2-OHE2 had a stimulating effect on cell proliferation while pharmacologic doses exerted an antimitogenic effect. The effects on cell growth were at least partially receptor-independent, as demonstrated by simultaneous receptor antagonization with fulvestrant. In conclusion, our results demonstrate that in pharmacological doses the estrogen metabolites 2-ME and 2-OHE2 show inhibiting effects on the proliferation of endometriotic cells and may be promising substances for the treatment of endometriosis.     

Association of immune checkpoint inhibitors with respiratory infections: A review

Treatment with immune-checkpoint inhibitors (ICIs) has shown efficacy against a variety of cancer types. The use of anti PD-1, anti PD-L1, and anti CTLA-4 antibodies is rapidly expanding. The side effects of ICIs are very different from conventional cytocidal anticancer and molecular target drugs, and may extend to the digestive organs, respiratory organs, thyroid gland, pituitary gland, skin, and others. Although the details of these adverse events are becoming increasingly apparent, much is unknown regarding the effects and adverse events related to infections. This review focuses specifically on the impact of ICIs on respiratory infections.The impact of ICIs on pathogens varies depending on the significance of the role of T-cell immunity in the immune response to the specific pathogen, as well as the different modes of infection (i.e., acute or chronic), although the impact of ICIs on the clinical outcome of infections in humans has not yet been well studied. Enhanced clearance of many pathogens has been shown because immune checkpoint inhibition activates T cells. In contrast, reactivation of tuberculosis associated with ICI use has been reported, and therefore caution is warranted. In COVID-19 pneumonia, ICI administration may lead to exacerbation; however, it is also possible that ICI may be used for the treatment of COVID-19. It has also been shown that ICI has potential in the treatment of intractable filamentous fungal infections. Therefore, expanded clinical applications are expected.     

Evaluation of chemicals for immunomodulatory effects using an in vitro antibody-producing assay

Several chemicals were examined for immunomodulatory effects using the Mishell — Dutton in vitro antibody-producing assay. The chemicals studied were either of environmental concern and/or of special interest to the food industry. A number of these compounds have been shown by others to be immunosuppressive in whole animal exposure studies, at least in certain species and in relatively high doses. Azathioprine (Imuran) (0.5 μg/culture), gallic acid (7 μg/culture), dextran sulfate (100 μg/culture), methyl paraben (100 μg/culture), and vanillin (200 μg/culture) were all found to directly suppress the in vitro anti-sheep red blood cell (SRBC) antibody response at noncytotoxic doses. All of these chemicals appeared to interrupt an early phase of the immune response, and had no effect on the actual release of specific anti-SRBC antibody. The Mishell — Dutton in vitro antibody-producing assay was found to be a sensitive detection system for direct-acting immunosuppressive chemicals. Chemicals that require activation to immunosuppressive intermediates are not detectable in this assay.     

The development of tamoxifen for breast cancer therapy: A tribute to the late Arthur L. Walpole

Summary Tamoxifen, a nonsteroidal antiestrogen, is now the endocrine treatment most widely used in breast cancer, both in the adjuvant and advanced disease settings. Here we will trace the development of tamoxifen for advanced breast cancer in postmenopausal patients, consider the biological basis for the recent successful use of tamoxifen for long-term adjuvant therapy, and discuss the use of tamoxifen in premenopausal patients with advanced disease. In part, this will be a historical review offered as a tribute to the late Dr. Arthur L. Walpole, who must receive the chief credit for the discovery of tamoxifen and its subsequent application as an anticancer agent.     

Comparison of the new atypical antipsychotics olanzapine and ICI 204,636 with clozapine on behavioural responses to the selective “D1-like” dopamine receptor agonist A 68930 and selective “D2-like” agonist RU 24213

The effects of the putative atypical antipsychotics olanzapine and ICI 204,636 on behavioural responses to the selective D₂-like dopamine receptor agonist RU 24213 and to the selective D₁-like agonist A 68930 were compared with those of the prototype atypical antipsychotic clozapine, the selective D₁-like antagonist SCH 23390 and the selective D₂-like antagonist YM 09151-2. Olanzapine (0.4–2.0 mg/kg) and ICI 204,636 (4.0–36.0 mg/kg), like clozapine (4.0–36.0 mg/kg) and SCH 23390 (0.01–1.0 mg/kg), effected at best modest reduction in typical sniffing and locomotor responses and, with the exception of ICI 204,636, released episodes of atypical myoclonic jerking to RU 24213 (12.5 mg/kg); a high dose of olanzapine (10.0 mg/kg), like YM 09151-2 (0.005–0.5 mg/kg), blocked all responsivity to RU 24213. Conversely, olanzapine (0.4–2.0 mg/kg) and ICI 204,636 (4.0–36.0 mg/kg), like clozapine (4.0–12.0 mg/kg) and SCH 23390 (0.01–0.1 mg/kg), readily blocked typical grooming responses to A 68930 (0.5 mg/kg); YM 09151-2 failed to block grooming and exerted more variable effects. Olanzapine and, to a lesser extent, ICI 204,636 share with clozapine a preferential action to attenuate D₁-mediated function; given their lack of selective affinity for D₁-like receptors, this common effect may be exerted at an alternative level of synaptic function. The action of olanzapine and particularly ICI 204,636 to release additional episodes of atypical vacuous chewing to A 68930 indicates some deviation from a wholly clozapine-like profile, the clinical significance of which remains to be specified.     

Effects of cholesterol depletion on compartmentalized cAMP responses in adult cardiac myocytes

β₁-Adrenergic receptors (β₁ARs) and E-type prostaglandin receptors (EPRs) both produce compartmentalized cAMP responses in cardiac myocytes. The role of cholesterol-dependent lipid rafts in producing these compartmentalized responses was investigated in adult rat ventricular myocytes. β₁ARs were found in lipid raft and non-lipid raft containing membrane fractions, while EPRs were only found in non-lipid raft fractions. Furthermore, β₁AR activation enhanced the L-type Ca²⁺ current, intracellular Ca²⁺ transient, and myocyte shortening, while EPR activation had no effect, consistent with the idea that these functional responses are regulated by cAMP produced by receptors found in lipid raft domains. Using methyl-β-cyclodextrin to disrupt lipid rafts by depleting membrane cholesterol did not eliminate compartmentalized behavior, but it did selectively alter specific receptor-mediated responses. Cholesterol depletion enhanced the sensitivity of functional responses produced by β₁ARs without having any effect on EPR activation. Changes in cAMP activity were also measured in intact cells using two different FRET-based biosensors: a type II PKA-based probe to monitor cAMP in subcellular compartments that include microdomains associated with caveolar lipid rafts and a freely diffusible Epac2-based probe to monitor total cytosolic cAMP. β₁AR and EPR activation elicited responses detected by both FRET probes. However, cholesterol depletion only affected β₁AR responses detected by the PKA probe. These results indicate that lipid rafts alone are not sufficient to explain the difference between β₁AR and EPR responses. They also suggest that β₁AR regulation of myocyte contraction involves the local production of cAMP by a subpopulation of receptors associated with caveolar lipid rafts.     

阴茎勃起功能障碍的检测及法医学鉴定

目的探讨阴茎海绵体内药物试验、夜间阴茎勃起监测、视听性刺激、阴茎皮肤交感反应等四种检查方法在外伤性阴茎勃起功能障碍的法医学鉴定中的应用价值,分析外伤性阴茎勃起功能障碍的伤残等级评定问题.方法收集50例道路交通事故损伤所致外伤性阴茎勃起功能障碍司法鉴定案例的资料,采用统计学方法对资料进行分析.结果本文资料中损伤构成比为单纯骨盆骨折18例（36%）,骨盆骨折伴尿道断裂23例（46%）,会阴部软组织损伤、血肿5例（10%）,会阴部皮肤撕脱伤4例（8%）;交通方式为行人25例（50%）,骑自行车12例（24%）,乘坐自行车10例（20%）,驾驶员3例（6%）;阴茎海绵体内药物试验提示阴茎血管功能正常者41例（82%）,提示阴茎动脉或海绵体功能障碍者9例（18%）;夜间阴茎勃起监测正常17例（34%）,轻度异常20例（40%）,中度异常11例（22%）,重度异常2例（4%）;视听性刺激结果正常者42例（84%）,异常者8例（16%）;阴茎皮肤交感反应正常者23例（46%）,异常者27例（54%）.结论夜间阴茎勃起监测是最佳的检查方法阴茎海绵体内药物试验、视听性刺激、阴茎皮肤交感反应的检查结果进行综合分析,可有助于判断鉴定.