Multi-Disciplinary Management in Rectal Cancer Survivorship: A Clinical Practice Review.

Colorectal cancer (CRC) is the third most common cancer in the USA and worldwide. In the USA, nearly one-third of CRC cases are anatomically classified as rectal cancer. Over the past few decades, continued refinement of multimodality treatment and the introduction of new therapeutic agents have enhanced curative treatment rates and quality of life outcomes. As treatments improve and the incidence of young onset rectal cancer rises, the number of rectal cancer survivors grows each year. This trend highlights the growing importance of rectal cancer survivorship. Multimodality therapy with systemic chemotherapy, chemoradiation, and surgery can result in chronic toxicities in multiple organ systems, requiring a multi-disciplinary care model with services ranging from appropriate cancer surveillance to management of long-term toxicities and optimization of modifiable risk factors. Here, we review the evidence on these long-term toxicities and provide management considerations from consensus guidelines. Specific topics include bowel dysfunction from radiation and surgery, oxaliplatin-induced neuropathy, accelerated bone degeneration, the impact of fluoropyrimidines on long-term cardiovascular health, urinary incontinence, sexual dysfunction, and psychosocial distress. Additionally, we review modifiable risk factors to inform providers and rectal cancer survivors of various lifestyle and behavioral changes that can be made to improve their long-term health outcomes.

Molecular Epidemiology of Cryptosporidium parvum and Giardia lamblia in Different Water Bodies, Soil, and Vegetables in Pakistan.

There is a dearth of knowledge regarding transmission of Cryptosporidium (C) and Giardia (G) species through water and water-related sources in Pakistan. To this end, we conducted a study to evaluate the prevalence of these parasites in different water bodies, soil, and mixed raw vegetables in Pakistan. Researchers collected 200 samples from each reservoir including municipal water, sewage water, canal water, raw vegetables, soil of public parks, and soil of grazing areas. Researchers amplified the 18S ribosomal RNA gene of parasites using newly designed genus-specific primers through polymerase chain reaction testing. The sequencing analysis revealed that the obtained sequences belonged to C parvum and G lamblia. Phylogenetic clustering and sequence analysis of C parvum showed that the C parvum Pak1 (OM540369) and C parvum Pak2 (OM540370) as well as C parvum Pak3 (OM510450) and C parvum Pak6 (OM510445) were closely similar to each other. In the case of G lamblia, all the sequences appeared in the same clade. The epidemiological data showed lower prevalence of C parvum (11.5%) in all reservoirs, compared with G lamblia (20.5%). Among different reservoirs, prevalence of Cryptosporidium and Giardia was observed in sewage water (C = 13%, G = 26.5%), municipal water (C = 10%, G = 35%), canal water (C = 9.5%, G = 18.5%), raw vegetables (C = 5.5%, G = 8%), soil of public parks (C = 13%, G = 14%), and soil of grazing areas (C = 18.5%, G = 21.5%). Among targeted risk factors, poor hygienic conditions significantly affected the prevalence of parasites in sewage water (C = 20%, G = 41.2%), municipal water (C = 14.7%, G = 48.8.5%), raw vegetables (C = 11.3%, G = 15.1%), and soil of public parks (C = 19.5%, G = 21.9%). Similarly, contamination with sewage waste significantly affected (P < .05) the prevalence of these parasites in municipal water (C = 13.6%, G = 41.1%), canal water (C = 13.3%, G = 25%), raw vegetables (C = 12.1%, G = 15.1%), and soil of public parks (C = 23.3%, G = 15%). Results of this study illustrated a high risk of parasitic zoonosis through water bodies, soil, and vegetables.

The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory complex assembly and function in mice.

Emerging evidence indicates that a subset of RNA molecules annotated as noncoding contain short open reading frames that code for small functional proteins called microproteins, which have largely been overlooked due to their small size. To search for cardiac-expressed microproteins, we used a comparative genomics approach and identified mitolamban (Mtlbn) as a highly conserved 47-amino acid transmembrane protein that is abundantly expressed in the heart. Mtlbn localizes specifically to the inner mitochondrial membrane where it interacts with subunits of complex III of the electron transport chain and with mitochondrial respiratory supercomplexes. Genetic deletion of Mtlbn in mice altered complex III assembly dynamics and reduced complex III activity. Unbiased metabolomic analysis of heart tissue from Mtlbn knockout mice further revealed an altered metabolite profile consistent with deficiencies in complex III activity. Cardiac-specific Mtlbn overexpression in transgenic (TG) mice induced cardiomyopathy with histological, biochemical, and ultrastructural pathologic features that contributed to premature death. Metabolomic analysis and biochemical studies indicated that hearts from Mtlbn TG mice exhibited increased oxidative stress and mitochondrial dysfunction. These findings reveal Mtlbn as a cardiac-expressed inner mitochondrial membrane microprotein that contributes to mitochondrial electron transport chain activity through direct association with complex III and the regulation of its assembly and function.

The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy.

Calcium (Ca2+) dysregulation is a hallmark of heart failure and is characterized by impaired Ca2+ sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca2+-ATPase (SERCA). We recently discovered a micropeptide named DWORF (DWarf Open Reading Frame) that enhances SERCA activity by displacing phospholamban (PLN), a potent SERCA inhibitor. Here we show that DWORF has a higher apparent binding affinity for SERCA than PLN and that DWORF overexpression mitigates the contractile dysfunction associated with PLN overexpression, substantiating its role as a potent activator of SERCA. Additionally, using a well-characterized mouse model of dilated cardiomyopathy (DCM) due to genetic deletion of the muscle-specific LIM domain protein (MLP), we show that DWORF overexpression restores cardiac function and prevents the pathological remodeling and Ca2+ dysregulation classically exhibited by MLP knockout mice. Our results establish DWORF as a potent activator of SERCA within the heart and as an attractive candidate for a heart failure therapeutic.

MOXI Is a Mitochondrial Micropeptide That Enhances Fatty Acid ß-Oxidation.

Micropeptide regulator of ß-oxidation (MOXI) is a conserved muscle-enriched protein encoded by an RNA transcript misannotated as non-coding. MOXI localizes to the inner mitochondrial membrane where it associates with the mitochondrial trifunctional protein, an enzyme complex that plays a critical role in fatty acid ß-oxidation. Isolated heart and skeletal muscle mitochondria from MOXI knockout mice exhibit a diminished ability to metabolize fatty acids, while transgenic MOXI overexpression leads to enhanced ß-oxidation. Additionally, hearts from MOXI knockout mice preferentially oxidize carbohydrates over fatty acids in an isolated perfused heart system compared to wild-type (WT) animals. MOXI knockout mice also exhibit a profound reduction in exercise capacity, highlighting the role of MOXI in metabolic control. The functional characterization of MOXI provides insight into the regulation of mitochondrial metabolism and energy homeostasis and underscores the regulatory potential of additional micropeptides that have yet to be identified.

Percentage of reactor animals to single comparative cervical intradermal tuberculin (SCCIT) in small ruminants in Punjab Pakistan.

To investigate the percentage reactor animals to SCCIT in sheep and goat the present study was carried out by using bovine and avian PPDs at 7 Livestock Experiment Stations of Punjab and villages around two cities. The overall percentage of reactor animals to SCCIT at farms in sheep and goat was 0.9% and 2.4%, while it was 0.4% and 0.0% around two cities, respectively. Hundred percent of goat and 86% of sheep farms under study had positive reactor animals. The reactor animals to SCCIT around two cities were 0% in goat and 0.4% in sheep. Goats (P<0.05) and sheep (P<0.001) kept with large ruminants at farms had higher percentage of reactor animals. Age showed significant (P<0.01) association with tuberculosis in sheep and goat. In goats of more than 6 years of age, the reactor animals to SCCIT were 5, 8 and 11 times higher than goats of 4.1-6, 3-4 and <3 years of age. The reactor animals were significantly (P<0.05) higher in goats of <30kg (3.5%) and>40kg (3.5%) body weights, while these were less in goats weighing between 30 and 40kg (1.5%). Sheep and goat breeds showed significant (P<0.001; P<0.05) difference in percentage of reactor animals to SCCIT. Beetal (3.9%) and Teddy breeds (2.9%) had 3.3 and 2.4 times higher percentages of reactor animals to SCCIT as compared to Pak-Angora (1.2%) breed. However, no animal of Nachhi and Dera Din Pinah breeds showed positive reaction to PPDs.