Essential medicines list in national cancer control plans: a secondary analysis from a global study.

With the advent of innovative therapeutics for and the rising costs of cancer management, low-income and middle-income countries face increasing challenges to deliver effective and sustainable health care. Understanding of how countries are selecting and prioritising essential cancer interventions is poor, including in the formulation of policies for essential medicines. We did an in-depth subanalysis from a global dataset of national cancer control plans (NCCPs), aiming to identify possible determinants of inclusion of policies related to essential medicines in the NCCP. The results showed poor global comprehensiveness of NCCPs, and substantial deficits in policies for financial hardships due to cancer care, specifically for access to cancer medicines. Specification of budget allocations, policy of protection from catastrophic health expenditure, and national treatment guidelines in the NCCPs contributed to more consistent policies on essential cancer medicines. The bedrock to deliver effective cancer programmes resides in the assurance of comprehensive, consistent, and coherent policy formulation, to orient resource selection and health investments, ultimately delivering equitable health for all.

Pathology and Laboratory Medicine in cancer care: A global analysis of national cancer control plans.

In order to understand the structure and effectiveness of national cancer control systems, the International Cancer Control Partnership, the World Health Organization, the National Cancer Institute and the Union for International Cancer Control underwent a review of available national cancer health plans (NCCPs) and noncommunicable diseases plans (NCDPs) worldwide. Pathology and Laboratory Medicine (PALM) plays a major role in cancer management, from prevention and screening to patient care (diagnosis and treatment) and population-level cancer surveillance. This review concentrates on the analysis of elements in national cancer care plans pertaining to PALM. Of 157 countries surveyed, 90 (57%) had a NCCP and 123 (78%) had a NCDP. While 54% of plans included guidelines on cancer diagnosis or plans to develop standards protocols for diagnosis, only 14% included PALM as a component of the plan. PALM-related variables such as synoptic pathology reporting, cancer staging guidelines and cancer genetics programs were similarly underrepresented (being mentioned in only 6%, 17% and 16% of plans, respectively). Absence of PALM-related variables tended to be more frequent in lower-income countries. Our analysis highlights an important gap in national cancer control initiatives worldwide represented by the overall lack of inclusion of PALM resources. Cancer control will only be effective if laboratory sciences are placed as a priority. Based on the data presented herein, there is a need to increase awareness about the importance of PALM in cancer care, and to incorporate this discipline in the design and implementation of multilevel cancer control strategies.

Core elements of national cancer control plans: a tool to support plan development and review.

When developed and implemented effectively, national cancer control plans (NCCPs) improve cancer outcomes at the population level. However, many countries do not have a high-quality, operational NCCP, contributing to disparate cancer outcomes globally. Until now, a standard reference of NCCP core elements has not been available to guide development and evaluation across diverse countries and contexts. In this Policy Review, we describe the methods, process, and outcome of an initiative to develop an itemised and evidence-based comprehensive checklist of core elements for NCCP formulation. The final list provides a ready-to-use guide to support NCCP development and to facilitate internal and external critical appraisal of existing NCCPs for countries of all income levels and settings. Governments, policy makers, and stakeholders can utilise this checklist, while considering their own unique contexts and priorities, from the drafting through to the implementation of NCCPs.

National cancer control plans: a global analysis.

There is increasing global recognition that national cancer plans are crucial to effectively address the cancer burden and to prioritise and coordinate programmes. We did a global analysis of available national cancer-related health plans using a standardised assessment questionnaire to assess their inclusion of elements that characterise an effective cancer plan and, thereby, improve understanding of the strengths and limitations of existing plans. The results show progress in the development of cancer plans, as well as in the inclusion of stakeholders in plan development, but little evidence of their implementation. Areas of continued unmet need include setting of realistic priorities, specification of programmes for cancer management, allocation of appropriate budgets, monitoring and evaluation of plan implementation, promotion of research, and strengthening of information systems. We found that countries with a non-communicable disease (NCD) plan but no national cancer control plan (NCCP) were less likely than countries with an NCCP and NCP plan or an NCCP only to have comprehensive, coherent, or consistent plans. As countries move towards universal health coverage, greater emphasis is needed on developing NCCPs that are evidence based, financed, and implemented to ensure translation into action.

Stress-activated miR-21/miR-21* in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption.

OBJECTIVE: miR-21 is an oncomir highly upregulated in hepatocellular carcinoma and in early stages of liver diseases characterised by the presence of steatosis. Whether upregulation of miR-21 contributes to hepatic metabolic disorders and their progression towards cancer is unknown. This study aims at investigating the role of miR-21/miR-21* in early stages of metabolic liver disorders associated with diet-induced obesity (DIO). DESIGN: Constitutive miR-21/miR-21* knockout (miR21KO) and liver-specific miR-21/miR-21* knockout (LImiR21KO) mice were generated. Mice were then fed with high-fat diet (HFD) and alterations of the lipid and glucose metabolism were investigated. Serum and ex vivo explanted liver tissue were analysed. RESULTS: Under normal breeding conditions and standard diet, miR-21/miR-21* deletion in mice was not associated with any detectable phenotypic alterations. However, when mice were challenged with an obesogenic diet, glucose intolerance, steatosis and adiposity were improved in mice lacking miR-21/miR-21*. Deletion of miR-21/miR-21* specifically in hepatocytes led to similar improvements in mice fed an HFD, indicating a crucial role for hepatic miR-21/miR-21* in metabolic disorders associated with DIO. Further molecular analyses demonstrated that miR-21/miR-21* deletion in hepatocytes increases insulin sensitivity and modulates the expression of multiple key metabolic transcription factors involved in fatty acid uptake, de novo lipogenesis, gluconeogenesis and glucose output. CONCLUSIONS: Hepatic miR-21/miR-21* deficiency prevents glucose intolerance and steatosis in mice fed an obesogenic diet by altering the expression of several master metabolic regulators. This study points out miR-21/miR-21* as a potential therapeutic target for non-alcoholic fatty liver disease and the metabolic syndrome.

Insulin and IGF1 receptors are essential for XX and XY gonadal differentiation and adrenal development in mice.

Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5.

Ten Years of the International Cancer Control Partnership: Promoting National Cancer Control Plans to Shape the Health System Response for Cancer Control.

Growing premature mortality because of cancer is an increasing public health concern in all countries. This article reviews 10 years of the International Cancer Control Partnership (ICCP) considering the themes of National Cancer Control Plan (NCCP) support, technical assistance, governance, and the renewed momentum of global calls to action. ICCP has provided key resources for the cancer community by hosting a portal with national cancer control and noncommunicable disease (NCD) plans, strategies, guidelines, and key implementation guides for a growing community of best practices. ICCP partners have responded to the changing needs of country planners, adjusting technical guidance as needs evolve from planning to implementation at the national level with an associated shift to peer-to-peer learning and knowledge exchange. The ICCP offer to assist countries in cancer planning continues to be relevant as countries focus on implementation of global initiatives for breast, cervical, and childhood cancers. These initiatives are important to drive priority actions and a systems approach in the emerging road map on NCDs-a message that will be supported by a second global review of NCCPs in 2023. This is critical for driving national action in all countries on cancer and other NCDs in line with global health commitments made for 2030 and adopted by the United Nations General Assemblies. ICCP sees robust systems and financial planning for implementation, monitoring, and evaluation of NCCPs and protection from cancer-related catastrophic expenditure, as critical to longer-term sustainability and success. ICCP calls for national policymakers to prioritize integration of cancer prevention and control into emerging universal health care approaches, including pandemic preparedness/health system resilience and calls for an equity focus in new NCCPs.

An analysis of survivorship care strategies in national cancer control plans in Africa.

PURPOSE: In 2017, the World Health Organization urged member states to develop and implement national cancer control plans (NCCPs) and to anticipate and promote cancer survivor follow-up care, which is a critical yet often overlooked component of NCCPs. This study aims to examine the inclusion of cancer survivorship-related strategies and objectives in NCCPs of African countries. METHODS: Independent reviewers extracted strategies, objectives, and associated indicators related to survivorship care from 21 current or recently expired NCCPs in African countries. Building on a similar analysis of the US state cancer control plans, reviewers categorized these strategies according to an adapted version of the ten recommendations for comprehensive survivorship care detailed in the 2006 National Academy of Medicine report. RESULTS: A total of 202 survivorship-related strategies were identified, with all NCCPs including between 1 and 23 references to survivorship. Eighty-three (41%) strategies were linked to measurable indicators, and 128 (63%) of the survivorship-related strategies were explicitly focused on palliative care. The most frequent domains referenced were models of coordinated care (65 strategies), healthcare professional capacity (45), and developing and utilizing evidence-based guidelines (23). The least-referenced domains were survivorship care plans (4) and adequate and affordable health insurance (0). CONCLUSIONS: The results of this study indicate that survivorship objectives and strategies should extend beyond palliative care to encompass all aspects of survivorship and should include indicators to measure progress. IMPLICATIONS FOR CANCER SURVIVORS: Stakeholders can use this baseline analysis to identify and address gaps in survivorship care at the national policy level.

[Non-coding small RNAs and spermatogenesis]. / Petits ARN non codants et spermatogenèse.

The continuous production of spermatozoa is a tightly regulated biological process, both at the transcriptional and post-transcriptional levels. Recently, different classes of small non-coding RNAs have emerged as important regulators of spermatogenesis. Available molecular and genetic data, although still fragmented, underscore their crucial role in regulating the fine tuning of gene expression required for testicular function. Here, we review the latest advances accomplished in this domain, spanning from the biogenesis of these small non-coding RNAs to their roles in male reproductive function.

[The mouse hairless gene: its function in hair root and at the heart of a subtle pleiotropy]. / Le gène hairless de la souris: fonctions à la racine du poil et au coeur d'une subtile pléiotropie.

The hairless gene in mammals encodes a nuclear factor that is highly expressed in skin and appears to control hair follicle integrity and cycling. In the absence of a normal and functional Hairless (Hr) protein, the hair bulb undergoes premature apoptosis during the first catagen stage of the hair cycle. The most striking effects of the mutation are loss of hair follicles and formation of epidermal utricles and dermal cysts. The hairless gene expression appears to be widespread and temporally regulated. The gene is strongly expressed in different compartments of the brain. Hairless mRNAs were detected in cartilage, gonads, thymus and colon. In addition to alopecia, hairless mice strains show subtle defects in the development and differentiation of various tissues and organs. The Hr protein is localised in cell nuclei and functions as a transcriptional regulator. Although its role has not been resolved in molecular terms, it was demonstrated that Hr is able to interact with multiple nuclear hormone receptors. Hr seems to be a part of a large multiprotein complex capable to repress transcription by its association to chromatin remodelling factors such as histone deacetylases. Recent experimental data suggest that Hr might be involved in Hox gene regulation, cell adhesion modulation and progenitor cells identity. At least in the skin, but probably in other organs, the Hr repressor seems to be responsible for the timing of epithelial cells differentiation.

Germ cell-specific targeting of DICER or DGCR8 reveals a novel role for endo-siRNAs in the progression of mammalian spermatogenesis and male fertility.

Small non-coding RNAs act as critical regulators of gene expression and are essential for male germ cell development and spermatogenesis. Previously, we showed that germ cell-specific inactivation of Dicer1, an endonuclease essential for the biogenesis of micro-RNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs), led to complete male infertility due to alterations in meiotic progression, increased spermatocyte apoptosis and defects in the maturation of spermatozoa. To dissect the distinct physiological roles of miRNAs and endo-siRNAs in spermatogenesis, we compared the testicular phenotype of mice with Dicer1 or Dgcr8 depletion in male germ cells. Dgcr8 mutant mice, which have a defective miRNA pathway while retaining an intact endo-siRNA pathway, were also infertile and displayed similar defects, although less severe, to Dicer1 mutant mice. These included cumulative defects in meiotic and haploid phases of spermatogenesis, resulting in oligo-, terato-, and azoospermia. In addition, we found by RNA sequencing of purified spermatocytes that inactivation of Dicer1 and the resulting absence of miRNAs affected the fine tuning of protein-coding gene expression by increasing low level gene expression. Overall, these results emphasize the essential role of miRNAs in the progression of spermatogenesis, but also indicate a role for endo-siRNAs in this process.

Dicer is required for haploid male germ cell differentiation in mice.

BACKGROUND: The RNase III endonuclease Dicer is an important regulator of gene expression that processes microRNAs (miRNAs) and small interfering RNAs (siRNAs). The best-characterized function of miRNAs is gene repression at the post-transcriptional level through the pairing with mRNAs of protein-encoding genes. Small RNAs can also act at the transcriptional level by controlling the epigenetic status of chromatin. Dicer and other mediators of small RNA pathways are present in mouse male germ cells, and several miRNAs and endogenous siRNAs are expressed in the testis, suggesting that Dicer-dependent small RNAs are involved in the control of the precisely timed and highly organised process of spermatogenesis. PRINCIPAL FINDINGS: Being interested in the Dicer-mediated functions during spermatogenesis, we have analysed here a male germ cell-specific Dicer1 knockout mouse model, in which the deletion of Dicer1 takes place during early postnatal development in spermatogonia. We found that Dicer1 knockout testes were reduced in size and spermatogenesis within the seminiferous tubules was disrupted. Dicer1 knockout epididymides contained very low number of mature sperm with pronounced morphological abnormalities. Spermatogonial differentiation appeared unaffected. However, the number of haploid cells was decreased in knockout testes, and an increased number of apoptotic spermatocytes was observed. The most prominent defects were found during late haploid differentiation, and Dicer was demonstrated to be critical for the normal organization of chromatin and nuclear shaping of elongating spermatids. CONCLUSIONS/SIGNIFICANCE: We demonstrate that Dicer and Dicer-dependent small RNAs are imperative regulators of haploid spermatid differentiation and essential for male fertility.

Dicer1 depletion in male germ cells leads to infertility due to cumulative meiotic and spermiogenic defects.

BACKGROUND: Spermatogenesis is a complex biological process that requires a highly specialized control of gene expression. In the past decade, small non-coding RNAs have emerged as critical regulators of gene expression both at the transcriptional and post-transcriptional level. DICER1, an RNAse III endonuclease, is essential for the biogenesis of several classes of small RNAs, including microRNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs), but is also critical for the degradation of toxic transposable elements. In this study, we investigated to which extent DICER1 is required for germ cell development and the progress of spermatogenesis in mice. PRINCIPAL FINDINGS: We show that the selective ablation of Dicer1 at the early onset of male germ cell development leads to infertility, due to multiple cumulative defects at the meiotic and post-meiotic stages culminating with the absence of functional spermatozoa. Alterations were observed in the first spermatogenic wave and include delayed progression of spermatocytes to prophase I and increased apoptosis, resulting in a reduced number of round spermatids. The transition from round to mature spermatozoa was also severely affected, since the few spermatozoa formed in mutant animals were immobile and misshapen, exhibiting morphological defects of the head and flagellum. We also found evidence that the expression of transposable elements of the SINE family is up-regulated in Dicer1-depleted spermatocytes. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that DICER1 is dispensable for spermatogonial stem cell renewal and mitotic proliferation, but is required for germ cell differentiation through the meiotic and haploid phases of spermatogenesis.

The "bald Mill Hill" mutation in the mouse is associated with an abnormal, mislocalized HR bmh protein.

We have previously identified a mutation in the mouse hairless locus-hairless rhino bald Mill Hill (Hr(rhbmh)). The genetic alteration in these mice consists in a large 296 bp deletion at the 3' part of the hairless gene (ID:MGI:3039558; J:89321). Here, we show that this deletion removes the stop codon and creates a new reading frame at the C terminus of the hairless protein, generating a larger mutant protein harboring an additional sequence of 117 amino acids. The mutant hairless gene mRNA is expressed during the embryonic and post-natal development of the hair follicle. The mutant protein is identified in bmh mouse skin at different stages of development by a specific antibody. We demonstrate that the HR bmh protein is able to interact with the vitamin D receptor (VDR), but is not able to repress VDR-mediated transactivation. Immunofluorescence analysis reveals that HR bmh protein displays an abnormal cellular localization in transfected cell lines, as well as in the epidermis and hair follicle of bmh mutant mice. We discuss the relevance of the hairless protein mis localization in cell signalling pathways and with respect to the specific skin phenotype of mouse hairless mutants.