Reporting sex or gender in anatomical research: Which is appropriate?

Sex- and gender-based differences need to be considered in evidence-based medical research as there are anatomical and physiological differences between males and females. Females are underrepresented in studies, with results from males often generalized to both sexes. The Sex and Gender Equity in Research (SAGER) guidelines were published in 2016 to address sex- and gender-bias in research. Correct understanding and appropriate use of the terms "sex" and "gender" are essential. These terms are discussed in an anatomical context and recommendations are made as to how the SAGER guidelines can guide the reporting of anatomical studies to minimize the risk of reporting bias. Clin. Anat. 32:697-698, 2019. © 2019 Wiley Periodicals, Inc.

The surgical anatomy of the sural nerve: An ultrasound study.

The aim of this study was (a) to examine the anatomy of the sural nerve (SN) in a sample of 30 patients and (b) to analyze the incidence of different origins of the SN, and the distance of the SN from planned arthroscopic portals. An ultrasound (USG) examination of the SN was performed bilaterally on thirty healthy patients with no history of surgery or trauma of the lower limb. The SNs were classified into six main types of pattern, with an additional category for new and unclassified types. Each of Types 1 and 3 had two subdivisions. The distances from the superior border of the calcaneal tuberosity to the three simulated arthroscopy portal sites (Z1, Z1.5, Z2) to the SN were measured. A total of 30 patients (n = 60 limbs) with an average age of 27 ± 7.5 years were examined and the SN was visualized in all cases. The most common origin was Type 3A, accounting for 30% of limbs. Type 2 was the second most common seen in 18.3%. The distances of the SN from arthroscopic portal placement sites above the lateral malleolus were 2.07 ± 0.39 cm at the Z1 portal, 2.15 ± 0.38 cm at Z1.5, and 2.28 ± 0.33 cm at Z2. The variability in the anatomy of the SN warrants the use of USG to locate it accurately, thus preventing iatrogenic injury when portals are placed for arthroscopy, improving proper administration of anesthesia, and helping to localize the nerve for graft harvesting. Clin. Anat. 31:450-455, 2018. © 2017 Wiley Periodicals, Inc.

The evidence-based surgical anatomy of the popliteal artery and the variations in its branching patterns.

OBJECTIVE: The goal of our study was to analyze the prevalence of branching pattern variations in the popliteal artery (PA) along with morphometrics of the PA to better address its importance in disease and vascular surgical procedures. METHODS: An extensive search for the PA and its anatomic variations was done in the major online medical databases. The anatomic data found were extracted and pooled for a meta-analysis. RESULTS: A total of 33 studies (N = 12,757 lower limbs) were included in the analysis. The most common variant was a division of the PA below the knee into the anterior tibial artery and a common trunk for the posterior tibial and peroneal arteries, with a prevalence of 92.6% (95% confidence interval [CI], 90.2-93.8). The second most common variation was a trifurcation pattern of all three branches dividing within 0.5 cm of each other, with a prevalence of 2.4% (95% CI, 1.4-3.5). Of the three studies that reported the diameter of the PA at the level of the subcondylar plane, a mean diameter of 8 mm (95% CI, 7.29-8.70) was found. CONCLUSIONS: The PA most commonly divides below the knee into the anterior tibial artery and the common trunk of the posterior tibial artery and the peroneal artery. Knowledge of the prevalence of possible variations in this anatomy as well as morphometric data is crucial in the planning and execution of any surgical intervention in the area of the knee.

Risk of iatrogenic injury to the infrapatellar branch of the saphenous nerve during hamstring tendon harvesting: A meta-analysis.

INTRODUCTION: Our goal was to conduct a comprehensive analysis of studies reporting data on the rate of injury to the infrapatellar branch of the saphenous nerve following hamstring tendon graft harvesting with respect to the type of incision over the pes anserinus. METHODS: A broad search through all major electronic databases was conducted to identify articles eligible for inclusion. All available data were extracted and pooled into the analysis. RESULTS: Eleven studies (n = 1,050 patients) were included in the meta-analysis. The study revealed that a vertical incision during hamstring tendon harvesting over the pes anserinus was associated with the highest rate of injury with a pooled rate of 51.4% (95% confidence interval [CI], 34.6-67.2%). This was followed by oblique and horizontal incisions with pooled rates of 26.0% (95% CI,1.3-61.3%) and 22.4% (95% CI, 5.4-45.5%), respectively. CONCLUSIONS: We highly recommend the use of the shortest possible oblique incision during hamstring tendon harvesting over the pes anserinus. Muscle Nerve 56: 930-937, 2017.

Development of the anatomical quality assessment (AQUA) tool for the quality assessment of anatomical studies included in meta-analyses and systematic reviews.

Critical appraisal of anatomical studies is essential before the evidence from them undergoes meta-epidemiological synthesis. However, no instrument for appraising anatomical studies with inherent applicability to different study designs is available. We aim to develop a generic yet comprehensive tool for assessing the quality of anatomical studies using a formal consensus method. The study steering committee formulated an initial conceptual design and generated items for a preliminary tool on the basis of a literature review and expert opinion. A Delphi procedure was then adopted to assess the validity of the preliminary tool. Feedback from the Delphi panelists was used to improve it. The Delphi procedure involved 12 experts in anatomical research. It comprised two rounds, after which unanimous consensus was reached about the items to be included. The preliminary tool consisted of 20 items, which were phrased as signaling questions and organized into five domains: 1. Aim and subject characteristics, 2. Study design, 3. Characterization of methods, 4. Descriptive anatomy, and 5. Results reporting. Each domain was set to end with a risk of bias question. Following round 1, some of the items underwent major revision, although agreement was reached regarding inclusion of all the domains and signaling questions in the preliminary tool. The tool was revised only for minor language inaccuracies after round 2. The AQUA Tool was designed to assess the quality and reliability of anatomical studies. It is currently undergoing a validation process. Clin. Anat. 30:6-13, 2017. © 2016 Wiley Periodicals, Inc.

Variations in the origin of the deep femoral artery: A meta-analysis.

The deep femoral artery (DFA) is the largest branch of the femoral artery (FA) and is responsible for vascularization of the thigh muscles. Knowledge of the anatomical variations in its origin point is important for surgeons and interventional radiologists. The aim of our study was to provide a comprehensive evidence-based assessment of its anatomical properties. An extensive search through the major electronic databases was conducted to find all articles reporting data on the anatomical characteristics of the DFA. No date limits or language restrictions were imposed. A total of 25 articles (n = 2,502 lower limbs) were included in the meta-analysis. Six different patterns of origin of the DFA from the FA were identified, the most common type being a posterior origin (38.8%, 95% CI 22.8-49.5%). The DFA most commonly branched off in the proximal third of the thigh, with a prevalence of 47.6% (95% CI 35.8-59.2%). The pooled mean distance of the DFA from its point of origin to the mid-inguinal point was 41.15 mm (95% CI 32.39-53.73). The point and level of origin of the DFA from the FA varies widely in the general population. Owing to this variability, accurate anatomical knowledge regarding the DFA is crucial for clinicians if iatrogenic injuries are to be avoided during procedures in the femoral region. Clin. Anat. 30:106-113, 2017. © 2016 Wiley Periodicals, Inc.

Development of the Anatomical Quality Assurance (AQUA) checklist: Guidelines for reporting original anatomical studies.

The rise of evidence-based anatomy has emphasized the need for original anatomical studies with high clarity, transparency, and comprehensiveness in reporting. Currently, inconsistencies in the quality and reporting of such studies have placed limits on accurate reliability and impact assessment. Our aim was to develop a checklist of reporting items that should be addressed by authors of original anatomical studies. The study steering committee formulated a preliminary conceptual design and began to generate items on the basis of a literature review and expert opinion. This led to the development of a preliminary checklist. The validity of this checklist was assessed by a Delphi procedure, and feedback from the Delphi panelists, who were experts in the area of anatomical research, was used to improve it. The Delphi procedure involved 12 experts in anatomical research. It comprised two rounds, after which unanimous consensus was reached regarding the items to be included in the checklist. The steering committee agreed to name the checklist AQUA. The preliminary AQUA Checklist consisted of 26 items divided into eight sections. Following round 1, some of the items underwent major revision and three new ones were introduced. The checklist was revised only for minor language inaccuracies after round 2. The final version of the AQUA Checklist consisted of the initial eight sections with a total of 29 items. The steering committee hopes the AQUA Checklist will improve the quality and reporting of anatomical studies. Clin. Anat. 30:14-20, 2017. © 2016 Wiley Periodicals, Inc.

Anatomical variability and histological structure of the ulnar nerve in the Guyon's canal.

OBJECTIVES: The goal of our study was to analyze the prevalence of variations, branching patterns, and histology of the ulnar nerve (UN) in Guyon's canal to address its importance in hand surgery, particularly decompression of the UN. METHODS: Fifty fresh cadavers were dissected bilaterally, and the nerve in the area of Guyon's canal was visualized. Samples for histology were also taken and prepared. The collected data were then analyzed. RESULTS: Morphometric measurements of the hands and histological studies were not found to have significant differences when compared by left or right side or by sex. Three major branching patterns were found, with division into deep and superficial UN being the most common (85%). Additional findings included a majority (70%) presenting with a cutaneous branch within the canal and/or with an anastomosis of its distant branches with those of the median nerve (57%). CONCLUSION: The UN is most commonly found to divide into a superficial and deep ulnar branch within Guyon's canal. However, additional branches and anastomoses are common and should be taken into careful consideration when approached during surgery in the area, particularly during decompression procedures of Guyon's canal.

Median and ulnar nerve anastomoses in the upper limb: A meta-analysis.

INTRODUCTION: The most frequently described anomalous neural connections between the median and ulnar nerves in the upper limb are: Martin-Gruber anastomosis (MGA), Marinacci anastomosis (MA), Riche-Cannieu anastomosis (RCA), and Berrettini anastomosis (BA). The reported prevalence rates and characteristics of these anastomoses vary significantly between studies. METHODS: A search of electronic databases was performed to identify all eligible articles. Anatomical data regarding the anastomoses were pooled into a meta-analysis using MetaXL 2.0. RESULTS: A total of 58 (n = 10,562 upper limbs) articles were included in the meta-analysis. The pooled prevalences were: MGA, 19.5% (95% confidence interval [CI], 16.2%-23.1%); MA, 0.7% (95% CI, 0.1%-1.7%); RCA, 55.5% (95% CI, 30.6%-79.1%); and BA, 60.9% (95% CI, 36.9%-82.6%). The results also showed that MGA was more commonly found unilaterally (66.8%), on the right side (15.7%), following an oblique course (84.8%), and originating from the anterior interosseous nerve with a prevalence of 57.6%. CONCLUSIONS: As anastomoses between the median and ulnar nerves occur commonly, detailed anatomical knowledge is essential for accurate interpretation of electrophysiological findings and reducing the risk of iatrogenic injuries during surgical procedures. Muscle Nerve 54: 36-47, 2016.

Regiodefined synthesis of brominated hydroxyanthraquinones related to proisocrinins.

Dibromobenzoisofuranone 12, synthesized in six steps, was regiospecifically annulated with 5-substituted cyclohexenones 13/36 in the presence of LiOt-Bu to give brominated anthraquinones 14/38 in good yields. Darzens condensation of 30 was shown to give chain-elongated anthraquinone 32. Alkaline hydrolysis of 38 furnished 39 representing desulfoproisocrinin F.

A regioselective facile synthesis of furo[3,4-b]carbazolones: application to the total synthesis of mafaicheenamine E and claulansine D.

1-Hydroxycarbazole-2,3-dicarboxylates have been shown to undergo chemoselective reductive cyclization to furo[3,4-b]carbazolones on reaction with LiAlH4. One of the furocarbazolones is utilized to accomplish the first total synthesis of claulansine D and mafaicheenamine E in 9 and 6 steps respectively. The other key steps of the syntheses are addition of an allylic indium reagent and CC double bond isomerization.

Association of migraine headaches with anatomical variations of the Circle of Willis: Evidence from a meta-analysis.

BACKGROUND: Several studies have attempted to investigate whether variations in the Circle of Willis (COW) are more common in migraine patients and whether the subsequent changes in perfusion may contribute to the pathomechanism of migraine. However, studies are not in agreement as to whether or not there is an increased prevalence of COW variations in migraineurs. OBJECTIVE: To determine if migraine headaches are associated with variations in morphology of the COW. METHODS: A systemic search of the major electronic databases was performed for articles studying the association of variations in the COW and migraine. Data on the prevalence of variations in patients with migraine were extracted and pooled into the meta-analysis. RESULTS: A total of four articles (n=807 patients) were deemed eligible for the meta-analysis. Migraine, regardless of subtype, was found to be associated with variations in the COW (OR=2.27, 95%CI 1.53-3.38, p<0.0001). An incomplete posterior circle (OR=2.60, 95%CI 1.79-3.76, p<0.00001) was found to be more strongly associated with migraine than an incomplete anterior circle (OR=2.01, 95%CI 1.15-3.53, p=0.01). In sub-group analysis, migraine with aura was found to be associated with both an incomplete posterior (OR=3.55, 95%CI 2.25-5.59, p<0.00001) and an incomplete anterior circle (OR=2.35, 95%CI 1.20-4.62, p=0.01). Migraine without aura was found only to be associated with an incomplete posterior circle (OR=2.10, 95%CI 1.39-3.17, p=0.0004). CONCLUSIONS: Migraine is associated with anatomical variations in both the anterior and posterior portions of the COW. However, larger prospective trials are needed to determine the true prevalence of variations and their pathological significance.

Regiodivergent and short total synthesis of calothrixins.

The anionic annulation of MOM-protected furoindolone with 4-bromoquinoline followed by deprotection of the N-MOM group provides calothrixin B, whereas that with 3-bromoquinoline yields isocalothrixin B. The outcomes are explained by the divergence of the reaction mechanism from commonly perceived quinolyne intermediate. A sequence of addition-cyclization-elimination is proposed to account for the formation of calothrixin from 4-bromoquinoline.

Therapies for the Treatment of Advanced/Metastatic Estrogen Receptor-Positive Breast Cancer: Current Situation and Future Directions.

The hormone receptor-positive (HR+) type is the most frequently identified subtype of breast cancer. HR+ breast cancer has a more positive prognosis when compared to other subtypes, such as human epidermal growth factor protein 2-positive disorder and triple-negative disease. The advancement in treatment outcomes for advanced HR+ breast cancer has been considerably elevated due to the discovery of cyclin-dependent kinase 4/6 inhibitors and their combination effects with endocrine therapy. However, despite the considerable effectiveness of tamoxifen, a selective estrogen receptor modulator (SERMs), and aromatase inhibitors (AI), the issue of treatment resistance still presents a significant challenge for HR+ breast cancer. As a result, there is a focus on exploring new therapeutic strategies such as targeted protein degradation and covalent inhibition for targeting ERα. This article discusses the latest progress in treatments like oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimera (PROTAC) degraders, and combinations of CDK4/6 inhibitors with endocrine therapy. The focus is specifically on those compounds that have transitioned into phases of clinical development.

Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs.

Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality that show promise to open a target space not accessible to conventional small molecules via a degradation-based mechanism. PROTAC degraders, due to their bifunctional nature, which is categorized as 'beyond the Rule of Five', have gained attention as a distinctive therapeutic approach for oral administration in clinical settings. However, the development of PROTACs with adequate oral bioavailability remains a significant hurdle, largely due to their large size and less than ideal physical and chemical properties. This review encapsulates the latest advancements in orally delivered PROTACs that have entered clinical evaluation as well as developments highlighted in recent scholarly articles. The insights and methodologies elaborated upon in this review could be instrumental in supporting the discovery and refinement of novel PROTAC degraders aimed at the treatment of various human cancers.

MicroRNAs in Parkinson's disease: a systematic review and diagnostic accuracy meta-analysis.

Current clinical tests for Parkinson's disease (PD) provide insufficient diagnostic accuracy leading to an urgent need for improved diagnostic biomarkers. As microRNAs (miRNAs) are promising biomarkers of various diseases, including PD, this systematic review and meta-analysis aimed to assess the diagnostic accuracy of biofluid miRNAs in PD. All studies reporting data on miRNAs expression in PD patients compared to controls were included. Gene targets and significant pathways associated with miRNAs expressed in more than 3 biofluid studies with the same direction of change were analyzed using target prediction and enrichment analysis. A bivariate model was used to calculate sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. While miR-24-3p and miR-214-3p were the most reported miRNA (7 each), miR-331-5p was found to be consistently up regulated in 4 different biofluids. Importantly, miR-19b-3p, miR-24-3p, miR-146a-5p, and miR-221-3p were reported in multiple studies without conflicting directions of change in serum and bioinformatic analysis found the targets of these miRNAs to be associated with pathways important in PD pathology. Of the 102 studies from the systematic review, 15 studies reported sensitivity and specificity data on combinations of miRNAs and were pooled for meta-analysis. Studies (17) reporting sensitivity and specificity data on single microRNA were pooled in a separate meta-analysis. Meta-analysis of the combinations of miRNAs (15 studies) showed that biofluid miRNAs can discriminate between PD patients and controls with good diagnostic accuracy (sensitivity = 0.82, 95% CI 0.76-0.87; specificity = 0.80, 95% CI 0.74-0.84; AUC = 0.87, 95% CI 0.83-0.89). However, we found multiple studies included more males with PD than any other group therefore possibly introducing a sex-related selection bias. Overall, our study captures key miRNAs which may represent a point of focus for future studies and the development of diagnostic panels whilst also highlighting the importance of appropriate study design to develop representative biomarker panels for the diagnosis of PD.

First-in-Class NADH/Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) Antagonist for the Treatment of Pancreatic Cancer.

Pancreatic cancer cells adapt to nutrient-scarce metabolic conditions by increasing their oxidative phosphorylation reserve to survive. Here, we present a first-in-class small-molecule NDUFS7 antagonist that inhibits oxidative phosphorylation (OXPHOS) for the treatment of pancreatic cancer. The lead compound, DX2-201, suppresses the proliferation of a panel of cell lines, and a metabolically stable analogue, DX3-213B, shows significant efficacy in a syngeneic model of pancreatic cancer. Exome sequencing of six out of six clones resistant to DX2-201 revealed a pV91M mutation in NDUFS7, providing direct evidence of its drug-binding site. In combination studies, DX2-201 showed synergy with multiple metabolic modulators, select OXPHOS inhibitors, and PARP inhibitors. Importantly, a combination with 2-deoxyglucose overcomes drug resistance in vivo. This study demonstrates that an efficacious treatment for pancreatic cancer can be achieved through inhibition of OXPHOS and direct binding to NDUFS7, providing a novel therapeutic strategy for this hard-to-treat cancer.

Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer.

Sigma 2 receptor (σ2R) is overexpressed in select cancers and is regarded as a biomarker for tumor proliferation. σ2R ligands are emerging as promising theranostics for cancer and neurodegenerative diseases. Herein, we describe the design and synthesis of a series of novel quinolyl pyrazinamides as selective and potent σ2R ligands that show sub-micromolar potency in pancreatic cancer cell lines. Compounds 14 (JR1-157) and 17 (JR2-298) bind σ2R with Ki of 47 and 10 nM, respectively. Importantly, compound 14 has an oral bioavailability of 60% and shows significant in vivo efficacy without obvious toxicity in a syngeneic model of pancreatic cancer. The cytotoxicity of the quinolyl pyrazinamides significantly enhanced in the presence of copper and diminished in the presence of the copper-chelator tetrathiomolybdate. In conclusion, compound 14 is water-soluble, metabolically stable, orally active, and increases the expression of the autophagy marker LC3B and warrants further development for the treatment of pancreatic cancer.

Multiparameter Optimization of Oxidative Phosphorylation Inhibitors for the Treatment of Pancreatic Cancer.

Targeting oxidative phosphorylation (OXPHOS) complexes is an emerging strategy to disrupt the metabolism of select cancer subtypes and to overcome resistance to targeted therapies. Here, we describe our lead optimization campaign on a series of benzene-1,4-disulfonamides as novel OXPHOS complex I inhibitors. This effort led to the discovery of compound 23 (DX3-213B) as one of the most potent complex I inhibitors reported to date. DX3-213B disrupts adenosine triphosphate (ATP) generation, inhibits complex I function, and results in the growth inhibition of pancreatic cancer cells in the low nanomolar range. Importantly, the oral administration of DX3-213B resulted in significant in vivo efficacy in a pancreatic cancer syngeneic model without obvious toxicity. Our data clearly demonstrate that OXPHOS inhibition can be a safe and efficacious strategy to treat pancreatic cancer.

Discovery and Lead Optimization of Benzene-1,4-disulfonamides as Oxidative Phosphorylation Inhibitors.

Inhibition of oxidative phosphorylation (OXPHOS) is a promising therapeutic strategy for select cancers that are dependent on aerobic metabolism. Here, we report the discovery, optimization, and structure-activity relationship (SAR) study of a series of novel OXPHOS inhibitors. The hit compound, benzene-1,4-disulfonamide 1, was discovered in a phenotypic screen selective for cytotoxicity in a galactose-containing medium. Our multi-parameter optimization campaign led to the discovery of 65 (DX3-235), showing nanomolar inhibition of complex I function and adenosine triphosphate (ATP) production in a galactose-containing medium resulting in significant cytotoxicity. Importantly, 64 (DX3-234), a close analogue of 65, is well tolerated in mice and shows significant single agent efficacy in a Pan02 syngeneic pancreatic cancer model, suggesting that highly potent and selective OXPHOS inhibitors can be useful for the treatment of pancreatic cancer.