Citations

The body and mind are instruments that, through the senses, provide a gateway to conscious experience. One could reduce the totality of human existence to the body and mind alone, yet superficial appearances can be misleading. According to the yogic system, humans are comprised progressively subtle sheaths or koshas, ranging from the physical to the mind, energy, intellect, and bliss body. Furthermore, harnessing the intellect brings a level of control over energy, thoughts, behaviors, and quality of life. This understanding reorients the traditional, allopathic approach, which tends to emphasize the physical body in terms of anatomy, physiology, and clinical pathology. Recognizing deeper layers of self reminds physicians to see patients more holistically, while empowering patients to have greater authority over their own health outcomes.

AbstractBackgroundAbsent “organic” disease, dyspeptic symptoms may arise from abnormal gastric sensation, accommodation, motility or emptying (GE). Extensive gastric sensorimotor evaluation is rarely undertaken because testing is prolonged, invasive, poorly tolerated or unavailable.AimsTo investigate whether gastric antral motor function, evaluated with scintigraphy, predicts GE. To explore whether motor testing with symptom recording predicts day‐to‐day symptoms in patients with dyspepsia.MethodsGE was determined using a scintigraphic solid‐meal protocol (296 kcal, 35% fat). Antral motility was estimated from 10 min of scintigraphic time‐activity curves acquired 40 min after meal consumption. An antral motility index (MI) was derived from contraction amplitude and frequency. Intra‐gastric distribution of the meal on scintograms at 1 h (IGD1) was determined. Meal‐induced symptoms were evaluated by questionnaire. Patients completed the Gastroparesis Cardinal Symptom Index Daily Diary (GCSI‐DD) for 14 days.ResultsTwelve healthy participants and 23 prospectively recruited patients completed the study. Nine patients had delayed, and 2 had rapid, GE. In univariate analysis MI explained 42% of GE half‐time. In multivariate analysis MI and GE half‐time explained 25% of the variance in meal‐induced symptoms. While scintigraphic evaluation of gastric motor function with symptom recording explained 80% of the variance in the GCSI‐DD, meal‐induced symptoms were the only significant predictor. However, among patients with delayed GE, MI, GE half‐time, IGD1, and meal‐induced symptoms all significantly predicted GCSI‐DD.ConclusionsAntral motility predicts GE. In exploratory analyses, only meal‐induced symptoms predicted daily symptoms among patients with dyspepsia. However, motor function also predicted symptoms in patients with delayed GE.

AbstractBackgroundPassively collected smartphone sensor data provide an opportunity to study physical activity and mobility unobtrusively over long periods of time and may enable disease monitoring in people with amyotrophic lateral sclerosis (PALS).MethodsWe enrolled 63 PALS who used Beiwe mobile application that collected their smartphone accelerometer and GPS data and administered the self‐entry ALS Functional Rating Scale‐Revised (ALSFRS‐RSE) survey. We identified individual steps from accelerometer data and used the Activity Index to summarize activity at the minute level. Walking, Activity Index, and GPS outcomes were then aggregated into day‐level measures. We used linear mixed effect models (LMMs) to estimate baseline and monthly change for ALSFRS‐RSE scores (total score, subscores Q1–3, Q4–6, Q7–9, Q10–12) and smartphone sensor data measures, as well as the associations between them.FindingsThe analytic sample (N = 45) was 64.4% male with a mean age of 60.1 years. The mean observation period was 292.3 days. The ALSFRS‐RSE total score baseline mean was 35.8 and had a monthly rate of decline of −0.48 (p‐value <0.001). We observed statistically significant change over time and association with ALSFRS‐RSE total score for four smartphone sensor data‐derived measures: walking cadence from top 1 min and log‐transformed step count, step count from top 1 min, and Activity Index from top 1 min.InterpretationSmartphone sensors can unobtrusively track physical changes in PALS, potentially aiding disease monitoring and future research.

The primary cilium is a microtubule-based sensory organelle that plays a critical role in signaling pathways and cell cycle progression. Defects in the structure and/or function of the primary cilium result in developmental diseases collectively known as ciliopathies. However, the constituents and regulatory mechanisms of the primary cilium are not fully understood. In recent years, the activity of the epigenetic modifier SMYD3 has been shown to play a key role in the regulation of cell cycle progression. However, whether SMYD3, a histone/lysine methyltransferase, contributes to the regulation of ciliogenesis remains unknown. Here, we report that SMYD3 drives ciliogenesis via the direct and indirect regulation of cilia-associated components. We show that SMYD3 is a novel component of the distal appendage and is required for centriolar appendage assembly. The loss of SMYD3 decreased the percentage of ciliated cells and resulted in the formation of stumpy cilia. We demonstrated that SMYD3 modulated the recruitment of centrosome proteins (Cep164, Fbf1, Ninein, Ttbk2 and Cp110) and the trafficking of intraflagellar transport proteins (Ift54 and Ift140) important for cilia formation and maintenance, respectively. In addition, we showed that SMYD3 regulated the transcription of cilia genes and bound to the promoter regions of C2cd3, Cep164, Ttbk2, Dync2h1 and Cp110. This study provides insights into the role of SMYD3 in cilia biology and suggests that SMYD3-mediated cilia formation/function may be relevant for cilia-dependent signaling in ciliopathies.

Discovery of effective systemic therapies for patients with advanced penile cancer has been slow to occur. Comprehensive genomic profiling from several studies shed light on the molecular oncogenesis of penile squamous cell carcinoma (PSCC) and differences between HPV-related and unrelated tumors. While these two subsets of PSCC appear distinct in their biology, there are not yet specific treatment strategies recommended on that basis. Cell surface proteins have been identified that may potentially serve as drug targets for monoclonal antibodies or small molecule inhibitors. Here, we review some of the new biological insights regarding PSCC that could lead to improved therapies, as well as the related clinical trials recently completed or in progress. We conclude that antibody-drug conjugates are especially promising, as are the combinations of immune checkpoint inhibitors with other types of drugs.

Abstract Background The National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib. Methods Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response. Results Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because &lt;85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed. Conclusion Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual. ClinicalTrials.gov Identifier NCT03233204. IRB approved: initial July 24, 2017.