Somatic maintenance and cell survival rely on proper protein homeostasis to ensure reliable functions across the cell and to prevent proteome collapse. Maintaining protein folding and solubility is ...central to proteostasis and is coordinated by protein synthesis, chaperoning, and degradation capacities. An emerging aspect that influences proteostasis is the dynamic protein partitioning across different subcellular structures and compartments. Here, we review recent literature related to nucleocytoplasmic partitioning of proteins, nuclear and cytoplasmic quality control mechanisms, and their impact on the development of age-related diseases. We also highlight new points of entry to modulate spatially-regulated proteostatic mechanisms to delay aging.
Mantle Cell lymphoma (MCL) is a mature B-cell lymphoma with a well-known hallmark genetic alteration in most cases, t (11,14)(q13q32)/
. However, our understanding of the genetic and epigenetic ...alterations in MCL has evolved over the years, and it is now known that translocations involving
, or cryptic insertion of enhancer elements of
or
gene, can also lead to MCL. On a molecular level, MCL can be broadly classified into two subtypes, conventional MCL (cMCL) and non-nodal MCL (nnMCL), each with different postulated tumor cell origin, clinical presentation and behavior, mutational pattern as well as genomic complexity. This article reviews both the common and rare alterations in MCL on a gene mutational, chromosomal arm, and epigenetic level, in the context of their contribution to the lymphomagenesis and disease evolution in MCL. This article also summarizes the important prognostic factors, molecular diagnostic tools, and treatment options based on the most recent MCL literature.
Tubulobulbar complexes (TBCs) are actin-based structures that help establish close contact between Sertoli-Sertoli cells or Sertoli-mature germ cells (spermatids) in the seminiferous tubules of the ...testes. They are actin-rich push-through devices that eliminate excess spermatid cytoplasm and prepare mature spermatids for release into the tubular lumen. Just prior to spermiation, the elongated spermatid interacts with the Sertoli cell via an extensive structure comprising various adhesion molecules called the apical ectoplasmic specialization which is partially replaced by the apical TBC, on the concave surface of the spermatid head. The sperm release process involves extensive restructuring, namely the disassembly and reassembly of junctions at the Sertoli-spermatid interface in the seminiferous epithelium. Based on the presence of different classes of molecules in the TBCs or the defects observed in the absence of TBCs, the main functions attributed to TBCs are elimination of excess spermatid cytoplasm, endocytosis and recycling of junctional molecules, shaping of the spermatid acrosome, and forming transient anchoring devices for mature spermatids before they are released. This review summarizes the recent findings that focus on the role of TBCs in cell cytoskeleton restructuring during sperm release in the testes and the molecular mechanism involved.
Up-front autologous stem cell transplantation (ASCT) is the established standard of care for younger, transplant-eligible MCL patients and is associated with a prolonged progression-free survival ...(PFS) benefit. However, there is no randomized controlled trial data, with therapy including rituximab and cytarabine, that has established a PFS and overall survival (OS) benefit with ASCT in the modern era. Multiple retrospective studies have failed to identify an OS benefit associated with ASCT in younger MCL patients. The high-risk patient subgroup with evidence of baseline TP53 mutation has a dismal outcome with intensive chemoimmunotherapy followed by ASCT, thus up-front ASCT is not optimal for this patient subset. Ongoing randomized clinical trials will help to clarify the role of up-front ASCT in the future. For example, the ongoing European MCL Network Triangle study incorporating ibrutinib into chemoimmunotherapy induction and maintenance with and without ASCT will help define the role of ASCT in the era of novel biologically targeted agents (ClinicalTrials.gov identifier: NCT02858258). Additionally, minimal residual disease (MRD) assessment is a powerful prognostic tool in MCL, and the ongoing Eastern Cooperative Oncology Group-American College of Radiology Imaging Network E4151 study is comparing maintenance rituximab alone vs ASCT consolidation in MCL patients who achieve remission and MRD-undetectable status post induction (ClinicalTrials.gov identifier: NCT03267433). ASCT remains a highly efficacious initial therapy for younger MCL patients; however, ultimately the decision to pursue ASCT requires discussion of risks vs benefits, incorporating patient preferences and values.
Summary
While Hodgkin lymphoma (HL) is highly curable in younger patients, older patients have higher relapse and death rates, which may reflect age‐related factors, distinct disease biology and/or ...treatment decisions. We described the association between patient, disease and geographic factors and first‐line treatment in older patients (≥65 years) with incident HL using Surveillance, Epidemiology, and End Results (SEER)‐Medicare data from 1999 to 2014 (n = 2825). First‐line treatment initiated at ≤4 months after diagnosis was categorised as: full chemotherapy regimen (n = 699, 24·7%); partial chemotherapy regimen (n = 1016, 36·0%); single chemotherapy agent or radiotherapy (n = 382, 13·5%); and no treatment (n = 728, 25·8%). Among the fully treated, ABVD doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine/AVD was most common (n = 635, 90·8%). Adjusted multinomial logistic regression identified factors associated with treatment. Older age, Medicaid dual eligibility, not married, frailty, cardiac comorbidity, prior cancer, earlier diagnosis date, histology, advanced disease Stage, B symptoms and South region were independently associated with increased odds of not receiving full chemotherapy regimens. In conclusion, we found variability in first‐line HL treatment for older patients. Treatment differences by Medicaid and region may indicate disparities. Even after adjusting for frailty and cardiac comorbidity, age was associated with treatment, suggesting factors such as end‐of‐life care or shared decision‐making may influence treatment in older patients.
In low-resource settings, a point-of-care test for cervical cancer screening that can give an immediate result to guide management is urgently needed. A transvaginal digital device, “Smart Scope®” ...(SS), with an artificial intelligence-enabled auto-image-assessment (SS-AI) feature, was developed. In a single-arm observational study, eligible consenting women underwent a Smart Scope®-aided VIA-VILI test. Images of the cervix were captured using SS and categorized by SS-AI in four groups (green, amber, high-risk amber (HRA), red) based on risk assessment. Green and amber were classified as SS-AI negative while HRA and red were classified as SS-AI positive. The SS-AI-positive women were advised colposcopy and guided biopsy. The cervix images of SS-AI-negative cases were evaluated by an expert colposcopist (SS-M); those suspected of being positive were also recommended colposcopy and guided biopsy. Histopathology was considered a gold standard. Data on 877 SS-AI, 485 colposcopy, and 213 histopathology were available for analysis. The SS-AI showed high sensitivity (90.3%), specificity (75.3%), accuracy (84.04%), and correlation coefficient (0.670, p = 0.0) in comparison with histology at the CINI+ cutoff. In conclusion, the AI-enabled Smart Scope® test is a good alternative to the existing screening tests as it gives a real-time accurate assessment of cervical health and an opportunity for immediate triaging with visual evidence.
Estrogen receptors (ESR1 and ESR2) play crucial roles in various processes during spermatogenesis. To elucidate individual roles of ESRs in male fertility, we developed in vivo selective ESR agonist ...administration models. Adult male rats treated with ESR1 and ESR2 agonist for 60 days show spermatogenic defects leading to reduced sperm counts and fertility. While studying epigenetic changes in the male germ line that could have affected fertility, we earlier observed a decrease in DNA methylation and its machinery upon ESR2 agonist treatment. Here, we explored the effects on histone modifications, which could contribute to decreased male fertility upon ESR agonist administration. ESR1 agonist treatment affected testicular levels of histone modifications associated with active and repressed chromatin states, along with heterochromatin marks. This was concomitant with deregulation of corresponding histone modifying enzymes in the testis. In addition, there was increased retention of histones along with protamine deficiency in the caudal spermatozoa after ESR1 agonist treatment. This could be due to the observed decrease in several chromatin remodeling proteins implicated in mediating histone-to-protamine exchange during spermiogenesis. The activating and repressing histone marks in spermatozoa, which play a critical role in early embryo development, were deregulated after both the ESR agonist treatments. Together, these epigenetic defects in the male germ line could affect the spermatozoa quality and lead to the observed decrease in fertility. Our results thus highlight the importance of ESRs in regulating different epigenetic processes during spermatogenesis, which are crucial for male fertility.
Rhabdomyolysis is often associated with sepsis and gram positive bacterial pathogens are reported to be the most frequent cause of sepsis induced rhabdomyolysis. We report the pattern of infecting ...bacterial pathogens and associated causal factors in a South-Indian cohort. DESIGN, SETTING, PARTICIPANTS #ENTITYSTARTX00026;
Retrospective cohort study of adult patients with community acquired bacterial sepsis complicated by rhabdomyolysis from March 2003--August 2008. Rhabdomyolysis was defined as serum creatine kinase >2000 IU/L. The study population was divided into group-I (sepsis with gram positive pathogens), group-II (sepsis with gram negative pathogens) and group-III (culture negative sepsis).
103 patients (group I -15, group II- 34 and group III- 54) formed the study cohort. Mean age was 55 years and two-third had diabetes. Mean creatine kinase was 7114 IU/L and mean serum creatinine on admission was 2.4 mg/dl. Causative pathogen of sepsis was identified in 47.5%. Gram negative pathogens were more frequently (33%) associated with rhabdomyolysis than gram positive pathogens (14.5%). Lung was the commonest foci of sepsis (38.8%). 78.6% of the study population had one or more additional causal factor for rhabdomyolysis like statin intake, chronic alcoholism, hypokalemia, hypernatremia and hypophosphatemia. Mortality was 59%.
Gram negative bacterial pathogens were more frequently associated with rhabdomyolysis than gram positive pathogens. Rhabdomyolysis in patients with sepsis is multifactorial and is associated with high mortality.
Hodgkin Lymphoma (HL) survivors are at risk of treatment-related late effects (LEs). With these potential risks and increasing numbers of treatment options for newly diagnosed patients, communication ...and shared decision making are essential to supporting patients throughout the cancer care continuum. We aimed to gather perspectives of HL survivors about their actual role in treatment decision making and their understanding of LEs.
After initial pilot testing at a cancer survivor conference, we disseminated a 23-question survey in a single-wave e-mail through the Leukemia & Lymphoma Society's national listserv. We focused on 4 constructs: (1) patient's understanding of HL at diagnosis; (2) initial discussions with an oncologist; (3) factors in decision making of treatment, and (4) current health status.
A total of 135 participants responded to the survey. While 73% of survey respondents perceived some involvement in decision making, one-half of respondents felt the treatment plan was a shared decision with their provider. Among patient-level factors, side effects/LEs were most frequently endorsed as important to treatment decisions. Eighty-four percent of respondents had been educated about risk for potential LEs. Thirty-six percent had been diagnosed with a LE at the time of survey completion with 3% reporting a second cancer diagnosis.
Survey respondents described their role in treatment decision making for newly diagnosed HL. Nearly half of patients did not endorse participating in shared decision making. A substantial number had experienced LEs. Future work should focus on improving patient-provider communication in decision processes for newly diagnosed HL.
We disseminated a national survey to learn about Hodgkin Lymphoma survivors’ perspectives about their role in treatment decisions and understanding about late effects. We found variation in patients’ roles in treatment decisions, with one-fourth having treatment decisions made solely by their doctors. Our study highlights the opportunity to improve shared decision making for patients with Hodgkin Lymphoma.
In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but their ...role in longevity is unclear. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we uncovered an important role for lipid droplets in proteostasis and longevity. Using genome-wide RNAi screening, we identified several SQST-1 modulators, including lipid droplets-associated and aggregation-prone proteins. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene atgl-1/ATGL enhanced autophagy, and extended lifespan. Notably, a substantial amount of ubiquitinated proteins were found on lipid droplets. Reducing lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised, and significantly reduced the lifespan of long-lived daf-2 animals. Altogether, our study uncovered a key role for lipid droplets in C. elegans as a proteostatic mediator that modulates ubiquitinated protein accumulation, facilitates autophagy, and promotes longevity.
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•Elevated levels of SQST-1/SQSTM1 are detrimental to lifespan in C. elegans•Low lipid stores challenge the ability of SQST-1 to facilitate protein degradation•High lipid droplet content stabilizes aggregation-prone proteins•Age-related proteostatic decline is mitigated by lipid droplets
Biological sciences; Biochemistry
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