Early detection of multiple endocrine neoplasia type 1: A case report

BACKGROUND Multiple endocrine neoplasias(MENs)are a group of hereditary diseases invol-ving multiple endocrine glands,and their prevalence is low.MEN type 1(MEN1)has diverse clinical manifestations,mainly involving the parathyroid glands,gastrointestinal tract,pancreas and pituitary gland,making it easy to miss the clinical diagnosis.CASE SUMMARY We present the case of a patient in whom MEN1 was detected early.A middle-aged male with recurrent abdominal pain and diarrhea was admitted to the hos-pital.Blood tests at admission revealed hypercalcemia and hypophosphatemia,and emission computed tomography of the parathyroid glands revealed a hy-perfunctioning parathyroid lesion.Gastroscopy findings suggested a duodenal bulge and ulceration.Ultrasound endoscopy revealed a hypoechoic lesion in the duodenal bulb.Further blood tests revealed elevated levels of serum gastrin.Surgery was performed,and pathological analysis of the surgical specimens revealed a parathyroid adenoma after parathyroidectomy and a neuroendocrine tumor after duodenal bulbectomy.The time from onset to the definitive diagnosis of MEN1 was only approximately 1 year.CONCLUSION For patients who present with gastrointestinal symptoms accompanied by hyper-calcemia and hypophosphatemia,clinicians need to be alert to the possibility of MEN1.

Impacts of different pancreatic resection ranges on endocrine function in Suncus murinus

BACKGROUND Surgical intervention involving the pancreas can lead to impaired glucose tolerance and other types of endocrine dysfunction.The scope of pancreatectomy and whether it includes the ventral pancreas are the key factors in the development of postoperative diabetes.The ventral and dorsal pancreases are almost separated in Suncus murinus(S.murinus).AIM To investigate the effects of different extents of pancreatic resection on endocrine function in S.murinus.METHODS Eight-week-old male S.murinus shrews were randomly divided into three experimental groups according to different pancreatic resection ranges as follows:ventral pancreatectomy(VPx)group;partial pancreatectomy(PPx)group;subtotal pancreatectomy(SPx)group;and a sham-operated group.Postprandial serum insulin,glucagon-like peptide-1(GLP-1),pancreatic polypeptide(PP),and somatostatin(SST)levels,as well as food intake,weight,blood glucose,and glucose tolerance were regularly measured for each animal.RESULTS S.murinus treated with PPx and SPx suffered from varying degrees of impaired glucose tolerance,but only a small proportion of the SPx group developed diabetes.Only S.murinus in the SPx group showed a significant decrease in food intake accompanied by severe weight loss,as well as a significant increase in postprandial serum GLP-1 levels.Postprandial serum PP levels decreased in both the VPx and PPx groups,but not in the SPx group.Postprandial serum SST levels decreased in both VPx and PPx groups,but the decrease was marginal.CONCLUSION Severe weight loss after pancreatectomy may be related to loss of appetite caused by compensatory elevation of GLP-1.PP and GLP-1 may play a role in resisting blood glucose imbalance.

Circadian rhythm disruption and endocrine-related tumors

This review delved into the intricate relationship between circadian clocks and physiological processes,emphasizing their critical role in maintaining homeo-stasis.Orchestrated by interlocked clock genes,the circadian timekeeping system regulates fundamental processes like the sleep-wake cycle,energy metabolism,immune function,and cell proliferation.The central oscillator in the hypothalamic suprachiasmatic nucleus synchronizes with light-dark cycles,while peripheral tissue clocks are influenced by cues such as feeding times.Circadian disruption,linked to modern lifestyle factors like night shift work,correlates with adverse health outcomes,including metabolic syndrome,cardiovascular diseases,infec-tions,and cancer.We explored the molecular mechanisms of circadian clock genes and their impact on metabolic disorders and cancer pathogenesis.Specific associ-ations between circadian disruption and endocrine tumors,spanning breast,ovarian,testicular,prostate,thyroid,pituitary,and adrenal gland cancers,are highlighted.Shift work is associated with increased breast cancer risk,with PER genes influencing tumor progression and drug resistance.CLOCK gene expression correlates with cisplatin resistance in ovarian cancer,while factors like aging and intermittent fasting affect prostate cancer.Our review underscored the intricate interplay between circadian rhythms and cancer,involving the regulation of the cell cycle,DNA repair,metabolism,immune function,and the tumor microenvir-onment.We advocated for integrating biological timing into clinical consider-ations for personalized healthcare,proposing that understanding these connec-tions could lead to novel therapeutic approaches.Evidence supports circadian rhythm-focused therapies,particularly chronotherapy,for treating endocrine tumors.Our review called for further research to uncover detailed connections between circadian clocks and cancer,providing essential insights for targeted treatments.We emphasized the importance of public health interventions to mitigate lifestyle-related circadian disruptions and underscored the critical role of circadian rhythms in disease mechanisms and therapeutic interventions.

Detection of Endocrine Disruptors in Water around Landfills

[Objectives]This study was conducted to explore the occurrence levels of endocrine disruptors(EDCs)in rural areas around a county landfill in Tongren City.[Methods]The water around the landfill was sampled and analyzed.A solid-phase extraction and high performance liquid chromatography-tandem mass spectrometry(SPE-UPLC-MS/MS)method was established for the determination of 27 EDCs.After the HLB solid-phase extraction column was activated,a water sample,which was adjusted with phosphoric acid to a pH of 2(±0.5)and added with 500 mg of disodium EDTA,was loaded,and 5 ml of water and 20%methanol water was added for washing.Next,10 ml of elution solution was added for elution,and the collected eluate was evaporated under reduced pressure at 40℃to near dryness,and 1 ml of reconstitution solution was added to a constant volume.An ACQUITY UPLC BEH C18(100×2.1 mm,2.6μm)chromatographic column was adopted for LC separation by gradient elution with pure water solution-acetonitrile as the mobile phase.For MS detection,the MRM mode was adopted for collection,and the positive and negative ion modes were switched for simultaneous determination,and the internal standard method was used for quantification.[Results]The correlation coefficient R2 was greater than 0.99 in the linear range of each target substance.The limits of quantitation in the method were between 0.05 and 2.00 ng/L,and the recoveries ranged from 75.3%to 105.7%.[Conclusions]The method has high sensitivity,good accuracy and strong practical value.

Mixed epithelial endocrine neoplasms of the colon and rectum–An evolution over time:A systematic review

BACKGROUND Mixed tumors of the colon and rectum,composed of a combination of epithelial and endocrine elements of benign and malignant potential are rare neoplasms.These can occur anywhere in the gastrointestinal tract and are often diagnosed incidentally.Though they have been a well-documented entity in the pancreas,where the exocrine-endocrine mixed tumors have been known for a while,recognition and accurate diagnosis of these tumors in the colon and rectum,to date,remains a challenge.This is further compounded by the different terminologies that have been attributed to these lesions over the years adding to increased confusion and misclassification.Therefore,dedicated literature reviews of these lesions in the colon and rectum are inconsistent and are predominantly limited to case reports and case series of limited case numbers.Though,most of these tumors are high grade and of advanced stage,intermediate and low grade lesions of these mixed tumors are also increasingly been reported.There are no established independent consensus based guidelines for the therapeutic patient management of these unique lesions.AIM To provide a comprehensive targeted literature review of these complex mixed tumors in the colon and rectum that chronicles the evolution over time with summarization of historical perspectives of terminology and to further our understanding regarding their pathogenesis including genomic landscape,clinicoradiological features,pathology,treatment,prognosis,the current status of the management of the primary lesions,their recurrences and metastases.METHODS A comprehensive review of the published English literature was conducted using the search engines PubMed,MEDLINE and GOOGLE scholar.The following search terms[“mixed tumors colon”OR mixed endocrine/neuroendocrine tumor/neoplasm/lesion colon OR adenocarcinoma and endocrine/neuroendocrine tumor colon OR mixed adenocarcinoma and endocrine/neuroendocrine carcinoma colon OR Amphicrine tumors OR Collision tumors]were used.Eligibility criteria were defined and all potential relevant items,including full articles and/or abstracts were independently reviewed,assessed and agreed upon items were selected for in-depth analysis.RESULTS In total 237 full articles/abstracts documents were considered for eligibility of which 45 articles were illegible resulting in a total of 192 articles that were assessed for eligibility of which 139 have been selected for reference in this current review.This seminal manuscript is a one stop article that provides a detailed outlook on the evolution over time with summarization of historical perspectives,nomenclature,clinicoradiological features,pathology,treatment,prognosis and the current status of the management of both the primary lesions,their recurrences and metastases.Gaps in knowledge have also been identified and discussed.An important outcome of this manuscript is the justified proposal for a new,simple,clinically relevant,non-ambiguous terminology for these lesions to be referred to as mixed epithelial endocrine neoplasms(MEENs).CONCLUSION MEEN of the colon and rectum are poorly understood rare entities that encompass an extensive range of heterogeneous tumors with a wide variety of combinations leading to tumors of high,intermediate or low grade malignant potential.This proposed new revised terminology of MEEN will solve the biggest hurdle of confusion and misclassification that plagues these rare unique colorectal neoplasms thus facilitating the future design of multi institutional prospective randomized controlled clinical trials to develop and evaluate newer therapeutic strategies that are recommended for continued improved understanding and personal optimization of clinical management of these unique colorectal neoplasms.

Myo-inositol versus metformin effects on clinical features, endocrine and metabolic profiles in infertile women with polycystic ovary syndrome: A randomized controlled trial

Objective:To compare the effectiveness of inositol and metformin on the clinical characteristics,and endocrine and metabolic profiles of infertile polycystic ovarian syndrome(PCOS)women from Vietnam.Methods:From June 2018 to August 2022,a randomized trial was undertaken at the Hue Center for Endocrinology and Reproduction on infertile women aged 18 to 40 years with polycystic ovarian syndrome.The clinical,endocrine,and metabolic features of these individuals were assessed before and after 3 months of treatment with 2 g of inositol or 1700 mg of metformin per day.Natural pregnancy rates,adverse effects,and tolerance of inositol were recorded.Results:The study included 171 infertile PCOS women who were eligible to participate and took part in the baseline assessment,of whom 132 women participated in data analysis after 3 months.After metformin treatment,42.1%of women with oligomenorrhea experienced regular menstruation.Metformin significantly lowered body mass index(BMI),waist circumference and testosterone levels,but had no effect on other clinical characteristics,endocrine profiles,or metabolic profiles.29.2%Of women reported experiencing side effects.21%Of them attained pregnancy,which resulted in 17.1%of live births.In the inositol group,the rate of regular cycle increased by 18.2%and the total testosterone concentration significantly decreased.In overweight/obese women with PCOS,inositol significantly decreased weight,BMI,waist and hip circumferences(P<0.05).100%Of women tolerated inositol and continued treatment.18.9%Of them became pregnant,leading to 17%of live births.Conclusions:Metformin and inositol can improve weight and waist circumference in overweight/obese infertile women with PCOS.Metformin is associated with a higher rate of regular menstruation,whereas inositol is associated with a lower rate of adverse effects.The spontaneous conception,clinical pregnancy,and live birth rates between two groups are comparable.

Systematic review and meta-analysis of endometrial thickening during endocrine therapy combined with Chinese herbal medicine intervention after breast cancer surgery

Objective:To systematically evaluate the endometrial thickening and Chinese herbal medicine intervention effects during endocrine therapy following breast cancer surgery.Methods:Computerized searches were performed on CNKI,CBM,Wanfang,VIP,Pub Med,Embase,and Cochrane to gather randomized controlled trials(RCTs)of endometrial thickening combined with Chinese herbal medicine intervention during endocrine therapy after breast cancer surgery.The meta analysis is done using Rev Man 5.4,and the retrieval range is from the database's creation to January 2023.Results:There were 710 patients enrolled in a total of 12 RCTs.The results of Meta-analysis were as follows:combined with Chinese herbal medicine treatment for 3 months of endometrial thickness(MD=-1.12,95%CI[-1.47,0.77],P<0.00001);6 months endometrial thickness(MD=-1.90,95%CI[-2.38,-1.42],P<0.00001);endometrial thickness at 12 months(MD=-2.24,95%CI[-2.96,-1.52],P<0.00001);modified Kupperman score(MD=-10.45,95%CI[-19.10,-1.80],P=0.02);TCM syndrome score(SMD=-1.53,95%CI[-1.84,-1.22],P<0.00001);KPS score(MD=3.75,95%CI[2.81,4.68],P<0.00001);there was no significant difference in CA153,CEA,FSH and E2 between the two groups.Conclusion:After breast cancer surgery,endocrine therapy combined with Chinese herbal medicine can significantly lessen endometrial thickening and enhance patient quality of life.

Recent standardization of treatment strategy for pancreatic neuroendocrine tumors

Recent advances in localization techniques,such as the selective arterial secretagogue injection test(SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors(PNET).For patients with sporadic functioning PNET,curative resection surgery has been established by localization with the SASI test using secretin or calcium.For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1(MEN 1) which are usually multiple and sometimes numerous,resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test.As resection surgery of PNET has increased,several important pathological features of PNET have been revealed.For example,in patients with Zollinger-Ellison syndrome(ZES),duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma,and in patients with MEN 1 and ZES,gastrinomas have been located mostly in the duodenum,and pancreatic gastrinoma has been found to co-exist in 13% of patients.Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation.The most important prognos-tic factor in patients with PNET is the development of hepatic metastases.The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit.The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed.

Primary large cell neuroendocrine carcinoma in the common bile duct:First Asian case report

Large cell neuroendocrine carcinoma(LCNEC)in the biliary system is a poorly differentiated,high-grade neuroendocrine tumor.These tumors exhibit aggressive behavior and an increased tendency for early nodal and distant metastases.Herein,we report an unusual case of a pure primary LCNEC of the common bile duct(CBD).A 75-year-old female presented with nausea and jaundice.The patient underwent a CBD excision with lymph node dissection.Upon histological and immunohistochemical examination,the tumor exhibited pure large cell-type neuroendocrine features.Metastases were noted in two of the eight lymph nodes.The patient was administered adjuvant chemotherapy.The patient’s cancer recurred 7 mo after surgery,and the patient died from liver failure 5 mo after recurrence.The prognosis of LCNEC of CBD remains poor despitecurative resection and adjuvant chemotherapy.The role of additional therapies,such as multimodal treatment including radiation therapy,must be further studied to improve the prognoses of patients.

关于Endocrine Disruptors的译名

当今环境科学的发展十分迅速 ,新的名词术语大量涌现 ,但由于对这些名词翻译和使用上的不统一 ,给广大的科技工作者和关心环境问题的普通百姓造成了工作中或认识上的麻烦和混乱。例如 ,“一类来源于环境中的、能干扰生物体内分泌功能的物质” ,就有“环境内分泌干扰物”、“内分泌干扰物”、“内分泌紊乱剂”、“环境激素”、“环境荷尔蒙”等多种中文名称 ,其英文名称也有“endocrinedisruptors”、“environ mentalendocrinedisruptors”、“endocrinedisruptingchemicals”、“environmentalhormones”等多种表述 ,并且对这类物质的定义 ,在国际上还没有达到完全一致 ,亟待统一和规范。为了尽快统一和规范环境科学的名词术语 ,我们邀请有关专家在本刊对一些新近出现的影响较大、分歧较多的环境科学名词术语进行研究和讨论 ,以期为将来名词的最终审定奠定基础。我们欢迎广大读者来稿发表意见 ,以使审定的名词更科学、更准确、更有利于普及利用。

Current surgical management of pancreatic endocrine tumor liver metastases

BACKGROUND: The management of metastatic disease in pancreatic endocrine tumors (PETs) demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved. DATA SOURCES: A PubMed search of relevant articles published up to February 2011 was performed to identify current information about PET liver metastases regarding diagnosis and management, with an emphasis on surgery. RESULTS: The early diagnosis of metastases and their accurate localization, most commonly in the liver, is very important. Surgical options include radical excision, and palliative excision to relieve symptoms in case of failure of medical treatment. The goal of the radical excision is to remove the primary tumor bulk and all liver metastases at the same time, but unfortunately it is not feasible in most cases. Palliative excisions include aggressive tumor debulking surgeries in well-differentiated carcinomas, trying to remove at least 90% of the tumor mass, combined with other additional destructive techniques such as hepatic artery embolization or chemoembolization to treat metastases or chemoembolization to relieve symptoms in cases of rapidly growing tumors. The combination of chemoembolization and systemic chemotherapy results in better response and survival rates. Other local destructive techniques include ethanol injection, cryotherapy and radiofrequency ablation. CONCLUSION: It seems that the current management of PETs can achieve important improvements, even in advanced cases.

Comprehensive treatment of rare multiple endocrine neoplasia type 1:A case report

BACKGROUND Multiple endocrine neoplasia type 1(MEN1)is a rare hereditary disorder caused by mutations of the MEN1 gene.It is characterized by hyperparathyroidism and involves the pancreas,anterior pituitary,duodenum,and adrenal gland.Here,we report a 40-year-old male patient with MEN1 who first manifested as thymic carcinoid,then primary hyperparathyroidism and prolactinoma,and a decade later pancreatic neuroendocrine tumor.CASE SUMMARY The patient underwent a thymectomy because of the thymic carcinoid 10 years prior and a prolactinoma resection 2 years prior.His sister suffered from prolactinoma.His parents displayed a typical triad of amenorrhea,galactorrhea,and infertility.Computed tomography revealed a strong signal in the upper portion of the left lobes and posterior portion of the right lobes of the thyroid and irregular soft tissue densities of the pancreatic body.Positron emission tomography/computed tomography imaging further showed strong 18Fflurodeoxyglucose uptake in the tail of the pancreatic body and segment IV of the liver.The patient underwent pancreatic body tail resection,pancreatic head mass enucleation,and ultrasound-guided radio-frequency ablation for liver cancer.Pathology results reported neuroendocrine tumor grade 2.Whole exome sequencing revealed a verified pathogenic mutation c.378G>A(p.Trp126*)in the MEN1 gene.The diagnosis of MEN1 was confirmed.At the 1.5-year follow-up,the patient appeared healthy without any sign of reoccurrence.CONCLUSION The present case may add some insight into the diagnosis and treatment of patients with MEN1.

Integrative rodent models for assessing male reproductive toxicity of environmental endocrine active substances

In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance （EAS） exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action （MOA） of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool （together with the epidemiological approach） for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction.

Extensive multiarterial resection attending total duodenopancreatectomy and adrenalectomy for MEN-1-associated neuroendocrine carcinomas

Pancreatic neuroendocrine tumors(PNTs) are relatively uncommon although these neoplasms have been noted to grow in occurrence in recent decades.Surgical removal of locally advanced PNTs involving major vessels and adjacent organs is warranted by reason of an appreciably more favorable prognosis as compared to exocrine pancreas cancer.We are reporting a case of successful multi-organ resection combined with a wide excision of the superior mesenteric,common,proper,left and right hepatic arteries(in the presence of the hepatomesenteric trunk variant of aberrant arterial anatomy) for multifocal PNTs in the setting of multiple neuroendocrine neoplasia type 1 syndrome.The procedure resulted in pain abolition,a significant improvement in the patient's life quality and allowed her to return to work.Follow-up computed tomography at 15 mo post-surgery showed no evidence of disease recurrence.

Functionality is not an independent prognostic factor for pancreatic neuroendocrine tumors

BACKGROUND Pancreatic neuroendocrine neoplasms(pNENs)that produce hormones leading to symptoms are classified as functional tumors,while others are classified as nonfunctional tumors.The traditional view is that functionality is a factor that affects the prognosis of pNEN patients.However,as the sample sizes of studies have increased,researches in recent years have proposed new viewpoints.AIM To assess whether functionality is an independent factor for predicting the prognosis of pNEN patients.METHODS From January 2004 to December 2016,data of patients who underwent surgery at the primary site for the treatment of pNENs from the Surveillance,Epidemiology,and End Results(SEER)database and West China Hospital database were retrospectively analyzed.RESULTS Contemporaneous data from the two databases were analyzed separately as two cohorts and then merged as the third cohort to create a large sample that was suitable for multivariate analysis.From the SEER database,age(P=0.006)and T stage(P<0.001)were independent risk factors affecting the survival.From the West China Hospital database,independent prognostic factors were age(P=0.034),sex(P=0.032),and grade(P=0.039).The result of the cohort consisting of the combined populations from the two databases showed that race(P=0.015),age(P=0.002),sex(P=0.032)and T stage(P<0.001)were independent prognostic factors.In the West China Hospital database and in the total population,nonfunctional pNETs and other functional pNETs tended to have poorer prognoses than insulinoma.However,functionality was not associated with the survival time of patients with pNETs in the multivariate analysis.CONCLUSION Functionality is not associated with prognosis.Race,age,sex,and T stage are independent factors for predicting the survival of patients with pNETs.

Neuro Endocrine Tumor of the Gall Bladder: A Case Report

Neuroendocrine tumors (NET) of the gallbladder are a rare entity with only 0.2% of all NET located in the gall bladder. Well-differentiated NETs occur at a relatively lower age group unlike other gallbladder tumors, whereas neuroendocrine carcinoma (NEC) occurs in an older category of patients. The aim of our study is to discuss the current level of evidence regarding this pathological entity by means of a rare case report on a neuroendocrine carcinoma of the gall bladder in a 63-year-old patient with a history of diabetes. Patient underwent cholecystectomy for acute cholecystitis. Pathology findings on surgical specimen came back for neuroendocrine tumour.

Paracrine and endocrine actions of bone——the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts

The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes,and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin（SOST） that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influencea A osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or ＂osteokines＂from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin（OCN） secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2（LCN2） is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain.We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process.

Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer

The estrogen receptor(ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, posttranslational modification of ER, deregulation of ER coactivators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin(m TOR), Mitogen activated kinase(MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modificationincluding dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific micro RNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the m TOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in Pub Med, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at Clinical Trials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.

Overcoming endocrine resistance in metastatic breast cancer: Current evidence and future directions

About 75% of all breast cancers are estrogen receptor(ER)-positive. They generally have a more favorable clinical behavior, prognosis, and pattern of recurrence, and endocrine therapy forms the backbone of treatment. Anti-estrogens(such as tamoxifen and fulvestrant) and aromatase inhibitors(such as anastrozole, letrozole, and exemestane) can effectively control the disease and induce tumor responses in a large proportion of patients. However, the majority of patients progress during endocrine therapy(acquired resistance) and a proportion of patients may fail to respond to initial therapy(de novo resistance). Endocrine resistance is therefore of clinical concern and there is great interest in strategies that delay or circumvent it. A deeper knowledge of the molecular mechanisms that drive endocrine resistance has recently led to development of new strategies that have the promise to effectivelyovercome it. Many resistance mechanisms have been described, and the crosstalk between ER and growth factor receptor signaling pathways seems to represent one of the most relevant. Compounds that are able to inhibit key elements of these pathways and restore endocrine sensitivity have been studied and more are currently under development. The aim of this review is to summarize the molecular pathophysiology of endocrine resistance in breast cancer and its impact on current clinical management.

Endocrine disruptors and estrogenic effects on male reproductive axis

Endocrine disruptors （e.g., polychlorinated biphenyls [PCBs], dichlorodiphenyl-trichloroethane [DDT], dioxin, and some pesticides） are estrogen-like and anti-androgenic chemicals in the environment. They mimic natural hormones, inhibit the action of hormones, or alter the normal regulatory function of the endocrine system and have potential hazardous effects on male reproductive axis causing infertility. Although testicular and prostate cancers, abnormal sexual development, undescended testis, chronic inflammation, Sertoli-cell-only pattern, hypospadias, altered pituitary and thyroid gland functions are also observed, the available data are insufficient to deduce worldwide conclusions. The development of intra-cytoplasmic sperm injection （ICSI） is beyond doubt the most important recent breakthrough in the treatment of male infertility, but it does not necessarily treat the cause and may inadvertently pass on adverse genetic consequences. Many well-controlled clinical studies and basic scientific discoveries in the physiology, biochemistry, and molecular and cellular biology of the male reproductive system have helped in the identification of greater numbers of men with male factor problems. Newer tools for the detection of Y-chromosome deletions have further strengthened the hypothesis that the decline in male reproductive health and fertility may be related to the presence of certain toxic chemicals in the environment. Thus the etiology, diagnosis, and treatment of male factor infertility remain a real challenge. Clinicians should always attempt to identify the etiology of a possible testicular toxicity, assess the degree of risk to the patient being evaluated for infertility, and initiate a plan to control and prevent exposure to others once an association between occupation/toxicant and infertility has been established.